Infectious diseases are the second leading cause of mortality worldwide and the main factor in generating disability-adjusted life years (DALYs), which a DALY corresponds to the loss of 1 year of healthy life (World Health Organization, 2000). They are diseases of great weight for health surveillance due to being associated with poverty and inappropriate living conditions (de Souza et al., 2020). The social, demographic, economic, and health control transformations that occurred between 1950 and the 2000s were extremely important for reducing the magnitude of various infectious diseases in several countries around the world. However, from the end of the 20th century, there was a behavior of reappearance of emerging diseases, such as polio, measles, tetanus, diphtheria, pertussis, tuberculosis, malaria, and acquired immunodeficiency virus (HIV/AIDS) disease and new diseases, for example, coronavirus disease 2019 (COVID-19) that counterbalanced this situation and took global proportions (Waldman et al., 1999).

In a population endemic to a disease, some individuals are diagnosed with active infection, which can generate unfavorable clinical outcomes and even death, while others remain asymptomatic (Janeway and Medzhitov, 2002). This can be explained by the distinct immunological response developed by each individual, which is largely correlated with his genetic background. Immunogenetic studies involving genetic background factors have become of great value in the evaluation of susceptibility or infection protection roles (Johnson et al., 2006; Doetschman, 2009).

Single nucleotide polymorphisms (SNPs) are the most frequent type of mutation in the human genome. They can serve as important biological markers for defining therapeutic, diagnostic, and prophylactic strategies for diseases, including infectious ones (Caetano, 2009). Thus, a study of strategies for prevention and control of the occurrence of diseases in humans through health promotion improves the quality of life of the community and contributes to new public health perspectives (Souza and Grundy, 2004). Epidemiological studies seek, in general, to analyze this occurrence of diseases and investigate control measures (Ishikawa and Gomide, 2019).

Toll-like Receptors (TLRs) are a family of type 1 transmembrane receptors and are evolutionarily characterized and conserved proteins in vertebrates and invertebrates (Medzhitov et al., 1997). In this way, TLR4 functions as a specific cell receptor for viruses, bacterial and fungal components, can act both on the cell surface and endosomes for recognition of the linker and to initiate activation of cytokine production by the innate immune response and conduction of the adaptive immune response (Reis et al., 2016). It is an important mediator in the detection of lipopolysaccharide (LPS) and manuronic acid polymers, both found in Gram-negative bacteria. LPS is a key factor in triggering systemic inflammatory response that can lead to sepsis, organ failure, and septic shock (Jabłońska et al., 2020). TLR4 also recognizes lipoteichoic acid (LTA) from Gram-positive bacteria (Takeuchi et al., 1999), mannans from fungal pathogens (Campos et al., 2004) and mycobacteria such as Mycobacterium tuberculosis (Sánchez et al., 2010). The physico-chemical properties and location of LTA in Gram-positive bacterial cells are similar to those of LPS in Gram-negative bacteria (Takeuchi et al., 1999).

TLR4 can be activated by oxidized phospholipids, which also appear in viral lung infections, such as in the detection of respiratory syncytial virus fusion protein (Kurt-Jones et al., 2000) and severe acute respiratory coronavirus syndrome 2 (SARS-CoV-2) (Aboudounya and Heads, 2021). Therefore, it activates the innate immune response (Khanmohammadi and Rezaei, 2021). Furthermore, it can identify certain molecular patterns associated with damage (DAMPs) generated by dead or lysed cells after host tissue injury or viral infection (Aboudounya and Heads, 2021).

The human TLR4 gene is located on the human chromosome 9q33.1 and has three exons and two introns (Vaure and Liu, 2014). In this gene, SNP rs4986790, also known as 896A/G, is a non-synonymous mutation characterized by substitution within the 3rd exon of the TLR4 gene, from an adenine (A) to a guanin (G) at position 896 (896A>G) which leads to modification of the conserved residue of aspartic acid to a glycine in amino acid 299 of the protein sequence (Asp299Gly) on, in or at the domain of the extracellular structure of TLR4. It is responsible for causing change in the function of the encoded protein, diminished function, i.e. missense (Ohto et al., 2012). It has already been associated with the susceptibility and protection of various infectious and non-infectious diseases, as well as the severity of some of them (Arbour et al., 2000). The frequency of the G allele of this SNP ranges from 0 to 20% among populations (Agnese et al., 2002). Figure 1 demonstrates the location of SNP rs4986790 in the TLR4 gene and protein in a didactic model.

