Thymus, undernutrition, and infection: Approaching cellular and molecular interactions

Abstract

Undernutrition remains a major issue in global health. Low protein-energy consumption, results in stunting, wasting and/or underweight, three deleterious forms of malnutrition that affect roughly 200 million children under the age of five years. Undernutrition compromises the immune system with the generation of various degrees of immunodeficiency, which in turn, renders undernourished individuals more sensitive to acute infections. The severity of various infectious diseases including visceral leishmaniasis (VL), influenza, and tuberculosis is associated with undernutrition. Immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs involved in the response to related pathogens. The thymus—a primary lymphoid organ responsible for the generation of T lymphocytes—is particularly compromised by both undernutrition and infectious diseases. In this respect, we will discuss herein various intrathymic cellular and molecular interactions seen in undernutrition alone or in combination with acute infections. Many examples illustrated in studies on humans and experimental animals clearly revealed that protein-related undernutrition causes thymic atrophy, with cortical thymocyte depletion. Moreover, the non-lymphoid microenvironmental compartment of the organ undergoes important changes in thymic epithelial cells, including their secretory products such as hormones and extracellular matrix proteins. Of note, deficiencies in vitamins and trace elements also induce thymic atrophy. Interestingly, among the molecular interactions involved in the control of undernutrition-induced thymic atrophy is a hormonal imbalance with a rise in glucocorticoids and a decrease in leptin serum levels. Undernutrition also yields a negative impact of acute infections upon the thymus, frequently with the intrathymic detection of pathogens or their antigens. For instance, undernourished mice infected with Leishmania infantum (that causes VL) undergo drastic thymic atrophy, with significant reduction in thymocyte numbers, and decreased levels of intrathymic chemokines and cytokines, indicating that both lymphoid and microenvironmental compartments of the organ are affected. Lastly, recent data revealed that some probiotic bacteria or probiotic fermented milks improve the thymus status in a model of malnutrition, thus raising a new field for investigation, namely the thymus-gut connection, indicating that probiotics can be envisioned as a further adjuvant therapy in the control of thymic changes in undernutrition accompanied or not by infection.

Introduction

Despite one of the global health priorities listed in the Sustainable Development Goals (SDGs) by the United Nations is combating hunger and ensuring sustainable food security and proper nutrition (1), malnutrition remains a serious public health problem worldwide. The World Health Organization (WHO) defines malnutrition as the deficiency or excess in the consumption of specific energy and/or nutrients in relation to the needs of an individual, resulting in corresponding pathologies: undernutrition or obesity (2). The lack of macro and micronutrients, and in particular the low consumption of proteins and calories results in four deleterious forms of undernutrition: (i) wasting, (ii) stunting, (iii) underweight, and (iv) micronutrient deficiencies. (i) Wasting is characterized as low weight-for-height, and in children it may be lethal if not appropriately treated; (ii) stunting occurs when the individual presents low height for the respective age, usually due to chronic undernutrition; (iii) underweight is defined as low weight-for-age, and underweighted children may be stunted, wasted or both. Lastly, (iv) micronutrient undernutrition refers to lack of vitamins and minerals that are essential for body functions (2). It is estimated that stunt and wasting affect virtually 200 million children under 5 years of age around the world, whereas in the adult population this number can reach 462 million. On the other hand, around 42 million children globally are overweight or obese (2).

Malnutrition thus constitutes a serious global public health issue, particularly in developing countries. According to a recent report (3) of the Food and Agriculture Organization (FAO) of the United Nations, 720–811 million people in the world suffered from hunger in 2020, increasing by 161 million the number of people who experienced hunger in 2019. The COVID-19 pandemic contributed substantially to this increase. The global assessment of food insecurity and malnutrition for 2020 shows that not only world hunger has increased, but also the prevalence of undernutrition rose by 4% in one single year (3).

Due to the pandemic, the prevalence of different forms of malnutrition has increased worldwide and it is estimated that these effects will be lasting, as already seen in 2021. In fact, the COVID-19 pandemic has widened and worsened inequalities between countries, affecting the livelihoods of an estimated 1.6 billion workers in the formal economy (1). Around 12% of the world’s population suffered from severe food insecurity in 2020. In Latin America and Caribbean region in 2020, 14 million more people were affected by hunger as compared with 2019 (3). Data from the National Survey on Food Insecurity in the Context of the COVID-19 Pandemic in Brazil showed that the country went back 15 years in five, and hunger returned to be a structural problem (4), as depicted in Figure 1.

FIGURE 1

The decrease in proper food intake results in a series of physiological changes, including: (i) growth restriction; (ii) reduction of fat, muscle, and visceral mass; as well as (iii) reduction in basal metabolic rate and energy expenditure (5). These alterations also comprise biochemical parameters with reduced levels of triiodothyroxine (T3), insulin, insulin-like growth factor-1 (IGF-1) and leptin, among others; together with increased levels of growth hormone (GH) and cortisol (5, 6). Overall, undernutrition induces changes in metabolic, hormonal and glucoregulatory mechanisms (5, 6). Also, undernutrition modulates the intestinal microbiota and dysbiotic events can be observed as a cause and/or consequence of undernutrition, accompanied by local and systemic chronic inflammation (7). Altered nutrient absorption and chronic inflammation seems to be related to the fact that malnourished individuals are more susceptible to various diseases (7–9).

The dynamic relationship between infection, nutrition and immunity is long recognized. Being a systemic disease, undernutrition also affects primary and secondary lymphoid organs, harming the immune system of malnourished individuals (10). Since the immune response depends on cell replication and the synthesis of active protein compounds, undernutrition clearly has a negative impact on immunity (11). Actually, immunosuppression caused by protein-energy undernutrition increases susceptibility to acute infections and leads to the development of more severe forms of disease, whether they are caused by parasites, protozoa, bacteria or viruses.

In the present review we aimed at focusing the effects of undernutrition and infection upon one specific compartment of the immune system, namely the thymus, particularly the changes in the organ involving cellular and molecular interactions. Yet, before going into this point, it seems worthwhile to provide a general, yet concise background of the thymus and the generation of T-lymphocytes.

The thymic microenvironment and intrathymic T-cell differentiation

The thymus is a primary organ in the immune response, where the maturation and differentiation of T cells take place (12). The correct selection and migration of T cells occurs through a series of proliferation and differentiation stages dependent upon receiving instructions from the specialized thymus non-lymphoid microenvironment (13). In mammals, the organ is histologically divided lobules, each one comprising two main regions, namely cortex and medulla, with the cortex being denser in lymphocytes than the medulla. Developing thymocytes in different stages of maturation are specifically located in those regions. For example, immature CD4-CD8- double-negative (DN) and CD4⁺ CD8⁺ double-positive (DP) thymocytes are localized in the cortical region of the thymic lobules, whereas more mature CD4⁺ CD8- or CD4-CD8⁺ single-positive (SP) thymocytes are placed in the medulla (13). Such specific distribution indicates that thymocyte maturation occurs in parallel with organized and coordinated cell migration (14). In fact, disruption or abnormal cell migration impacts thymocyte development, as seen for example in Chagas disease (15).

Intrathymic thymocyte differentiation and migration, from the entrance of precursor cells to the exit of mature SP cells, is dependent on interactions controlled by the thymic tridimensional network. This is composed by cellular components such as thymic epithelial cells (TEC), thymic dendritic cells (TDC), macrophages and fibroblasts, as well as non-soluble and soluble molecules such as the extracellular matrix (ECM) proteins fibronectin, laminin, type I and IV collagens; cytokines as interleukin (IL)-2, IL-6, IL-7, and IL-22; chemokines as CXCL12, CCL4, and CCL7; hormones as thymosin, thymopoietin, and thymulin; and different typical soluble components of nervous tissues, such as neuropeptides and neurotransmitters (12, 15, 16).

During thymocyte development, cells pass through the positive selection and negative selection events; both being derived from the molecular interactions involving expression and survival signaling by the recognition of the T-cell receptor (TCR), upon interacting with microenvironmental cells, particularly dendritic cells, and epithelial cells. Positive selection can be defined as the process through which TCR-expressing CD4⁺ CD8⁺ developing thymocytes are rescued from programmed cell death upon interaction with self-antigens presented to the TCR by molecules of the major histocompatibility complex (MHC) by thymic microenvironmental cells. Positively selected thymocytes still in the cortex of the thymic lobules then move into the boundary of the cortex and medulla of the thymus for the presentation of self-antigens by the medullary thymic epithelial cells for the second time. In the medulla, thymocytes pass through the negative selection. In this case, differentiating cells undergo apoptosis if their TCR interact with high avidity with self-antigens coupled to the MHC class I or class II molecules expressed by microenvironmental cells in the organ (12, 13). Different peripheral tissue antigens (PTAs)—or self-antigens—coupled to MHC molecules are expressed on the membrane of medullary thymic epithelial cells (mTEC). Such expression is regulated by the autoimmune regulator (AIRE) transcription factor and avoids the development of self-antigen reactive cells, therefore preventing autoimmunity (17, 18). Alternatively, some clones that recognize self-antigens with high avidity become regulatory CD4⁺ CD25⁺ Foxp3⁺ T cells (Treg), through a mechanism dependent on the TCR signaling avidity and duration (19, 20).

Positioning of developing thymocytes along with differentiation depend on multiple interactions involving cell-cell, cell-matrix as well as chemokine-mediated interactions. For example, CXCL12 is secreted by TEC, and preferentially attracts immature CD4-CD8- and CD4⁺ CD8⁺ cells, by ligation with the receptor CXCR4. The chemokine CCL25 also attracts immature thymocytes, although all thymocyte subsets are responsive, which is in keeping with the fact that its CCR9 receptor is expressed at all stages of murine thymocyte differentiation. Interestingly, CCL19/CCR7 interactions participate in thymocyte exit, illustrating that thymocytes may switch their responses to a given chemokine, tuning their migratory process (21).

Other stimuli can participate in the overall process of intrathymic T-cell development, including hormones. Thymulin is zinc-couple nonapeptide classically defined as a thymic hormone, being produced by TEC. This molecule enhances developing thymocyte proliferation and IL-2 production (22). Interestingly, TECs also produce other thymic hormones as thymopoietin and thymosin-α1 (23), both known to have extrathymic functions, but also to induce progression of thymocyte differentiation.

Overall, we can say that in physiological conditions, at the end of their journey, CD4-SP and CD8-SP thymocytes exit the thymus to populate the peripheral lymphoid organs and participate in adaptive immune responses. The main stages of thymocyte maturation, selective processes and components of the thymic microenvironment are represented in Figure 2.

FIGURE 2

Undernutrition causes thymic atrophy, with cortical thymocyte depletion

It is well described that the intestinal homeostasis is maintained by immunomodulation of the gut mucosa. This is promoted by the interaction of endogenous microbiota with, food and a large variety of vitamins and nutrients, generating a proper intestinal immunity, which in turn maintains an adequate systemic immunity, highlighting the importance of the interaction between the gut mucosa immunity and the systemic immune response (24, 25). In parallel, protein-energy undernutrition is also a systemic condition that causes atrophy of lymphoid tissues, and the thymus is one of the most affected organs, with severe thymocyte loss, particularly CD4⁺ CD8⁺ cells (26–33). The thymus undergoes atrophy, as seen by histology, with changes in the lymphoid and microenvironmental compartments (26, 28). It was observed that in severely malnourished mice and children the thymic intralobular extracellular matrix containing fibronectin, laminin and type IV collagen increased. The enhancement of these extracellular matrix was correlated with the degree of thymocyte depletion in both humans and experimental models (26–29), although a cause-effect relationship has not been determined so far.