Due to their importance in generating an immune response in the fight against pathogens, polymorphic variants of TLR4, such as rs4986790, have great value in identifying the risk and defense of infectious diseases. In this sense, the following problem arises: “In which Infectious Diseases is the SNP rs4986790 proven to be related to susceptibility or protection?".

A total of 172 articles were found for reading from the databases. After excluding 10 duplicate studies, in addition to 20 letters to the editor, 20 studies available only the abstract, removing 94 studies irrelevant to the theme based on title, abstract, and body of the text. The final sample consisted of 27 articles, most of them belonging to the case-control type (Figure 2). These included studies are presented in Table 1. The presence of the mutant allele of the SNP was associated with susceptibility to several infectious diseases: COVID-19 (Taha et al., 2021); Escherichia coli infection (Sampath et al., 2013); Orientia tsutsugamushi infection (Janardhanan et al., 2013); S. pyogenes and H. influenzae (Liadaki et al., 2011); mononucleosis (Jabłońska et al., 2020); UTI in Indian diabetic patients (Gond et al., 2018); dengue infection (Sharma et al., 2016); influenza H1N1 in the Italian population (Esposito et al., 2012a); HBV/HCV (Sghaier et al., 2019); HIV (Vidyant et al., 2019).

The presence of mutant allele of this SNP was associated with the protection of: Escherichia coli infection (Lee et al., 2011); severe respiratory syncytial virus disease (Kresfelder et al., 2011); urinary tract-UTI infection (Akil et al., 2012); prosthetic joint infection in the Czech population (Mrazek et al., 2013); renal parenchyma infection (Hussein et al., 2018); chronic periodontitis and chronic gengivitis (Garlet et al., 2012); P. gingivalis infection (Sellers et al., 2016) and with the reduction in severity of periodontitis (Sellers et al., 2016).

The forest plot of the meta-analysis was represented by Figure 3. The meta-analysis was performed for random effect due to the high heterogeneity found (I²) in the analysis of both subgroups and in general.

In a generalized analysis, the SNP TLR4 rs4986790 did not show a significant association with susceptibility to infections (OR = 1,11; 95% CI: 0,75–1,66; p = 0,59). Regarding the subgroups, for bacteria, although this SNP was not statistically significant, it showed a greater strength of association for the protection of infections related to them (OR = 0,86; 95% CI: 0,56–1,30; p = 0,47). It should be taken into account that, in the meta-analysis, the etiological agent of UTI considered was bacteria. Regarding viruses, a significantly positive relationship was found between the presence of this mutant SNP allele and the risk of contracting viral infections (OR = 2,16; 95% CI: 1,09–4,30; p = 0,03). For parasites, only one study was included, and therefore it was not possible to observe significant associations in this subgroup (no effect estimate).

A total of 5599 cases and 5871 controls were included. The numerical configuration of researches was composed of 19 studies (70.37%) for the bacteria subgroup, with 3848 cases and 4301 controls, while six researches (22.22%) were in virus subgroup (constituted of 1149 cases and 1233 controls) and only one for parasites (3.7%), forming a subgroup with 74 patients and 37 controls. A symmetrical funnel plot presented the reduced risk of bias in Figure 4.

Schematic presentation of the data found for TLR4 Signaling Transduction Pathways was performed in Figure 5 and these pathways in the presence of the investigated SNP of TLR4 in Figure 6.

Figure 5 represented its stages chronologically through numbers in ascending order. It starts at phase (1) Recognition of the microorganism: TLR4 is activated on the cell membrane by PAMPs of pathogens, such as lipoteichoic acid (LTA) from Gram-positive bacteria, LPS from Gram-negative bacteria, elements not fully unraveled for viruses, fungal mannans, and glycosphingolipid (GSPL) from parasites, while CD-14, liposaccharide binding protein (LBP) and MD-2 act as accessory proteins in a conformational complex. From this binding, in phase (2), the left and right routes for TLR4 signaling are shown to be MyD88-dependent and independent, respectively, in which there is the generation of pathways: TLR4 dimerizes and recruits downstream adapter proteins such as MyD88/MAL and TRIF/TRAM to mount an inflammatory response in the cytoplasm. (2.1) RIP1 is recruited to the receptor by binding to TRIF and is then phosphorylated and polyubiquitinated, inducing Akt phosphorylation. (2.2) Concurrently, the MyD88 molecule-dependent activations are facilitated with IRAK4, which contributes to the phosphorylation of IRAK1. This reaction allows the binding of the TRAF6 molecule to the complex. (2.3) Furthermore, binding of TRAF6 activates TAK1, which forms an aggregation with TAB2 and TAB3. After its formation, TAK1 induces the IKK complex through NEMOylation. (2.4) Then, both pathways converge in the generation of NF-kB. In addition to activating NF-κB, TAK1 also phosphorylates MKKs, which subsequently activate JUN N-terminal kinase (JNK) and p38 to further enhance the inflammatory response. In stage (3) the TRIF/TRAM pathway not only activates NF-κB (translocated to the nucleus), but also triggers IRF3 to mount an antiviral response by interferons (IFNs) actions. In step 4) TLR4 levels cause the expression of pro-inflammatory cytokines and the maturation of APCs of the innate immune system that will define the course of the infection. This stimulation of TLR4 is crucial for inducing powerful responses to protect against host damage. Innate immunity develops because of the coordinated effects of activating several TLRs, together with the activation of numerous additional receptors involved in host defense and is linked to the formation of adaptive immunity. Specific defense is made possible by cytokine induction; for example, IRF-3 facilitates antiviral responses via IFN-β, while interleukin (IL) - 12 is crucial for defense against intracellular infections. TLR-mediated up-regulation of inducible NO synthase contributes to macrophages’ ability to destroy phagocytosed bacteria.

Figure 6 represents at phase (1) Recognition of the microorganism: TLR4 is activated on the cell membrane by PAMPs of pathogens, such as lipoteichoic acid (LTA) from Gram-positive bacteria, LPS from Gram-negative bacteria, elements not fully unraveled for viruses, fungal mannans, and glycosphingolipid (GSPL) from parasites, while CD-14, liposaccharide binding protein (LBP) and MD-2 act as accessory proteins in a conformational complex. TLR4 mutation change the structure of TLR4 and limit its ability to interact with LPS, CD-14, and/or MD-2. The TLR4 SNP rs4986790 acts by decreasing the expression of TLR4 by 2 times. In this sense, the absence of myeloid differentiation factor 2 (MD-2), which forms a complex with TLR4 and LPS, this decrease is elevated in 10 times. From this binding, in phase (2), both MyD88-dependent and independent routes are affected by the presence of this mutation and there is the generation of TLR4 signaling pathways: the aforementioned vias (2.1), (2.2), (2.3), and (2.4). This mutation leads to suppressed recruitment of downstream adapter molecules and kinases involved in the TLR4 pathways, such as IRAK4, NEMO, IKKe and IRF3, which can thus eliminate signaling activity. In stage (3), there is suppression of all these vias, including, the NF-κB transactivation and translocation in human monocytes with the 896A/G TLR4 expression, which could lead to the development of adaptive immunity. In step (4), this dysfunctional stimulation of TLR4 is characterized by suppression of recognition and immune response to pathogens, generating an uncoordinated immune response and, consequently, in most cases, a poor prognosis to infectious diseases.

The analysis of host genetic factors such as SNPs can become a useful strategy to identify people at increased risk of specific infections, patients at higher risk of unfavorable disease outcomes, and contribute to more effective therapeutic interventions (Mukherjee et al., 2019). The pro-inflammatory response induced by TLRs is considered the first form of body defense against pathogens and marks substantial variations in antimicrobial defense of populations.

In this sense, the manifestation of infectious diseases may be related to mutations in the TLR4 gene due to the absence/presence of the mutant allele of SNPs, in addition to genetic, epigenetic, and environmental factors (Medzhitov and Janeway, 2000). SNP rs4986790 has been shown to cause hyporesponsiveness to LPS. This SNP causes local structural changes around the mutation area that can affect the effectiveness of folding, cell surface expression, protein stability, and interaction with downstream messenger proteins (Ohto et al., 2012). At the molecular level, this SNP has been reported to interfere with the interaction of TLR4 with downstream messengers, such as MyD88 and other downstream messengers (Figueroa et al., 2012). Additionally, SNP appears to affect the levels of functional expression of TLR4, causing a decrease of 2 times (Prohinar et al., 2010). This reduction is further amplified to 10 times in the absence of myeloid differentiation factor 2 (MD-2) that forms a complex with TLR4 and LPS (Park et al., 2009). This decline in functionality is further amplified before TLR4 and LPS form a complex (Prohinar et al., 2010).