In any case, it is interesting that even in mice developing non-severe undernutrition by food restriction, there is a marked thymic atrophy and cortical thymocyte depletion, due to massive apoptosis, as well as a significant depletion in all the cytokine producing cells assayed (IL-12, IL-4, IL-6, IL-10, TNF-α, IFN-γ), as compared to control animals (30), as summarized in Figure 3.

FIGURE 3

Finally, although not detailed herein, it is worthy to mention that deficiencies in vitamins, as well as in micronutrients (zinc, for example) also promote thymic atrophy with cortical thymocyte depletion and changes in the microenvironmental compartment (31). Particularly for the zinc, this should be linked to the fact that this element is important in several reactions in the thymus, being not only necessary to thymulin biological functions but also for promoting regeneration of TECs and T-cell reconstitution (22, 34).

The thymic microenvironment in protein undernutrition and infection

In addition to the lymphoid compartment, the thymic microenvironment is affected in various undernutritional and infectious conditions. Morphological changes in the thymic epithelium from protein-undernourished mice include the decrease in the volume of the epithelial tissue in the cortex and in the medulla of thymic lobules from undernourished mice, as compared to well-nourished control animals (32). By contrast, an increase, of intracytoplasmic accumulations of large, circular, homogeneously electron-dense profiles, rich in free and esterified cholesterol was reported in both in cortical and medullary TEC, of undernourished animals (33). Unfortunately, no data were reported concerning TEC death in this experimental model. In malnourished children the atrophy of the organ is clear with strong diminution of the cortex of the thymic lobules, with concomitant appearance of apoptotic thymocytes, particularly in the CD4⁺ CD8⁺ stage of differentiation.

In Trypanosoma cruzi-acutely infected mice, we also demonstrated changes in the expression of medullary and cortical specific TEC markers such as cytokeratins, as compared to controls, together with a general shrinkage of the thymic epithelial network (35). Such phenotypic changes do not prove functional changes of these cells in relation to the interaction with developing thymocytes. However, they did unravel an intrathymic pathology comprising both the cortical and medullary TEC network.

One functional parameter that has been largely evaluated in undernutrition conditions is the thymic hormone production by TEC. It was initially found that protein-undernourished mice exhibited abnormally low levels of circulating thymulin (32, 36), and that such a decrease was also observed in protein-undernourished rats and humans (37). Interestingly, even in human protein undernutrition secondary to anorexia nervosa, low thymulin serum levels were reported (38). Furthermore, decreased thymulin serum levels were reported in mice submitted to diets designed to trigger deficiency in zinc, iron, or vitamins (36, 39, 40). At least regarding zinc deficiency, similar results were found in humans (41). Remarkably, in severe infection conditions thymic endocrine function is also affected. We observed in T. cruzi-infected mice a transient decrease in the serum levels of the thymic hormone thymulin (31). In human HIV infection we and others showed a consistent and long-term diminution of thymulin secretion, in terms of both serum levels and intrathymic contents of the hormone (39–44).

It is noteworthy that the decrease in thymic hormone serum levels seen in undernutrition is not restricted to thymulin, since it was also reported as regards thymopoietin production. Prenatal undernutrition was significantly associated with reduced thymopoietin production in interaction with the duration of exclusive breast-feeding (45). These findings provide support for the importance of fetal and early infant programming of thymic function, and long-term implications for the immune system, and consequently adult disease risk.

As mentioned above, in addition to the abnormalities seen in thymic epithelial cells, the thymus from undernourished children presents a further microenvironmental alteration, namely, an increase in the deposition of ECM proteins. We studied by histological, ultrastructural and immunohistochemical means, thymuses obtained in necropsies from undernourished children. There is a consistent increase in the intralobular ECM-containing network, which could be ascertained histologically by the dense reticulin staining, and immunohistochemically by the higher contents of fibronectin, laminin, and type IV collagen. Importantly, the enhancement of thymic ECM in undernourished individuals positively correlated with the degree of thymocyte depletion (26). This correlation may represent a cause-effect relationship in which the contact of thymocytes with abnormally high amounts of thymic ECM triggers and/or enhances programmed cell death. However, this notion remains hypothetical, demanding experimental demonstration. In any case, it is noteworthy that developing thymocyte do express integrin-type ECM receptors (21), which makes this hypothesis feasible.

Interestingly, similar changes in thymic ECM were observed in glucocorticoid-hormone treated mice and TEC cultures (22), leading to hypothesis that the enhanced ECM deposition seen in undernutrition may be also related to high levels of serum glucocorticoid hormones. Actually, high glucocorticoid levels are seen in undernutrition (46, 47). Such an alteration was also seen in acute infections, as exemplified by experimental Chagas disease (35, 48). In this infection model, changes in ECM were accompanied by alterations in the migratory response of thymocytes, with abnormal export of CD4⁺CD8⁺ immature thymocytes, some of them having bypassed the normal negative selection process (48–50). Whether similar cell migration abnormalities exist in undernourished subjects, is to be investigated, although peripheral CD4⁺CD8⁺ T cells have been detected in the blood of chagasic patients (51).

Along with the changes in the thymic microenvironment seen in undernutrition conditions, obesity also induces severe alterations in this compartment, as seen in experimental models. One is the db/db mouse that develops a diabetes with obesity, due to a deficit in the expression of leptin receptor, which leads to obesity and type II Diabetes (52). We showed a precocious thymic involution in these animals, with cortical thymocyte depletion as well as changes in the TEC network, as ascertained by ultrastructural changes in these cells and a precocious decrease in the production of the TEC-derived thymulin (53–56). Again, these thymic events may be due to high corticosterone serum levels seen in these mice (57). In any case, these results unravel a thymic alteration in obese animals, which is likely related to an altered adaptive immune response. Whether such changes exist in humans need to be determined. Yet, it is conceivable since during age-dependent thymic atrophy, there is an increase in the numbers of adipose cells in the thymus (58).

Hormonal imbalance underlines thymic changes in protein undernutrition

Besides the alterations above cited, the impact of protein undernutrition in the thymus is accompanied by a hormonal imbalance in the organ. As mentioned above, decrease in thymic hormone production was first described in the 1970 decade, unraveling reduced levels of thymulin in the serum of children with severe undernutrition, in small for gestational age infants, and in thymuses of children who died in various stages of undernutrition (59, 60). In this case, children with the severe forms (marasmus, kwashiorkor, and marasmic kwashiorkor) presented tiny thymuses that contained very low contents of thymulin (37).

Other than thymic hormones, it has been shown that the circulating levels of corticosterone are increased in protein-undernourished mice, as compared to age-matched controls. High corticosterone levels are known to induce thymic atrophy by the depletion of immature thymocytes, which was also observed in protein-undernourished mice (46). Accordingly, we might predict a dysregulation of glucocorticoid control mechanisms.

The HPA axis encompasses the hypothalamus, with the secretion of the neuropeptide CRH (corticotrophin-releasing hormone), which in turn stimulates the adenopituitary gland to secrete ACTH (adrenocorticotrophic hormone) that enhances glucocorticoid secretion by the cortex of the adrenal glands. Physiologically, such axis is self-regulated by negative feed-back with glucocorticoids being able to negatively control the production of both ACTH and CRH. Yet, it has been demonstrated that maternal food restriction during the perinatal period or during lactation disturbs the activity of the HPA axis at weaning, with pups presenting reduced adrenal, thymus and liver weight, and increased circulating free corticosterone levels (61). Disturbances in the HPA axis during protein deprivation were also reported (62). To determine if corticotropin-releasing hormone (CRH) and glucocorticoids were respectively required for hypophagia and catabolism in undernutrition, CRH-deficient mice were subjected to dietary protein deprivation. Interestingly, these animals did not exhibit increased plasma corticosterone as control individuals. In the same vein, CRH deficiency attenuated body and thymus weight loss induced by the restricted diet, suggesting that those effects were dependent on glucocorticoid regulation.

Mild maternal protein deprivation during lactation in rats affects thymic homeostasis in the young progeny, which presents lower body and thymus weights, significant alterations in CD4/CD8-defined T cell subsets and enhanced expression of leptin receptor ObRb in thymocytes. Although alterations in leptin circulating levels were not observed in this study, an increase in leptin signaling response of thymocytes from protein-deprived rats was described, together with a decreased rate of thymocyte spontaneous apoptosis when compared to controls (63). Interestingly, leptin/leptin receptor-deficient animals exhibit an atrophy of lymphoid tissues, particularly the thymus, and such a defect can be reversed by the reposition of the hormone (64, 65). Actually, complementary studies showed that there is a balance between systemic levels of leptin and glucocorticoids, controlling thymic atrophy. It is thus conceivable that in malnutritional states, the imbalance between the levels of leptin and glucocorticoid hormones could be, at least in part, responsible for the thymocyte depletion and consequent thymic atrophy (31). Yet, further studies are necessary to define if such imbalance is also involved in infection-related thymic atrophy.

Undernutrition yields a further negative impact of acute infections upon the thymus

It is known that the thymic atrophy induced by undernutrition produces a negative impact in the immune response against infections (31, 66, 67). In this respect and considering that protein-energy undernutrition can be reversed with an appropriate re-nutrition, it might be possible to recover the functional capacity of the thymus, through adequate food intake. Actually, this is definitely plausible since thymopoiesis is a continuous process along with life, although decreasing with aging. This is important particularly in facing infant malnutrition and infection, telling us that we must develop public policies to extinguish food insecurity and hunger on the planet.

As mentioned above, several findings in humans and mice showed that the thymus is also a target for infection (68, 69), as it has been well described for various types of pathogens, including viruses, bacteria, and parasites, such as T. cruzi, Plasmodium and Leishmania (Table 1). In fact, different infectious agents are able to reach and infect the organ. On this regard, we have recently shown that the thymus of BALB/c mice is a target during experimental infection by Leishmania infantum (70). The presence of the parasite infecting cells of the thymic microenvironment was observed both in well-nourished animals and in malnourished mice. However, it remains to be determined which cell populations are permissive to the parasite infection. Interestingly, it was possible to observe many more intact amastigotes in the undernourished animals than in the well-nourished ones (70). Recent reports have confirmed, using bioluminescence, the presence of the parasite in the thymus of well-nourished BALB/c mice infected with L. donovani (71). These observations demonstrate that the thymus is a target organ during infection by viscerotropic species of Leishmania, including L. infantum and L. donovani. This was further confirmed by the presence of the parasite in the thymus in dogs naturally infected with L. infantum (72). In a broader way, several data show that various parasites as well as viruses and even fungi, can be found within the thymus parenchyma. For example, in respect to Chagas disease, previous work had revealed that both epithelial and non-epithelial thymic microenvironmental cells can be infected by T. cruzi, as ascertained both in vitro and in vivo (68).

As previously mentioned, immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs, involved in the response to pathogens, contributing to mortality and morbidity, especially in children (10). In addition, systemic hormonal and metabolic dysfunctions, as well as changes in intestinal barrier function and intestinal microbiota, caused by undernutrition, dramatically increase the susceptibility of individuals to infections, as seen in many different examples, such as visceral leishmaniasis (VL), influenza, dengue, Zika and tuberculosis, among others (10, 67, 140–151). In children aged less than 5 years, undernutrition is an underlying cause of 61% of deaths from diarrhea, 57% of deaths from malaria, 52% of deaths from pneumonia and 45% of deaths from measles (152). Furthermore, it has been estimated that the COVID-19 pandemic will increase childhood mortality from wasting by more than 20% (153). Indeed, recent report already described increased rates of fatal COVID-19 in areas with elevated burden of undernutrition (154).