In the present systematic review, most of the studies were observed to come from populations in the United States (5 studies - 18.51%) and the number of studies associated with susceptibility to infectious diseases was higher for the African continent (with 10 studies in all continents −37.03%). Despite the numerical supply of articles and the number of positive associations relating bacterial infections to the present SNP of TLR4, the strength of association of the meta-analysis did not generate a significant degree of due evidence from the analyzed researches, while for viruses there was a significant association. A total of 16 of the 27 studies (59.25%) did not report the ethnic group belonging to the investigated population, most of them coming from the Asian and African continent (5 researches each, with 31.25%) and, with respect to the country, mostly from the United States (with four researches, 25%). Therefore, there is a great bias in reporting these ethnic terms in these studies, especially from the United States.

In our analysis, the most studied diseases for SNP were those caused by bacterial infections (with 17 studies—62.96%), followed by viral infections, with seven studies, equivalent to 25.93% and urinary tract infection (UTI) with two studies (7.4%). The excess percentage was delimited by studies involving parasitic agents (1 study, 3.7%).

The most commonly associated infectious diseases in different countries for TLR4 SNP and susceptibility were those caused by viruses (6 researches, 85.71% in virus subgroup). The infectious diseases that for this SNP were most associated with protection in different countries had several studies in decreasing order among those caused by bacteria infections (n = 9, 33.33%), viruses (n = 1, 3.7%), and UTI (n = 1, 3.7%).

Contradictory findings were found for susceptibility related to the presence of the mutant allele of this SNP and infectious diseases were found in populations around the world and this may be directly related to environmental or even epigenetic factors, associated with the individual genetic background. Conflicting data were found in different populations for the following diseases: reduced risk of periodontitis in Brazilian population (Garlet et al., 2012), and a protective effect was conferred for periodontitis in a United States population (Sellers et al., 2016), while no association between this SNP and periodontitis was found in populations in China and United States (Sahingur et al., 2011; Li et al., 2019); what concerns gram-negative bacteria infection, otitis media has no association with this SNP in the American population (Carroll et al., 2012), a no significant association was observed for susceptibility to E. coli infection in Mexico population (Castro-Alarcón et al., 2019); a protective effect conferred by this SNP in the United States population (Lee et al., 2011), a higher risk of these infections in Greece, India, and United States populations (Liadaki et al., 2011; Janardhanan et al., 2013; Sampath et al., 2013); regarding to UTI, the study conducted by Akil et al., 2012 associated the presence of the mutant allele of this SNP with reduced risk of this disease in Turkey (Akil et al., 2012), while Gond et al., 2018 revealed a higher risk of this infection in India (Gond et al., 2018).

No significant statistical associations were observed for the diseases: periodontitis (in the American and Chinese population) (Sahingur et al., 2011; Li et al., 2019); malaria in the Burundi population (Esposito et al., 2012b); tuberculosis (in Moldavia and Mexico populations) (Torres-García et al., 2013; Varzari et al., 2019); endocarditis in the Russian population (Golovkin et al., 2015); rheumatoid arthritis (in Egyptian population, Netherlands) (Emonts et al., 2011; Taha et al., 2014); otitis media in the American population (Carroll et al., 2012); E. coli infection in Mexico population (Castro-Alarcón et al., 2019).

The data engendered in this study indicate the importance of the main TLR4 (LPS) linker for SNP rs4986790 and infectious agents, since the most associated and studied infectious diseases were infections by Gram-negative bacteria, mediated by LPS, even with nonsignificant association here. This meta-analysis also indicates a new association between infections and this TLR4 SNP with respect to viruses, with 2 times greater risk in this subgroup in a relationship of increased susceptibility to the presence of the mutant allele in individuals from different countries that needs to be further investigated.

In the same way that there are controversial results on susceptibility to infectious diseases, we report the need for immunogenetic studies that are performed in different populations. Furthermore, the study reveals the characterization of pathophysiology in clinical conditions of diseases associated with this SNP. From this perspective, new omic studies can help close the gaps in understanding the extent to which immunogenetics interferes with the outcome of infectious diseases. Therefore, this study provides an overview for the creation of strategies in the field of medicine with respect to the treatment of infectious diseases.