Another example of the deleterious role of acute infections in undernourished subjects it the study on predictors of mortality in adult patients with influenza infection in Switzerland. This analysis was conducted during four influenza seasons and identified undernutrition as a strong predictor of mortality among those patients (155). Experimental model of protein-energy undernutrition and influenza A virus infection showed that mice fed low-protein diet (2% protein content) exhibited more severe disease than mice fed a control protein diet (18% protein content). Undernourished animals presented higher and sustained virus titers in the lungs, trafficking of inflammatory cells to the lung tissue, and higher virus-induced mortality, when compared to what was seen in control mice. Interestingly, undernourished-infected mice fed with control diet improved virus clearance, as well as recovered protective immunity to viral challenge (67).

It has also been suggested that maternal protein undernutrition increases susceptibility to Zika virus infection, which causes the Congenital Zika Syndrome in children. This syndrome is characterized by multiple neurological, muscular and immune disturbances, secondary to infection in pregnant mothers. In neurological terms, the children may present severe microcephaly, decreased brain tissue with a specific pattern of brain damage, including subcortical calcifications, damage to the back of the eye, with macular scarring and focal retinal pigmentary mottling, congenital contractures, such as clubfoot or arthrogryposis and Hypertonia restricting body movement soon after birth (156). From an experimental perspective, it was showed that pregnant mice subjected to protein undernutrition and infected with Zika virus presented severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size as well as alterations in the expression of genes required for brain development (142). Still regarding arboviruses, experimental models of Dengue virus (DENV) infection have shown that, compared with well-nourished animals, mice fed low protein content diet (5% protein) had a significant reduction in the level of platelets, increased spleen pathology and higher viral titers in the spleen following infection (143). However, studies regarding the association between the nutritional status and dengue infection in humans are controversial; some studies reporting higher risk of dengue shock syndrome or dengue hemorrhagic fever in undernourished children, whereas other studies could not observe these associations (157, 158). Consequently, more data are needed to clarify the influence of nutritional status on dengue infection outcome.

Another controversial association is that observed between malaria and undernutrition. Data from different analyses present conflicting conclusions regarding the potentially protective or exacerbating effects that undernutrition has on Plasmodium spp. infection (159). Because in endemic regions there is a common seasonality of malaria and undernutrition (160), it is difficult to clearly point if one is cause or consequence of the other. Some studies suggested that undernutrition increases the susceptibility of children to infection and/or impairs the individual’s capability to recover from infection (161–163). It has been observed that malnourished children have decreased specific anti-Plasmodium antibody titers when compared to well-nourished children (164). On the other hand, data related to the risk of malaria infection in children with chronic undernutrition revealed a protective effect of undernutrition against infection (165, 166). Several studies in experimental models indicate that animals submitted to a low-protein diet had reduced parasitemia when compared to controls; however, the immune response was also suppressed, and the animals were unable to clear the infection (167, 168). Interestingly, the immunosuppression observed during the deficit in protein consumption makes parasitized animals protected from experimental cerebral malaria (169, 170), a severe form of malaria directly associated with an exacerbated inflammatory response. Notably, it was observed that a brief restriction of food intake prevents neuropathology in an experimental cerebral malaria murine model with P. berghei ANKA (170). One hypothesis that should be investigated is that undernutrition would induce lower inflammatory and adaptive immune response that would partially undermine the autoimmune environment seen in both human and experimental malaria (171).

In general, infection or undernutrition induces similar alterations to lymphoid organs. Independently, undernutrition or acute infectious diseases result in thymic atrophy with drastic reduction of immature CD4⁺CD8⁺ double positive (DP) T cells due to increased apoptosis and premature egress of immature thymocytes (29, 36, 68, 77, 92, 172–174). Intrathymic chemokines and extracellular matrix (ECM) components are also altered during pathological conditions of infection or undernutrition. The thymus of T. cruzi-infected mice exhibits increased fibronectin and chemokine deposition, and increased abundance of thymic ECM proteins such as fibronectin, laminin, and type IV collagen has been observed in undernourished children (26, 49). Thymus atrophy with thymocyte depletion, increased intra and inter-lobular connective tissue, and decreased cortico-medullary limits have been also observed in undernourished children (175–177). Indeed, a smaller thymus is a risk factor for mortality and is predictive of decreased immune competence (178). As mentioned above, one of the mechanisms underlining these effects on thymocytes is be related to the hormonal imbalance between the rise in glucocorticoids and the decrease in leptin (50). Yet, other hormonal circuits may be involved as seen in experimental acute Chagas disease, in which prolactin partially reverts the thymic atrophy and the corticosteroid levels (179). Should we emphasize however, that other non-hormone-mediated mechanisms may be involved, and should be investigated.

Consequences of undernutrition and Leishmania infection upon the thymus: Cellular and proteomic approaches

Visceral leishmaniasis (VL) is a neglected disease that frequently afflicts children and malnourished populations in tropical and subtropical regions of the world. The disease is caused by Leishmania infantum or L. donovani parasites, which infect the spleen, liver, bone marrow, and lymph nodes, causing fever, hepatosplenomegaly, and loss of weight. If not properly treated, VL can be fatal (180, 181).

Seminal prospective studies in children who acquired VL revealed that those who had a precondition of moderate to severe undernutrition before infection had 8.7 times greater risk of having classic and severe forms of the disease, whereas well-nourished children did not progress beyond subclinical infections (140). More recent epidemiological surveys revealed that in cases of VL in adults who died, 32.7% of patients had undernutrition as the main comorbidity (182). In Northwest Ethiopia it was observed that roughly 85% children aged under 5 years and 95.5% adults with VL were undernourished (183, 184).

Studies of the relationship between VL and undernutrition in experimental murine models established a murine scale of undernutrition based on weight for age in analogy to the anthropometric classification of human undernutrition. Using this model it was found that undernutrition led to a failure in the barrier function of the lymph nodes in mice infected with L. donovani and, consequently, anticipated the visceralization of the parasite (185), likely due to the reduction of phagocytic cells in the lymph nodes of undernourished animals (186). A reduction in the number of skin-resident dendritic cells (DCs) drained to satellite lymph nodes was also observed, as well as a deregulation in the expression of chemokines and corresponding receptors, involved in the migration of DCs to the lymph nodes (187).

Also, in an undernourished murine model of infection with L. infantum, we observed a drastic reduction in cellularity and changes in the microarchitecture of the spleen and thymus of infected animals, as well as changes in the subpopulations of thymocytes and splenocytes, which were aggravated when the infection was preceded by undernutrition (69, 70, 188, 189). Indeed, undernourished-infected mice exhibited a significant reduction in the cortex:medulla ratio (69).

Aiming at understanding the effects of protein undernutrition in the course of infection and immune response to L. infantum, we established a model of protein undernutrition and infection with L. infantum, which has allowed us to describe cellular and molecular alterations in the thymus, spleen and gut of mice and how they affect the response to the parasite (69, 70, 188–190), using BALB/c mice fed control (14% protein) or low protein (4% protein) isocaloric diets further infected with L. infantum infection. Undernourished-infected mice exhibited a significant reduction of body and thymus weight, showed a significant decrease in CD4⁺CD8⁺ (DP) thymocytes, and remarkable alterations in total single positive subpopulations (CD4⁺ and CD8⁺) of the organ (69, 70, 188). Those changes were accompanied by reduced systemic levels of leptin and IGF1 and increased corticosterone, all of which have been associated with thymocyte depletion in undernourished individuals (66). Notably, those defects were induced independently by each condition (undernutrition or parasite infection), but the synergy of both exacerbated the observed alterations, accelerating the pathological events seen during infection (69, 70, 188). We further observed a decreased intrathymic abundance of CCL5, CXCL12, CXCL9, and CXCL10 as well as IGF1 in undernourished-infected animals, suggesting altered migration of developing T cells. Nevertheless, in this combined condition thymocytes were able to migrate ex vivo in response to chemotactic stimuli, suggesting that undernutrition may compromise the production of soluble factors inside the thymic microenvironment, altering in vivo thymocyte migration, rather than migratory capability of T cells per se (70).

As mentioned above, the successful production of mature T cells depends on the constant migration of differentiating thymocytes through the thymic microenvironment, and such migration is a process controlled by complex interactions between cell surface molecules, extracellular matrix (ECM) proteins, cytokines, chemokines and hormones (21, 191, 192). We conducted a histopathological study of the tissue organization and using a quantitative mass spectrometry-based proteomics approach, to measure the protein abundance within the thymic interstitial space in undernourished BALB/c mice infected with L. infantum (69). Undernourished-infected animals exhibited a significant reduction of the thymic cortical-medullary ratio and altered the abundance of proteins secreted in the thymic interstitial fluid. Proteomic analyzes revealed that these alterations were accompanied by a significant change in the abundance of soluble factors that are secreted via exosomes into the thymic microenvironment, suggestive of defects in the intrathymic molecular communication mediated by these microvesicles in undernourished animals (69).

Also, early changes in protein abundance were observed in infected animals, and those alterations were exacerbated or annulated when animals were previously undernourished, reinforcing the deleterious role of undernutrition in the response to infection and revealing an unknown role of the thymus during VL (69). Functional analysis of proteomics data showed that molecules involved in cell migration and differentiation such as galectin-1, von Willebrand factor, Rho GDP-dissociation inhibitor 1 and 2, differentiation factor 1 and transgelin-2 were significantly reduced in undernourished-infected mice (69). In addition, we observed an increase in the amounts of proteins involved in β-oxidation of fatty acids as well as in those involved in Krebs’ cycle, both of which suggest a non-proliferative quiescent thymic microenvironment (Figure 4), which in fact was corroborated by the decreased detection of Ki67 proliferation marker in thymocyte subpopulations (69). Together these data compose a scenario where structural and soluble protein factors of the thymic microenvironment are altered by L. infantum infection and worsened by a precedent undernutrition condition.

FIGURE 4

As mentioned above, we detected parasites in the thymus of both well-nourished and undernourished animals infected with L. infantum, but amastigote nests were only observed in mice fed protein restricted diet (70). Furthermore, using qPCR, we observed a significantly higher parasite load in the thymus of undernourished animals when compared to the control mice (193).

Interestingly, T cells generated in the thymus previously infected by Mycobacterium avium are tolerant to the pathogen in the periphery (86). In this line, the persistence of infection and antigenic peptides in the thymus may favor the appearance of pathogen-tolerant T cells, thus contributing to its persistence in other tissues (194). In a similar way, the persistence of L. infantum in the thymus of undernourished animals could favor the emergence of Leishmania-tolerant T cells, impairing the resolution of the infection in the periphery, favoring parasite persistence in the spleen. Such reasoning can also apply for different intrathymic infections.

Probiotics: Potential immunotherapeutic tools for restoring undernutrition related thymic dysfunctions

A large reservoir of microorganisms is found in the gut, reaching a bacterial community that is 10 times more than the number of human eukaryotic cells, coexisting in a symbiotic relationship (195). The role of these microorganisms in the gut physiology and maintaining intestinal homeostasis is indisputable. They participate in the breakdown of food, nutrient absorption, synthesize vitamins, protect us against pathogens, act on the neurodevelopment, and participate in the development and regulation of the immune system (196, 197). The microbiota composition differs from one individual to another, being in direct relation to age, diversity of food consumed, lifestyle, ethnicity, environmental factors and following the use of medicines such as steroids, antibiotics, etc. (198, 199). Among the millions of microorganisms in the human digestive tract, probiotics are found. They can influence the intestinal immune system by several mechanisms including change in the microbiota composition and its function, as well as improvement of the intestinal epithelial barrier (200, 201).

The mechanisms involved in the remote effects of probiotic are poorly understood. Yet, they can balance the microbiota and modulate the expression of pro-inflammatory cytokines. Such an effect occurs through multiple mechanisms, including the modulation and stimulation on MAPK (mitogen-activated protein kinase) pathways, as well as upon the NF-kB transcription factor, especially by inhibiting IkB phosphorylation, thus hindering the transfer of NF-kB (202).

Much less is known about the putative action of probiotics upon the thymus. In a mouse model of non-severe protein undernutrition, we found that the administration of a probiotic fermented milk as a re-nutrition supplementation did improve the thymic microarchitecture, recovering the corticomedullary differentiation in the thymic lobules, in conjunction with a decrease in thymocyte apoptosis. All the structural changes of thymus were accompanied by changes at the functional level, with increase in the numbers of mature and immature thymocytes and enhancement of cytokine production (203).

In a second vein, studies in obese humans and in obese mice, showed a relation between obesity and involution of the thymus gland revealing the important role of nutrients intake on the anatomy and functionality of the thymus (65, 203, 204). The use of a probiotic yogurt as dietary supplementation resulted not only in the control of body weight, serum biochemical parameters, but also in the recovery of the histological structure and thymus weight in obese animals (205). This was confirmed by recent data showing that a probiotic strain L. casei CRL 431 administered in the drinking water to a high-fat diet consuming obese mice, improved the cellularity and functionality of the thymus, with an increase in IL-7 and IL-3 production as seen in Figure 5 (206). These two cytokines are involved in normal intrathymic T-cell development; IL-7 is secreted by TEC and stimulates survival and expansion of the immature thymocytes and increase thymocyte numbers (207) and IL-3, also produced by TECs, is a hematopoietic growth factor that promotes myeloid proliferation (208).

FIGURE 5

Concluding remarks and perspectives

As undernutrition remains a major issue in global health, studies on the pathophysiological aspects of this affection, associated or not with infection are yet important, particularly the mechanisms governing dysregulation of the immune response. In this respect, the immunosuppression resulting from protein-energy undernutrition severely impacts primary and secondary lymphoid organs involved in the response to a give pathogen. The thymus is particularly compromised by both undernutrition and infection, with a consistent cortical thymocyte depletion and important changes in thymic epithelial cells. Moreover, undernutrition yields a negative impact upon the thymus in acute infections, frequently with the intrathymic detection of pathogens or their antigens.

The impairment of the thymic cortical area due to undernutrition during acute infections may alter physiological processes crucial for T cell development, such as (i) intrathymic selection of the T cell repertoire (209), (ii) thymocyte proliferation, (iii) adequate migration of developing thymocyte, as well as (iv) changes in the microenvironmental component of the organ, and (v) intrathymic and systemic hormonal circuits (Figure 6), all of which having a deleterious impact in the adaptive immune responses in the periphery. As intrathymic T cell development is a continuous process, it exhibits a certain degree of plasticity, rendering possible the partial (or even total) restoration to normal steady state after a given deleterious stimulus has stopped. Accordingly, it seems plausible that those alterations can be at least partially reverted by dietary interventions, rescuing proper immune responses to infection. However, this remains to be investigated. Addressing whether nutritional rehabilitation combining balanced macronutrients, micronutrients and probiotics can recover the structural and cell differentiation damage caused by undernutrition in the thymus, would allow proposing nutrition-based interventions that would positively impact both the nutritional status of the individuals and their ability to respond adequately to infections.

FIGURE 6

References

• 1.

  United Nations. End Hunger, Achieve Food Security and Improved Nutrition and Promote Sustainable Agriculture. (2021). Available online at: https://sdgs.un.org/goals/goal2(accessed January 10, 2022).

  • Google Scholar

• 2.

  World Health Organization. Malnutrition. (2021). Available online at: https://www.who.int/news-room/fact-sheets/detail/malnutrition(accessed January 10, 2022).

  • Google Scholar

• 3.

  Food and Agriculture Organization. The State of Food Security and Nutrition in the World 2021: Transforming Food Systems for Food Security, Improved Nutrition and Affordable Healthy Diets for all. Rome: Food and Agriculture Organization (2021).

  • Google Scholar

• 4.

  PENSSAN Network. Relatório Sobre Insegurança Alimentar e Covid-19 no Brasil. (2021). Available online at: http://olheparaafome.com.br/VIGISAN_Inseguranca_alimentar.pdf(accessed January 10, 2022).

  • Google Scholar

• 5.

  Dipasquale V Cucinotta U Romano C . Acute malnutrition in children: pathophysiology, clinical effects and treatment.Nutrients. (2020) 12:2413. 10.3390/nu12082413

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6.

  Bhutta ZA Berkley JA Bandsma RHJ Kerac M Trehan I Briend A . Severe childhood malnutrition.Nat Rev Dis Primers. (2017) 3:17067. 10.1038/nrdp.2017.67

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7.

  Hashimoto T Perlot T Rehman A Trichereau J Ishiguro H Paolino M et al ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. (2012) 487:477–81. 10.1038/nature11228

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8.

  Bäckhed F Ley RE Sonnenburg JL Peterson DA Gordon JI . Host-bacterial mutualism in the human intestine.Science. (2005) 307:1915–20. 10.1126/science.1104816

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9.

  Kau AL Ahern PP Griffin NW Goodman AL Gordon JI . Human nutrition, the gut microbiome and the immune system.Nature. (2011) 474:327–36. 10.1038/nature10213

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10.

  Ibrahim MK Zambruni M Melby CL Melby PC . Impact of childhood malnutrition on host defense and infection.Clin Microbiol Rev. (2017) 30:919–71. 10.1128/CMR.00119-16

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11.

  Schaible UE Kaufmann SH . Malnutrition and infection: complex mechanisms and global impacts.PLoS Med. (2007) 5:e115. 10.1371/journal.pmed.0040115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12.

  Ciofani M Zúñiga-Pflücker JC . The thymus as an inductive site for T lymphopoiesis.Annu Rev Cell Dev Biol. (2007) 23:463–93. 10.1146/annurev.cellbio.23.090506.123547

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13.

  Savino W Mendes-da-Cruz DA Lepletier A Dardenne M . Hormonal control of T-cell development in health and disease.Nat Rev Endocrinol. (2016) 2:77–89. 10.1038/nrendo.2015.168

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14.

  Petrie HT Zúñiga-Pflücker JC . Zoned out: functional mapping of stromal signaling microenvironments in the thymus.Annu Rev Immunol. (2007) 25:649–79. 10.1146/annurev.immunol.23.021704.115715

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15.

  Pérez AR de Meis J Rodriguez-Galan MC Savino W . The thymus in Chagas disease: molecular interactions involved in abnormal T-cell migration and differentiation.Front Immunol. (2020) 11:1838. 10.3389/fimmu.2020.01838

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16.

  Francelin C Veneziani LP Farias ADS Mendes-da-Cruz DA Savino W . Neurotransmitters modulate intrathymic T-cell development.Front Cell Dev Biol. (2021) 9:668067. 10.3389/fcell.2021.668067

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17.

  Speck-Hernandez CA Assis AF Felicio RF Cotrim-Sousa L Pezzi N Lopes GS et al Aire disruption influences the medullary thymic epithelial cell transcriptome and interaction with thymocytes. Front Immunol. (2018) 9:964. 10.3389/fimmu.2018.00964

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18.

  Passos GA Speck-Hernandez CA Assis AF Mendes-da-Cruz DA . Update on Aire and thymic negative selection.Immunology. (2018) 153:10–20. 10.1111/imm.12831

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19.

  Santamaria JC Borelli A Irla M . Regulatory T cell heterogeneity in the thymus: impact on their functional activities.Front Immunol. (2021) 12:643153. 10.3389/fimmu.2021.643153

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20.

  Tao Z Jiang Y Xia S . Regulation of thymic T regulatory cell differentiation by TECs in health and disease.Scand J Immunol. (2021) 94:e13094. 10.1111/sji.13094

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21.

  Savino W Mendes-Da-Cruz D Smaniotto S Silva-Monteiro E Villa-Verde DMS . Molecular mechanisms governing thymocyte migration: combined role of chemokines and extracellular matrix.J Leukoc Biol. (2004) 75:951–61. 10.1189/jlb.1003455

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22.

  Savino W Dardenne M . Neuroendocrine control of thymus physiology.Endocr Rev. (2000) 21:412–43. 10.1210/edrv.21.4.0402

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23.

  Savino W Dardenne M . Thymic hormone-containing cells VI. Immunohistologic evidence for the simultaneous presence of thymulin, thymopoietin and thymosin alpha 1 in normal and pathological human thymuses.Eur J Immunol. (1984) 14:987–91. 10.1002/eji.1830141105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24.

  Gorbach SL Goldin BR . Nutrition and the gastrointestinal microflora.Nutrition Rev. (1992) 50:378–81. 10.1111/j.1753-4887.1992.tb02485.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25.

  Mitsuoka T . Bifidobacteria and their role in human health.J Ind Microbiol. (1990) 81:131–6. 10.1007/BF01575871

  • CrossRef
  • Google Scholar

• 26.

  Lyra JS Madi K Maeda CT Savino W . Thymic extracellular matrix in human malnutrition.J Pathol. (1993) 171:231–6. 10.1002/path.1711710312

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27.

  Roux E Dumont-Girard F Starobinski M Siegrist CA Helg C Chapuis B et al Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood. (2000) 96:2299–303.

  • Pubmed Abstract
  • Google Scholar

• 28.

  Savino W . The thymus gland is a target in malnutrition.Eur J Clin Nutr. (2002) 56(Suppl. 3):S46–9. 10.1038/sj.ejcn.1601485

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29.

  Ortiz R Cortés L Cortés E Medina H . Malnutrition alters the rates of apoptosis in splenocytes and thymocyte subpopulations of rats.Clin Exp Immunol. (2009) 155:96–106. 10.1111/j.1365-2249.2008.03796.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30.

  Maldonado Galdeano C Novotny Núñez I de Moreno de LeBlanc A Carmuega E Weill R Perdigón G . Impact of a probiotic fermented milk in the gut ecosystem and in the systemic immunity using a non-severe protein-energy-malnutrition model in mice.BMC Gastroenterol. (2011) 11:64. 10.1186/1471-230X-11-64

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31.

  Savino W Dardenne M . Nutritional imbalances and infections affect the thymus: consequences on T-cell-mediated immune responses.Proc Nutr Soc. (2010) 69:636–43. 10.1017/S0029665110002545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32.

  Mittal A Woodward B Chandra RK . Involution of thymic epithelium and low serum thymulin bioactivity in weanling mice subjected to severe food intake restriction or severe protein deficiency.Exp Mol Pathol. (1988) 48:226–35. 10.1016/0014-480090059-7

  • CrossRef
  • Google Scholar

• 33.

  Mittal A Woodward B . Thymic epithelial cells of severely undernourished mice: accumulation of cholesteryl esters and absence of cytoplasmic vacuoles.Proc Soc Exp Biol Med. (1985) 178:385–91. 10.3181/00379727-178-42021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34.

  Iovino L Cooper K deRoos P Kinsella S Evandy C Ugrai T et al Activation of the zinc-sensing receptor GPR39 promotes T-cell reconstitution after hematopoietic cell transplant in mice. Blood. (2022) 139:3655–66. 10.1182/blood.2021013950

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35.

  Savino W Leite-de-Moraes MC Hontebeyrie-Joskowicz M Dardenne M . Studies on the thymus in Chagas’ disease. I. Changes in the thymic microenvironment in mice acutely infected with Trypanosoma cruzi.Eur J Immunol. (1989) 19:1727–33. 10.1002/eji.1830190930

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36.

  Chandra RK . Protein-energy malnutrition and immunological responses.J Nutr. (1992) 122(3 Suppl.):597–600. 10.1093/jn/122.suppl_3.597

  • CrossRef
  • Google Scholar

• 37.

  Jambon B Ziegler O Maire B Hutin MF Parent G Fall M et al Thymulin (facteur thymique serique) and zinc contents of the thymus glands of malnourished children. Am J Clin Nutr. (1988) 48:335–42. 10.1093/ajcn/48.2.335

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38.

  Wade S Bleiberg F Mossé A Lubetzki J Flavigny H Chapuis P et al Thymulin (Zn-facteur thymique serique) activity in anorexia nervosa patients. Am J Clin Nutr. (1985) 42:275–80. 10.1093/ajcn/42.2.275

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39.

  Kuvibidila S Dardenne M Savino W Lepault F . Influence of iron-deficiency anemia on selected thymus functions in mice: thymulin biological activity, T-cell subsets, and thymocyte proliferation.Am J Clin Nutr. (1990) 51:228–32. 10.1093/ajcn/51.2.228

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40.

  Dardenne M Savino W Wade S Kaiserlian D Lemonnier D Bach JF . In vivo and in vitro studies of thymulin in marginally zinc-deficient mice.Eur J Immunol. (1984) 14:454–8. 10.1002/eji.1830140513

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41.

  Prasad AS Meftah S Abdallah J Kaplan J Brewer GJ Bach JF et al Serum thymulin in human zinc deficiency. J Clin Invest. (1988) 82:1202–10. 10.1172/JCI113717

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42.

  Dardenne M Bach JF Safai B . Low serum thymic hormone levels in patients with acquired immunodeficiency syndrome.N Engl J Med. (1983) 309:48–9. 10.1056/NEJM198307073090112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43.

  Incefy GS Pahwa S Pahwa R Sarngadharan MG Menez R Fikrig S . Low circulating thymulin-like activity in children with AIDS and AIDS-related complex.AIDS Res. (1986) 2:109–16. 10.1089/aid.1.1986.2.109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44.

  Savino W Dardenne M Marche C Trophilme D Dupuy JM Pekovic D et al Thymic epithelium in AIDS. An immunohistologic study. Am J Pathol. (1986) 122:302–7.

  • Pubmed Abstract
  • Google Scholar

• 45.

  McDade TW Beck MA Kuzawa CW Adair LS . Prenatal undernutrition and postnatal growth are associated with adolescent thymic function.J Nutr. (2001) 131:1225–31. 10.1093/jn/131.4.1225

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46.

  Barone KS O’Brien PC Stevenson JR . Characterization and mechanisms of thymic atrophy in protein-malnourished mice: role of corticosterone.Cell Immunol. (1993) 148:226–33. 10.1006/cimm.1993.1105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47.

  Monk JM Makinen K Shrum B Woodward B . Blood corticosterone concentration reaches critical illness levels early during acute malnutrition in the weanling mouse.Exp Biol Med. (2006) 231:264–8. 10.1177/153537020623100304

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48.

  Cotta-de-Almeida V Bonomo A Mendes-da-Cruz DA Riederer I De Meis J Lima-Quaresma KR et al Trypanosoma cruzi infection modulates intrathymic contents of extracellular matrix ligands and receptors and alters thymocyte migration. Eur J Immunol. (2003) 33:2439–48. 10.1002/eji.200323860

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49.

  Mendes-da-Cruz DA Silva JS Cotta-de-Almeida V Savino W . Altered thymocyte migration during experimental acute Trypanosoma cruzi infection: combined role of fibronectin and the chemokines CXCL12 and CCL4.Eur J Immunol. (2006) 36:1486–93. 10.1002/eji.200535629

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50.

  Lepletier W Villa-Verde DM Mendes-da-Cruz DA Silva-Monteiro E Perez AR Aoki Mdel P et al Cytokines and cell adhesion receptors in the regulation of immunity to Trypanosoma cruzi. Cytokine Growth Factor Rev. (2007) 18:107–24. 10.1016/j.cytogfr.2007.01.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51.

  Morrot A Terra-Granado E Pérez AR Silva-Barbosa SD Miliæeviæ NM Farias-de-Oliveira DA et al Chagasic thymic atrophy does not affect negative selection but results in the export of activated CD4+CD8+ T cells in severe forms of human disease. PLoS Negl Trop Dis. (2011) 5:e1268. 10.1371/journal.pntd.0001268

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52.

  Alpers CE Hudkins KL . Mouse models of diabetic nephropathy.Curr Opin Nephrol Hypertens. (2011) 20:278–84. 10.1097/MNH.0b013e3283451901

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53.

  Dardenne M Savino W Gastinel LN Nabarra B Bach JF . Thymic dysfunction in the mutant diabetic (db/db) mouse.J Immunol. (1983) 130:1195–9.

  • Google Scholar

• 54.

  Debray-Sachs M Dardenne M Sai P Savino W Quiniou MC Boillot D et al Anti-islet immunity and thymic dysfunction in the mutant diabetic C57BL/KsJ db/db mouse. Diabetes. (1983) 32:1048–54. 10.2337/diab.32.11.1048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55.

  Palmer G Aurrand-Lions M Contassot E Talabot-Ayer D Ducrest-Gay D Vesin C et al Indirect effects of leptin receptor deficiency on lymphocyte populations and immune response in db/db mice. J Immunol. (2006) 177:2899–907. 10.4049/jimmunol.177.5.2899

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56.

  Nabarra B Andrianarison I . Thymic reticulum of autoimmune mice. I. Ultrastructural studies of the diabetic (db/db) mouse thymus.Exp Pathol. (1986) 29:45–53. 10.1016/s0232-151380005-6

  • CrossRef
  • Google Scholar

• 57.

  Erickson RL Browne CA Lucki I . Hair corticosterone measurement in mouse models of type 1 and type 2 diabetes mellitus.Physiol Behav. (2017) 178:166–71. 10.1016/j.physbeh.2017.01.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58.

  Mello Coelho VD Bunbury A Rangel LB Giri B Weeraratna A Morin PJ et al Fat-storing multilocular cells expressing CCR5 increase in the thymus with advancing age: potential role for CCR5 ligands on the differentiation and migration of preadipocytes. Int J Med Sci. (2009) 7:1–14. 10.7150/ijms.7.1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59.

  Chandra RK . Serum thymic hormone activity and cell-mediated immunity in healthy neonates, preterm infants, and small-for-gestational age infants.Pediatrics. (1981) 67:407–11.

  • Pubmed Abstract
  • Google Scholar

• 60.

  Chandra RK . Serum thymic hormone activity in protein-energy malnutrition.Clin Exp Immunol. (1979) 38:228–30.

  • Google Scholar

• 61.

  Léonhardt M Lesage J Dufourny L Dickès-Coopman A Montel V Dupouy J-P . Perinatal maternal food restriction induces alterations in hypothalamo-pituitary-adrenal axis activity and in plasma corticosterone-binding globulin capacity of weaning rat pups.Neuroendocrinology. (2002) 75:45–54. 10.1159/000048220

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62.

  Jacobson L . Lower weight loss and food intake in protein-deprived, corticotropin releasing hormone-deficient mice correlate with glucocorticoid insufficiency.Endocrinology. (1999) 140:3543–51. 10.1210/endo.140.8.6910

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63.

  da Silva SV Salama C Renovato-Martins M Helal-Neto E Citelli M Savino W et al Increased leptin response and inhibition of apoptosis in thymocytes of young rats offspring from protein deprived dams during lactation. PLoS One. (2013) 8:e64220. 10.1371/journal.pone.0064220

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64.

  Farooqi IS Matarese G Lord GM Keogh JM Lawrence E Agwu C et al Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. (2002) 110:1093–103. 10.1172/JCI15693

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65.

  Howard JK Lord GM Matarese G Vendetti S Ghatei MA Ritter MA et al Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. J Clin Invest. (1999) 104:1051–9. 10.1172/JCI6762

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66.

  Savino W Dardenne M Velloso LA Dayse Silva-Barbosa S . The thymus is a common target in malnutrition and infection.Br J Nutr. (2007) 98(Suppl. 1):S11–6. 10.1017/S0007114507832880

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67.

  Taylor AK Cao W Vora KP De La Cruz J Shieh WJ Zaki SR et al Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J Infect Dis. (2013) 207:501–10. 10.1093/infdis/jis527

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68.

  Savino W . The thymus is a common target organ in infectious diseases.PLoS Pathog. (2006) 2:e62. 10.1371/journal.ppat.0020062

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69.

  Losada-Barragán M Umaña-Pérez A Durães J Cuervo-Escobar S Rodríguez-Vega A Ribeiro-Gomes FL et al Thymic microenvironment is modified by malnutrition and Leishmania infantum infection. Front Cell Infect Microbiol. (2019) 9:252. 10.3389/fcimb.2019.00252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70.

  Losada-Barragán M Umaña-Pérez A Cuervo-Escobar S Berbert LR Porrozzi R Morgado FN et al Protein malnutrition promotes dysregulation of molecules involved in T cell migration in the thymus of mice infected with Leishmania infantum. Sci Rep. (2017) 7:45991. Erratum Sci Rep. (2017) 7:46809. 10.1038/srep45991

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71.

  Domínguez-Asenjo B Gutiérrez-Corbo C Pérez-Pertejo Y Iborra S Balaña-Fouce R Reguera RM . Bioluminescent imaging identifies thymus, as overlooked colonized organ, in a chronic model of Leishmania donovani mouse visceral Leishmaniasis.ACS Infect Dis. (2021) 7:871–83. 10.1021/acsinfecdis.0c00864

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72.

  da Silva AVA de Souza TL Figueiredo FB Mendes AAV Jr Ferreira LC Filgueira CPB et al Detection of amastigotes and histopathological alterations in the thymus of Leishmania infantum-infected dogs. Immun Inflamm Dis. (2020) 8:127–39. 10.1002/iid3.285

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73.

  Da Costa SC Calabrese KS Bauer PG Savino W Lagrange PH . Studies of the thymus in Chagas’ disease: III. Colonization of the thymus and other lymphoid organs of adult and newborn mice by Trypanosoma cruzi.Pathol Biol (Paris). (1991) 39:91–7.

  • Pubmed Abstract
  • Google Scholar

• 74.

  Cotta-de-Almeida V Bertho AL Villa-Verde DM Savino W . Phenotypic and functional alterations of thymic nurse cells following acute Trypanosoma cruzi infection.Clin Immunol Immunopathol. (1997) 82:125–32. 10.1006/clin.1996.4283

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75.

  Baez NS Cerbán F Savid-Frontera C Hodge DL Tosello J Acosta-Rodriguez E et al Thymic expression of IL-4 and IL-15 after systemic inflammatory or infectious Th1 disease processes induce the acquisition of “innate” characteristics during CD8+ T cell development. PLoS Pathog. (2019) 15:e1007456. 10.1371/journal.ppat.1007456

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76.

  de Meis J Morrot A Farias-de-Oliveira DA Villa-Verde DM Savino W . Differential regional immune response in Chagas disease.PLoS Negl Trop Dis. (2009) 3:e417. 10.1371/journal.pntd.0000417

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77.

  Andrade CF Gameiro J Nagib PR Carvalho BO Talaisys RL Costa FT et al Thymic alterations in Plasmodium berghei-infected mice. Cell Immunol. (2008) 253:1–4. 10.1016/j.cellimm.2008.06.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78.

  Francelin C Paulino LC Gameiro J Verinaud L . Effects of Plasmodium berghei on thymus: high levels of apoptosis and premature egress of CD4(+)CD8(+) thymocytes in experimentally infected mice.Immunobiology. (2011) 216:1148–54. 10.1016/j.imbio.2011.03.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79.

  Gameiro J Nagib PR Andrade CF Villa-Verde DM Silva-Barbosa SD Savino W et al Changes in cell migration-related molecules expressed by thymic microenvironment during experimental Plasmodium berghei infection: consequences on thymocyte development. Immunology. (2010) 129:248–56. 10.1111/j.1365-2567.2009.03177.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80.

  Huldt G Gard S Olovson SG . Effect of Toxoplasma gondii on the thymus.Nature. (1973) 244:301–3. 10.1038/244301a0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81.

  Kugler DG Flomerfelt FA Costa DL Laky K Kamenyeva O Mittelstadt PR et al Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes. J Exp Med. (2016) 213:3041–56. 10.1084/jem.20151636

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82.

  Nobrega C Cardona P-J Roque S Pinto do OP Appelberg R Correia-Neves M . The thymus as a target for mycobacterial infections.Microbes Infect. (2007) 9:1521–9. 10.1016/j.micinf.2007.08.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83.

  Nobrega C Nunes-Alves C Cerqueira-Rodrigues B Roque S Barreira-Silva P Behar SM et al T cells home to the thymus and control infection. J Immunol. (2013) 190:1646–58. 10.4049/jimmunol.1202412

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84.

  Reiley WW Wittmer ST Ryan LM Eaton SM Haynes L Winslow GM et al Maintenance of peripheral T cell responses during Mycobacterium tuberculosis infection. J Immunol. (2012) 189:4451–8. 10.4049/jimmunol.1201153

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85.

  Hühns M Erbersdobler A Obliers A Röpenack P . Identification of HPV types and Mycobacterium tuberculosis complex in historical long-term preserved formalin fixed tissues in different human organs.PLoS One. (2017) 12:e0170353. 10.1371/journal.pone.0170353

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86.

  Nobrega C Roque S Nunes-Alves C Coelho A Medeiros I Castro AG et al Dissemination of mycobacteria to the thymus renders newly generated T cells tolerant to the invading pathogen. J Immunol. (2010) 184:351–8. 10.4049/jimmunol.0902152

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87.

  Borges M Barreira-Silva P Flórido M Jordan MB Correia-Neves M Appelberg R . Molecular and cellular mechanisms of Mycobacterium avium-induced thymic atrophy.J Immunol. (2012) 189:3600–8. 10.4049/jimmunol.1201525

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88.

  Ross EA Coughlan RE Flores-Langarica A Lax S Nicholson J Desanti GE et al Thymic function is maintained during Salmonella-induced atrophy and recovery. J Immunol. (2012) 189:4266–74. 10.4049/jimmunol.1200070

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89.

  Deobagkar-Lele M Chacko SK Victor ES Kadthur JC Nandi D . Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection.Immunology. (2013) 138:307–21. 10.1111/imm.12047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90.

  Chen W Kuolee R Austin JW Shen H Che Y Conlan JW . Low dose aerosol infection of mice with virulent type A Francisella tularensis induces severe thymus atrophy and CD4+ CD8+ thymocyte depletion.Microb Pathog. (2005) 39:189–96. 10.1016/j.micpath.2005.08.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91.

  Xiang L Hu X Zhang J She J Li M Zhou T . Immunodepression induced by influenza A virus (H1N1) in lymphoid organs functions as a pathogenic mechanism.Clin Exp Pharmacol Physiol. (2020) 47:1664–73. 10.1111/1440-1681.13358

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92.

  Liu B Zhang X Deng W Liu J Li H Wen M et al Severe influenza A(H1N1)pdm09 infection induces thymic atrophy through activating innate CD8(+)CD44(hi) T cells by upregulating IFN-γ. Cell Death Dis. (2014) 5:e1440. 10.1038/cddis.2014.323

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93.

  Fislová T Gocník M Sládková T Durmanová V Rajcáni J Varecková E et al Multiorgan distribution of human influenza A virus strains observed in a mouse model. Arch Virol. (2009) 154:409–19. 10.1007/s00705-009-0318-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94.

  Lamontagne L Jolicoeur P . Low-virulent mouse hepatitis viruses exhibiting various tropisms in macrophages, T and B cell subpopulations, and thymic stromal cells.Lab Anim Sci. (1994) 44:17–24.

  • Pubmed Abstract
  • Google Scholar

• 95.

  Lee S-K Youn H-Y Hasegawa A Nakayama H Goto N . Apoptotic changes in the thymus of mice infected with mouse hepatitis virus, MHV-2.J Vet Med Sci. (1994) 56:879–82. 10.1292/jvms.56.879

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96.

  Godfraind C Holmes KV Coutelier JP . Thymus involution induced by mouse hepatitis virus A59 in BALB/c mice.J Virol. (1995) 69:6541–7. 10.1128/JVI.69.10.6541-6547.1995

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97.

  Meissner EG Duus KM Loomis R D’Agostin R Su L . HIV-1 replication and pathogenesis in the human thymus.Curr HIV Res. (2003) 1:275–85. 10.2174/1570162033485258

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98.

  Calabrò ML Zanotto C Calderazzo F Crivellaro C Del Mistro A De Rossi A et al HIV-1 infection of the thymus: evidence for a cytopathic and thymotropic viral variant in vivo. AIDS Res Hum Retroviruses. (1995) 11:11–9. 10.1089/aid.1995.11.11

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99.

  Schmitt N Nugeyre MT Scott-Algara D Cumont MC Barré-Sinoussi F Pancino G et al Differential susceptibility of human thymic dendritic cell subsets to X4 and R5 HIV-1 infection. AIDS. (2006) 20:533–42. 10.1097/01.aids.0000210607.63138.bc

  • CrossRef
  • Google Scholar

• 100.

  Rozmyslowicz T Murphy SL Conover DO Gaulton GN . HIV-1 infection inhibits cytokine production in human thymic macrophages.Exp Hematol. (2010) 38:1157–66. 10.1016/j.exphem.2010.08.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101.

  Stanley SK McCune JM Kaneshima H Justement JS Sullivan M Boone E et al Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse. J Exp Med. (1993) 178:1151–63. 10.1084/jem.178.4.1151

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102.

  Su L Kaneshima H Bonyhadi M Salimi S Kraft D Rabin L et al HIV-1-induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo. Immunity. (1995) 2:25–36. 10.1016/1074-761390076-4

  • CrossRef
  • Google Scholar

• 103.

  Ho Tsong Fang R Colantonio AD Uittenbogaart CH . The role of the thymus in HIV infection: a 10 year perspective.AIDS. (2008) 22:171–84. 10.1097/QAD.0b013e3282f2589b

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104.

  Joshi VV Oleske JM Saad S Gadol C Connor E Bobila R et al Thymus biopsy in children with acquired immunodeficiency syndrome. Arch Pathol Lab Med. (1986) 110:837–42.

  • Google Scholar

• 105.

  Messias CV Loss-Morais G Carvalho JB González MN Cunha DP Vasconcelos Z et al Zika virus targets the human thymic epithelium. Sci Rep. (2020) 10:1378. 10.1038/s41598-020-58135-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106.

  Valdespino-Vázquez MY Sevilla-Reyes EE Lira R Yocupicio-Monroy M Piten-Isidro E Boukadida C et al Congenital Zika syndrome and extra-central nervous system detection of Zika virus in a pre-term newborn in Mexico. Clin Infect Dis. (2019) 68:903–12. 10.1093/cid/ciy616

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107.

  Halouani A Jmii H Bodart G Michaux H Renard C Martens H et al Assessment of thymic output dynamics after in utero infection of mice with Coxsackievirus B4. Front Immunol. (2020) 11:481. 10.3389/fimmu.2020.00481

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108.

  Jaïdane H Halouani A Jmii H Elmastour F Abdelkefi S Bodart G et al In-utero coxsackievirus B4 infection of the mouse thymus. Clin Exp Immunol. (2017) 187:399–407. 10.1111/cei.12893

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109.

  Halouani A Jmii H Michaux H Renard C Martens H Pirottin D et al Housekeeping gene expression in the fetal and neonatal murine thymus following Coxsackievirus B4 infection. Genes (Basel). (2020) 11:279. 10.3390/genes11030279

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110.

  Brilot F Geenen V Hober D Stoddart CA . Coxsackievirus B4 infection of human fetal thymus cells.J Virol. (2004) 78:9854–61. 10.1128/JVI.78.18.9854-9861.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111.

  Brilot F Chehadeh W Charlet-Renard C Martens H Geenen V Hober D . Persistent infection of human thymic epithelial cells by coxsackievirus B4.J Virol. (2002) 76:5260–5. 10.1128/jvi.76.10.5260-5265.2002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112.

  Jaïdane H Gharbi J Lobert PE Lucas B Hiar R M’hadheb MB et al Prolonged viral RNA detection in blood and lymphoid tissues from coxsackievirus B4 E2 orally-inoculated Swiss mice. Microbiol Immunol. (2006) 50:971–4. 10.1111/j.1348-0421.2006.tb03874.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113.

  Jaïdane H Gharbi J Lobert PE Caloone D Lucas B Sané F et al Infection of primary cultures of murine splenic and thymic cells with coxsackievirus B4. Microbiol Immunol. (2008) 52:40–6. 10.1111/j.1348-0421.2008.00002.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114.

  Brilot F Jaïdane H Geenen V Hober D . Coxsackievirus B4 infection of murine foetal thymus organ cultures. J Med Virol. (2008) 80:659-66.Erratum J Med Virol. (2008) 80:1131. 10.1002/jmv.21016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115.

  Jaïdane H Caloone D Lobert PE Sane F Dardenne O Naquet P et al Persistent infection of thymic epithelial cells with coxsackievirus B4 results in decreased expression of type 2 insulin-like growth factor. J Virol. (2012) 86:11151–62. 10.1128/JVI.00726-12

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116.

  Mocarski ES Bonyhadi M Salimi S McCune JM Kaneshima H . Human cytomegalovirus in a SCID-hu mouse: thymic epithelial cells are prominent targets of viral replication.Proc Natl Acad Sci U.S.A. (1993) 90:104–8. 10.1073/pnas.90.1.104

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117.

  Wainberg MA Numazaki K Destephano L Wong I Goldman H . Infection of human thymic epithelial cells by human cytomegalovirus and other viruses: effect on secretion of interleukin 1-like activity.Clin Exp Immunol. (1988) 72:415–21.

  • Pubmed Abstract
  • Google Scholar

• 118.

  Schwartz JN Daniels CA Klintworth GK . Lymphoid cell necrosis, thymic atrophy, and growth retardation in newborn mice inoculated with murine cytomegalovirus.Am J Pathol. (1975) 79:509–22.

  • Pubmed Abstract
  • Google Scholar

• 119.

  Numazaki K Goldman H Bai XQ Wong I Wainberg MA . Effects of infection by HIV-1, cytomegalovirus, and human measles virus on cultured human thymic epithelial cells.Microbiol Immunol. (1989) 33:733–45. 10.1111/j.1348-0421.1989.tb00960.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120.

  Auwaerter PG Kaneshima H McCune JM Wiegand G Griffin DE . Measles virus infection of thymic epithelium in the SCID-hu mouse leads to thymocyte apoptosis.J Virol. (1996) 70:3734–40. 10.1128/JVI.70.6.3734-3740.1996

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121.

  Mrkic B Odermatt B Klein MA Billeter MA Pavlovic J Cattaneo R . Lymphatic dissemination and comparative pathology of recombinant measles viruses in genetically modified mice.J Virol. (2000) 74:1364–72. 10.1128/jvi.74.3.1364-1372.2000

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122.

  Takeuchi K Takeda M Miyajima N Ami Y Nagata N Suzaki Y et al Stringent requirement for the C protein of wild-type measles virus for growth both in vitro and in macaques. J Virol. (2005) 79:7838–44. 10.1128/JVI.79.12.7838-7844.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123.

  Amarilla SP Gómez-Laguna J Carrasco L Rodríguez-Gómez IM Caridad Y Ocerín JM et al Thymic depletion of lymphocytes is associated with the virulence of PRRSV-1 strains. Vet Microbiol. (2016) 188:47–58. 10.1016/j.vetmic.2016.04.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124.

  Wang G Yu Y Cai X Zhou EM Zimmerman JJ . Effects of PRRSV infection on the porcine thymus.Trends Microbiol. (2020) 28:212–23. 10.1016/j.tim.2019.10.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125.

  Elsaesser HJ Mohtashami M Osokine I Snell LM Cunningham CR Boukhaled GM et al Chronic virus infection drives CD8 T cell-mediated thymic destruction and impaired negative selection. Proc Natl Acad Sci U.S.A. (2020) 117:5420–9. 10.1073/pnas.1913776117

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126.

  Gossmann J Löhler J Lehmann-Grube F . Entry of antivirally active T lymphocytes into the thymus of virus-infected mice.J Immunol. (1991) 146:293–7.

  • Pubmed Abstract
  • Google Scholar

• 127.

  Yoshimura FK Wang T Cankovic M . Sequences between the enhancer and promoter in the long terminal repeat affect murine leukemia virus pathogenicity and replication in the thymus.J Virol. (1999) 73:4890–8. 10.1128/JVI.73.6.4890-4898.1999

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128.

  Yoshimura FK Luo X . Induction of endoplasmic reticulum stress in thymic lymphocytes by the envelope precursor polyprotein of a murine leukemia virus during the preleukemic period.J Virol. (2007) 81:4374–7. 10.1128/JVI.02292-06

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129.

  Morse SS Valinsky JE . Mouse thymic virus (MTLV). A mammalian herpesvirus cytolytic for CD4+ (L3T4+) T lymphocytes.J Exp Med. (1989) 169:591–6. 10.1084/jem.169.2.591

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130.

  Patel SJ Zhao G Penna VR Park E Lauron EJ Harvey IB et al A Murine herpesvirus closely related to ubiquitous human herpesviruses causes T-cell depletion. J Virol. (2017) 91:e02463–16. 10.1128/JVI.02463-16

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131.

  Cavalcante P Barberis M Cannone M Baggi F Antozzi C Maggi L et al Detection of poliovirus-infected macrophages in thymus of patients with myasthenia gravis. Neurology. (2010) 74:1118–26. 10.1212/WNL.0b013e3181d7d884

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132.

  Cavalcante P Galbardi B Franzi S Marcuzzo S Barzago C Bonanno S et al Increased expression of Toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein-Barr virus infection. Immunobiology. (2016) 221:516–27. 10.1016/j.imbio.2015.12.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133.

  Cavalcante P Serafini B Rosicarelli B Maggi L Barberis M Antozzi C et al Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol. (2010) 67:726–38. 10.1002/ana.21902

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134.

  Cavalcante P Maggi L Colleoni L Caldara R Motta T Giardina C et al Inflammation and epstein-barr virus infection are common features of myasthenia gravis thymus: possible roles in pathogenesis. Autoimmune Dis. (2011) 2011:213092. 10.4061/2011/213092

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135.

  Brito VN Souto PCS Cruz-Höfling MA Ricci LC Verinaud L . Thymus invasion and atrophy induced by Paracoccidioides brasiliensis in BALB/c mice.Med Mycol. (2003) 41:83–7. 10.1080/mmy.41.2.83.87

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136.

  Alves da Costa T Di Gangi R Thomé R Barreto Felisbino M Pires Bonfanti A Lumi Watanabe Ishikawa L et al Severe changes in thymic microenvironment in a chronic experimental model of Paracoccidioidomycosis. PLoS One (2016) 11:e0164745. Erratum PLoS One. (2016) 11:e0168810. 10.1371/journal.pone.0168810

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137.

  Di Gangi R Alves da Costa T Thomé R Peron G Burger E Verinaud L . Paracoccidioides brasiliensis infection promotes thymic disarrangement and premature egress of mature lymphocytes expressing prohibitive TCRs.BMC Infect Dis. (2016) 16:209. 10.1186/s12879-016-1561-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138.

  Sotomayor CE Rubinstein HR Cervi L Riera CM Masih DT . Immunosuppression in experimental cryptococcosis in rats: induction of thymic suppressor cells.Mycopathologia. (1989) 108:5–10. 10.1007/BF00436777

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139.

  Sotomayor CE Rubinstein HR Riera CM Masih DT . Immunosuppression in experimental cryptococcosis: variation of splenic and thymic populations and expression of class II major histocompatibility complex gene products.Clin Immunol Immunopathol. (1995) 77:19–26. 10.1016/0090-122990132-9

  • CrossRef
  • Google Scholar

• 140.

  Cerf BJ Jones TC Badaro R Sampaio D Teixeira R Johnson WD . Malnutrition as a risk factor for severe visceral leishmaniasis.J Infect Dis. (1987) 156:1030–3. 10.1093/infdis/156.6.1030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141.

  Malafaia G Serafim TD Silva ME Pedrosa ML Rezende SA . Protein-energy malnutrition decreases immune response to Leishmania chagasi vaccine in BALB/c mice.Parasite Immunol. (2009) 31:41–9. 10.1111/j.1365-3024.2008.01069.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142.

  Barbeito-Andrés J Pezzuto P Higa LM Dias AA Vasconcelos JM Santos TMP et al Congenital Zika syndrome is associated with maternal protein malnutrition. Sci Adv. (2020) 6:eaaw6284. 10.1126/sciadv.aaw6284

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143.

  Chuong C Bates TA Akter S Werre SR LeRoith T Weger-Lucarelli J . Nutritional status impacts dengue virus infection in mice.BMC Biol. (2020) 18:106. 10.1186/s12915-020-00828-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144.

  Sinha P Lönnroth K Bhargava A Heysell SK Sarkar S Salgame P et al Food for thought: addressing undernutrition to end tuberculosis. Lancet Infect Dis. (2021) 21:e318–25. 10.1016/S1473-309930792-1

  • CrossRef
  • Google Scholar

• 145.

  Kasai A Gama P Alvares EP . Protein restriction inhibits gastric cell proliferation during rat postnatal growth in parallel to ghrelin changes.Nutrition. (2012) 28:707–12. 10.1016/j.nut.2011.10.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146.

  Mondal D Minak J Alam M Liu Y Dai J Korpe P et al Contribution of enteric infection, altered intestinal barrier function, and maternal malnutrition to infant malnutrition in Bangladesh. Clin Infect Dis. (2012) 54:185–92. 10.1093/cid/cir807

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147.

  Black RE Victora CG Walker SP Bhutta ZA Christian P de Onis M et al Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. (2013) 382:427–51. 10.1016/S0140-673660937-X

  • CrossRef
  • Google Scholar

• 148.

  Assa A Vong L Pinnell LJ Avitzur N Johnson-Henry KC Sherman PM . Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation.J Infect Dis. (2014) 210:1296–305. 10.1093/infdis/jiu235

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149.

  David LA Maurice CF Carmody RN Gootenberg DB Button JE Wolfe BE et al Diet rapidly and reproducibly alters the human gut microbiome. Nature. (2014) 505:559–63. 10.1038/nature12820

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150.

  Subramanian S Huq S Yatsunenko T Haque R Mahfuz M Alam MA et al Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature. (2014) 510:417–21. 10.1038/nature13421

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151.

  Bourke CD Jones KDJ Prendergast AJ . Current understanding of innate immune cell dysfunction in childhood undernutrition.Front Immunol. (2019) 10:1728. 10.3389/fimmu.2019.01728

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152.

  Bryce J Boschi-Pinto C Shibuya K Black RE WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet. (2005) 365:1147–52. 10.1016/S0140-673671877-8

  • CrossRef
  • Google Scholar

• 153.

  Roberton T Carter ED Chou VB Stegmuller AR Jackson BD Tam Y et al Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study. Lancet Glob Health. (2020) 8:e901–8. 10.1016/S2214-109X30229-1

  • CrossRef
  • Google Scholar

• 154.

  Mertens E Peñalvo JL . The burden of malnutrition and fatal COVID-19: a global burden of disease analysis.Front Nutr. (2021) 7:619850. 10.3389/fnut.2020.619850

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155.

  Papadimitriou-Olivgeris M Gkikopoulos N Wüst M Ballif A Simonin V Maulini M et al Predictors of mortality of influenza virus infections in a Swiss Hospital during four influenza seasons: role of quick sequential organ failure assessment. Eur J Intern Med. (2020) 74:86–91. 10.1016/j.ejim.2019.12.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156.

  Moore CA Staples JE Dobyns WB Pessoa A Ventura CV Fonseca EB et al Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. (2017) 171:288–95. 10.1001/jamapediatrics.2016.3982

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157.

  Nguyen TH Nguyen TL Lei H-Y Lin Y-S Le BL Huang K-J et al Association between sex, nutritional status, severity of dengue hemorrhagic fever, and immune status in infants with dengue hemorrhagic fever. Am J Trop Med Hyg. (2005) 72:370–4.

  • Pubmed Abstract
  • Google Scholar

• 158.

  Kalayanarooj S Nimmannitya S . Is dengue severity related to nutritional status?Southeast Asian J Trop Med Public Health. (2005) 36:378–84.

  • Google Scholar

• 159.

  Das D Grais RF Okiro EA Stepniewska K Mansoor R van der Kam S et al Complex interactions between malaria and malnutrition: a systematic literature review. BMC Med. (2018) 16:186. 10.1186/s12916-018-1177-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160.

  Page AL de Rekeneire N Sayadi S Aberrane S Janssens AC Rieux C et al Infections in children admitted with complicated severe acute malnutrition in Niger. PLoS One. (2013) 8:e68699. 10.1371/journal.pone.0068699

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161.

  Denoeud-Ndam L Dicko A Baudin E Guindo O Grandesso F Diawara H et al Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger. BMC Med. (2016) 14:167. 10.1186/s12916-016-0716-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162.

  Gone T Lemango F Eliso E Yohannes S Yohannes T . The association between malaria and malnutrition among under-five children in Shashogo district, Southern Ethiopia: a case-control study.Infect Dis Poverty. (2017) 6:9. 10.1186/s40249-016-0221-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163.

  Donovan CV McElroy P Adair L Pence BW Oloo AJ Lal A et al Association of malnutrition with subsequent malaria parasitemia among children younger than three years in Kenya: a secondary data analysis of the Asembo Bay cohort study. Am J Trop Med Hyg. (2021) 104:243–54. 10.4269/ajtmh.20-0002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164.

  Fillol F Sarr JB Boulanger D Cisse B Sokhna C Riveau G et al Impact of child malnutrition on the specific anti-Plasmodium falciparum antibody response. Malar J. (2009) 8:116. 10.1186/1475-2875-8-116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165.

  Alexandre MAA Benzecry SG Siqueira AM Vitor-Silva S Melo GC Monteiro WM et al The association between nutritional status and malaria in children from a rural community in the Amazonian region: a longitudinal study. PLoS Negl Trop Dis. (2015) 9:e0003743. 10.1371/journal.pntd.0003743

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166.

  Mitangala PN D’Alessandro U Donnen P Hennart P Porignon D Bisimwa Balaluka G et al Infection palustre et état nutritionnel: résultats d’une cohorte d’enfants âgés de 6 à 59 mois au Kivu en République démocratique du Congo. Rev Epidemiol Sante Publique. (2013) 61:111–20. 10.1016/j.respe.2012.06.404

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167.

  Edirisinghe JS Fern EB Targett GA . Resistance to superinfection with Plasmodium berghei in rats fed a protein-free diet.Trans R Soc Trop Med Hyg. (1982) 76:382–6. 10.1016/0035-920390196-1

  • CrossRef
  • Google Scholar

• 168.

  Bhatia A Vinayak VK . Dietary modulation of malaria infection in rats.Indian J Malariol. (1991) 28:237–42.

  • Google Scholar

• 169.

  Hunt NH Manduci N Thumwood CM . Amelioration of murine cerebral malaria by dietary restriction.Parasitology. (1993) 107(Pt 5):471–6. 10.1017/s0031182000068049

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170.

  Mejia P Treviño-Villarreal JH Hine C Harputlugil E Lang S Calay E et al Dietary restriction protects against experimental cerebral malaria via leptin modulation and T-cell mTORC1 suppression. Nat Commun. (2015) 6:6050. 10.1038/ncomms7050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171.

  Rivera-Correa J Rodriguez A . Autoimmune anemia in malaria.Trends Parasitol. (2020) 36:91–7. 10.1016/j.pt.2019.12.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172.

  Lepletier A de Almeida L Santos L da Silva Sampaio L Paredes B González FB et al Early double-negative thymocyte export in Trypanosoma cruzi infection is restricted by sphingosine receptors and associated with human chagas disease. PLoS Negl Trop Dis. (2014) 8:e3203. 10.1371/journal.pntd.0003203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173.

  Farias-de-Oliveira DA Cotta-de-Almeida V Villa-Verde DM Riederer I Meis JD Savino W . Fibronectin modulates thymocyte-thymic epithelial cell interactions following Trypanosoma cruzi infection.Mem Inst Oswaldo Cruz. (2013) 108:825–31. 10.1590/0074-0276130071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174.

  Khanam S Sharma S Pathak S . Lethal and nonlethal murine malarial infections differentially affect apoptosis, proliferation, and CD8 expression on thymic T cells.Parasite Immunol. (2015) 37:349–61. 10.1111/pim.12197

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175.

  Smythe PM Brereton-Stiles GG Grace HJ Mafoyane A Schonland M Coovadia HM et al Thymolymphatic deficiency and depression of cell-mediated immunity in protein-calorie malnutrition. Lancet. (1971) 2:939–43. 10.1016/s0140-673690267-4

  • CrossRef
  • Google Scholar

• 176.

  Schonland M . Depression of immunity in protein-calorie malnutrition: a post-mortem study.J Trop Pediatr Environ Child Health. (1972) 18:217–24. 10.1093/tropej/18.3.217

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177.

  Aref GH Abdel-Aziz A Elaraby II Abdel-Moneim MA Hebeishy NA Rahmy AI . A post-mortem study of the thymolymphatic system in protein energy malnutrition.J Trop Med Hyg. (1982) 85:109–14.

  • Pubmed Abstract
  • Google Scholar

• 178.

  Garly ML Trautner SL Marx C Danebod K Nielsen J Ravn H et al Thymus size at 6 months of age and subsequent child mortality. J Pediatr. (2008) 153:683–8, 688.e1–3. 10.1016/j.jpeds.2008.04.069

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179.

  Lepletier A de Carvalho VF Rodrigues e Silva PM Villar S Pérez AR Savino W et al Trypanosoma cruzi disrupts thymic homeostasis by altering intrathymic and systemic stress-related endocrine circuitries. PLoS Negl Trop Dis. (2013) 7:e2470. 10.1371/journal.pntd.0002470

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180.

  Murray HW Berman JD Davies CR Saravia NG . Advances in leishmaniasis.Lancet. (2005) 366:1561–77. 10.1016/S0140-673667629-5

  • CrossRef
  • Google Scholar

• 181.

  Burza S Croft SL Boelaert M . Leishmaniasis.Lancet. (2018) 392:951–70. 10.1016/S0140-673631204-2

  • CrossRef
  • Google Scholar

• 182.

  de Oliveira JM Fernandes AC Dorval MEC Alves TP Fernandes TD Oshiro ET et al Mortality due to visceral leishmaniasis: clinical and laboratory characteristics. Revista Sociedade Brasileira de Medicina Tropical. (2010) 43:188–93. 10.1590/s0037-86822010000200016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183.

  Mengesha B Endris M Takele Y Mekonnen K Tadesse T Feleke A et al Prevalence of malnutrition and associated risk factors among adult visceral leishmaniasis patients in Northwest Ethiopia: a cross sectional study. BMC Res Notes. (2014) 7:75. 10.1186/1756-0500-7-75

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184.

  Diro E Lynen L Gebregziabiher B Assefa A Lakew W Belew Z et al Clinical aspects of paediatric visceral leishmaniasis in North-west Ethiopia. Trop Med Int Health. (2015) 20:8–16. 10.1111/tmi.12407

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185.

  Anstead GM Chandrasekar B Zhao W Yang J Perez LE Melby PC . Malnutrition alters the innate immune response and increases early visceralization following Leishmania donovani infection.Infect Immun. (2001) 69:4709–18. 10.1128/IAI.69.8.4709-4718.2001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186.

  Ibrahim MK Barnes JL Anstead GM Jimenez F Travi BL Peniche AG et al The malnutrition-related increase in early visceralization of Leishmania donovani is associated with a reduced number of lymph node phagocytes and altered conduit system flow. PLoS Negl Trop Dis. (2013) 7:e2329. 10.1371/journal.pntd.0002329

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187.

  Ibrahim MK Barnes JL Osorio EY Anstead GM Jimenez F Osterholzer JJ et al Deficiency of lymph node-resident dendritic cells (DCs) and dysregulation of DC chemoattractants in a malnourished mouse model of Leishmania donovani infection. Infect Immun. (2014) 82:3098–112. 10.1128/IAI.01778-14

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188.

  Cuervo-Escobar S Losada-Barragán M Umaña-Pérez A Porrozzi R Saboia-Vahia L Miranda LH et al T-cell populations and cytokine expression are impaired in thymus and spleen of protein malnourished BALB/c mice infected with Leishmania infantum. PLoS One. (2014) 9:e114584. 10.1371/journal.pone.0114584

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189.

  Losada-Barragán M Umaña-Pérez A Rodriguez-Vega A Cuervo-Escobar S Azevedo R Morgado FN et al Proteomic profiling of splenic interstitial fluid of malnourished mice infected with Leishmania infantum reveals defects on cell proliferation and pro-inflammatory response. J Proteomics. (2019) 208:103492. 10.1016/j.jprot.2019.103492

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190.

  Gaitán-Albarracín F Losada-Barragán M Pinho N Azevedo R Durães J Arcila-Barrera JS et al Malnutrition aggravates alterations observed in the gut structure and immune response of mice infected with Leishmania infantum. Microorganisms. (2021) 9:1270. 10.3390/microorganisms9061270

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191.

  Savino W Mendes-da-Cruz DA Silva JS Dardenne M Cotta-de-Almeida V . Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines?Trends Immunol. (2002) 23:305–13. 10.1016/s1471-490602224-x

  • CrossRef
  • Google Scholar

• 192.

  Savino W Mendes-da-Cruz DA Golbert DC Riederer I Cotta-de-Almeida V . Laminin-mediated interactions in thymocyte migration and development.Front Immunol. (2015) 6:579. 10.3389/fimmu.2015.00579

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193.

  Durães J. Analysis of Malnutrition Effect on the Thymic Microenvironment of BALB/c Mice Infected With Leishmania (Leishmania) infantum . Ph.D. thesis. Rio de Janeiro: Fundação Oswaldo Cruz (2021).

  • Google Scholar

• 194.

  Nunes-Alves C Nobrega C Behar SM Correia-Neves M . Tolerance has its limits: how the thymus copes with infection.Trends Immunol. (2013) 34:502–10. 10.1016/j.it.2013.06.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195.

  Gilbert JA Blaser MJ Caporaso JG Jansson JK Lynch SV Knight R . Current understanding of the human microbiome.Nat Med. (2018) 24:392–400. 10.1038/nm.4517

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196.

  Unger S Stintzi A Shah P Mack D O’Connor DL . Gut microbiota of the very-low-birth-weight infant.Pediatr Res. (2015) 77:205–13. 10.1038/pr.2014.162

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197.

  Sordillo JE Korrick S Laranjo N Carey V Weinstock GM Gold DR et al Association of the infant gut microbiome with early childhood neurodevelopmental outcomes: an ancillary study to the VDAART randomized clinical trial. JAMA Netw Open. (2019) 2:e190905. 10.1001/jamanetworkopen.2019.0905

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198.

  Lynch SV Pedersen O . The human intestinal microbiome in health and disease.N Engl J Med. (2016) 375:2369–79. 10.1056/NEJMra1600266

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199.

  Rinninella E Raoul P Cintoni M Franceschi F Miggiano GAD Gasbarrini A et al What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms. (2019) 7:14. 10.3390/microorganisms7010014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200.

  Galdeano CM Perdigón G . Role of viability of probiotic strains in their persistence in the gut and in mucosal immune stimulation.J Appl Microbiol. (2004) 97:673–81. 10.1111/j.1365-2672.2004.02353.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201.

  Thomas CM Versalovic J . Probiotics-host communication: modulation of signaling pathways in the intestine.Gut Microbes. (2010) 1:148–63. 10.4161/gmic.1.3.11712

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202.

  Vincenzi A Goettert MI Volken de Souza CF . An evaluation of the effects of probiotics on tumoral necrosis factor (TNF-α) signaling and gene expression.Cytokine Growth Factor Rev. (2021) 57:27–38. 10.1016/j.cytogfr.2020.10.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203.

  Yang H Youm YH Vandanmagsar B Rood J Kumar KG Butler AA et al Obesity accelerates thymic aging. Blood. (2009) 114:3803–12. 10.1182/blood-2009-03-213595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204.

  Harrington KA Kennedy DS Tang B Hickie C Phelan E Torreggiani W et al Computed tomographic evaluation of the thymus-does obesity affect thymic fatty involution in a healthy young adult population? Br J Radiol. (2018) 91:20170609. 10.1259/bjr.20170609

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205.

  Balcells F Mariani C Weill R Perdigón G Maldonado-Galdeano C . Effect of yogurt with or without probiotic addition on body composition changes and immune system in an obese model.J Food Sci Nut. (2017) 3:022. 10.24966/FSN-0176/100022

  • CrossRef
  • Google Scholar

• 206.

  Balcells F Martínez Monteros MJ Gómez AL Cazorla SI Perdigón G Maldonado-Galdeano C . Probiotic consumption boosts thymus in obesity and senescence mouse models.Nutrients. (2022) 14:616. 10.3390/nu14030616

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207.

  Hosokawa H Rothenberg EV . Cytokines, transcription factors, and the initiation of T-cell development.Cold Spring Harb Perspect Biol. (2018) 10:a028621. 10.1101/cshperspect.a028621

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208.

  Dalloul AH Arock M Fourcade C Hatzfeld A Bertho JM Debré P et al Human thymic epithelial cells produce interleukin-3. Blood. (1991) 77:69–74.

  • Google Scholar

• 209.

  Mendes-da-Cruz DA de Meis J Cotta-de-Almeida V Savino W . Experimental Trypanosoma cruzi infection alters the shaping of the central and peripheral T-cell repertoire.Microbes Infect. (2003) 5:825–32. 10.1016/s1286-457900156-4

  • CrossRef
  • Google Scholar

• 210.

  Núñez IN Galdeano CM Carmuega E Weill R de Moreno de LeBlanc A Perdigón G . Effect of a probiotic fermented milk on the thymus in Balb/c mice under non-severe protein-energy malnutrition.Br J Nutr. (2013) 110:500–8. 10.1017/S0007114512005302

  • Pubmed Abstract
  • CrossRef
  • Google Scholar