Malaria patients in endemic regions are often co-infected with soil-transmitted helminths. Following infection of the mammalian host the larval stages of certain parasitic helminth species migrate to the lungs of the host where they cause pathology. The larvae typically induce strong pulmonary Th2 immune responses and are accompanied by the induction of alternatively activated macrophages. The combined actions of these immune responses are considered to help mediate parasite clearance and the repair of host tissues. In BALB/c mice infected with hookworms parasites such as Nippostrongylus brasiliensis, the development of a Th2-polarized immune response to the hookworm infection was impaired in those co-infected with P. chabaudi chabaudi malaria parasites. This effect also coincided with the reduced expression of alternatively activated macrophage-derived factors in the lung such as chitinase and resistin family members (6). Similarly, in a separate study the incidence of lung granulomas induced by infection with Litomosoides sigmodontis microfilariae was reduced in mice co-infected with either P. chabaudi or P. yoelii malaria parasites (7). These experimental mouse studies suggest that malaria infection can negatively impact on the ability of the host to induce a Th2-polarized specific immune response to co-infection with helminths. How malaria infection mediates these effects is not known. Further experiments are clearly necessary to determine whether they are a consequence of direct effects of the malaria parasites themselves or are an indirect consequence of the induction of a strong Th1-polarized immune response/cytokine milieu in response to the malaria infection.

Co-infections with parasites such as helminths may also have a significant impact on malaria pathogenesis and susceptibility (8). In mice infected with N. brasiliensis 2 weeks before subsequent infection with P. berghei malaria parasites, the induction of a malaria-driven Th1 cytokine response was impeded, affecting the activation phenotype of the macrophages in the lung (8). Helminth infections can promote the secretion of IL-10 by regulatory T cells (9, 10), and this can downregulate the expression of pro-inflammatory cytokines such as IL-12p70 and IFNγ. Since IFNγ plays an important role in protective immunity to P. falciparum infection, it is plausible that expression of an anti-inflammatory cytokine milieu during helminth infection might exacerbate malaria pathogenesis and susceptibility. In support of this hypothesis, co-infection of mice with the hookworm parasite N. brasiliensis was reported to impede the induction of a pro-inflammatory classically activated macrophage phenotype in the lungs of mice subsequently infected with malaria parasites (8). The induction of an effective Th1 response to P. berghei infection was similarly reduced in mice co-infected with schistosomes (S. mansoni). As a consequence, the co-infected mice were less able to control the malaria infection, displaying increased parasitemias during the early phase of P. berghei infection and increased fatality (11). Mice chronically infected with the gastrointestinal helminth pathogen Heligmosomoides polygyrus before a subsequent P. chabaudi AS infection likewise displayed reduced immunity to the bloodstream stage of malaria infection, including decreased production of IFNγ and malaria-specific Th1-associated IgG2a antibody production (12).

Parasite co-infections may also affect the magnitude of the pathology that develops in host tissues. For example, an exacerbation of immunopathology during P. chabaudi infection was observed in mice co-infected with L. sigmodontis microfilariae (13). The incidence of pathology in the co-infected mice was found to be associated with the absence of microfilaraemia. This implies that the presence of the microfilariae stimulates an immunomodulatory response in the host that can partially protect against severe malaria (13). However, helminth co-infections may differentially regulate murine malarial infections in a malaria strain-dependent way. For example, co-infection of mice with L. sigmodontis impaired the development of lesions in the kidneys caused by infection with either P. chabaudi or P. yoelii. However, the peak of malaria parasitaemia was decreased in mice co-infected P. yoelii, but not in those co-infected with P. chabaudi (7). Conversely, the growth of P. yoelii in the liver was inhibited in mice co-infected with S. mansoni, and malaria parasite gametocyte infectivity was much reduced (14).

Whether co-infections with helminths such as schistosomes can modulate susceptibility to malaria in humans is uncertain, but an experimental study in baboons (Papio anubis) suggests that this also plausible. This study showed that the baboons that were chronically infected with S. mansoni had significantly lower P. knowlesi malaria parasite burdens and were protected from anemia (15). A study of Senegalese children similarly showed that those with light S. haematobium infection had lower burdens of P. falciparum when compared to those that weren't co-infected with schistosomes (16). The mechanisms responsible for mediating these effects are not known. It is possible that the reduced levels of regulatory T cells or a Th2-polarized cytokine milieu in S. haematobium infected children may provide protection against falciparum malaria by modulating systemic expression of Th1 cytokines (17).

Severe forms of malaria are leading causes of mortality in infected children and pregnant mothers, presenting as cerebral malaria, severe anemia, or acidosis (18). The sequestration of malaria parasites across the blood-brain barrier leads to the influx of immune lymphocytes and leukocytes into the brain, particularly parasite-specific CD8⁺ T cells, which ultimately leads to the development of neuropathology. Studies using a murine experimental cerebral malaria (ECM) model show that co-infection with Chikungunya virus can impede the sequestration of malaria parasites into the brain and provide some protection against ECM (19). In this model co-infection system, the malaria parasite-specific pathogenic CD8⁺ T cells appeared to be retained in the spleens of mice co-infected with Chikungunya virus due to their reduced expression of the CXCR3 chemokine receptor (19). This implied that the reduced early migration of pathogenic CD8⁺ T cells into the brains of the virus co-infected mice may have impeded the development of ECM and brain pathology.

Systemic co-infection of mice with the schistosomes (S. mansoni) seven weeks before infection with P. berghei malaria parasites was similarly shown to reduce the severity of ECM (11, 20). In this study, protection from ECM was dependent on the relative doses of the parasites used in the co-infections. Here, infection with a high dose of schistosome cercariae resulted in higher protection against ECM when co-infected with a low dose of P. berghei malaria paratites. Conversely, when the mice were co-infected with S. mansoni and a higher dose of P. berghei, the development of ECM was unaffected when compared to mice infected with malaria parasites alone (21). Development of ECM in mice is considered to be Th1-associated. The switch toward a Th2-polarized cytokine profile in the S. mansoni co-infected mice suggests a mechanism by which the effects on ECM pathogenesis may have been mediated. Clearly further experiments are required to specifically confirm the identify of the cellular and molecular factors responsible for these effects. A predominantly Th1-polarized cytokine profile is observed in mice by 4 weeks after S. mansoni infection (before significant egg production occurs). When mice were co-infected with malaria parasites 4 weeks after S. mansoni infection (prior to the onset of the Th1/Th2 switch), no improvements to ECM pathogenesis were observed (20), supporting the hypothesis that a Th2-polarized cytokine response may have a protective role.

Co-infections with the helminth parasites A. lumbricoides and T. trichiura have also been associated with reductions in risk of cerebral malaria in humans (22). However, it is interesting to note that the beneficial effects of T. trichiura were reduced when the individuals were also co-infected with hookworms (22). This study reveals an additional layer of complexity in naturally affected host-species where the outcome on the host of interactions between two parasite species can be modified by the presence of a third. These data emphasize how the relationships between multiple parasite communities in an individual host can significantly affect disease outcomes.

The liver fluke Fasciola hepatica is highly prevalent in ruminant livestock species, but can also establish infection in a wide range of other mammalian species including humans. Infection of livestock with F. hepatica occurs through the ingestion of pasture contaminated with encysted cercariae. The parasites then migrate through the gut wall and peritoneal cavity to the liver and bile ducts, where they mature and produce large numbers of eggs that are excreted into the environment. In common with many helminth infections, the migrating juvenile parasite stages induce a strong Th2-polarized immune response in the mammalian host. Infection of mice with F. hepatica can down-regulate Th1-responses in vivo, even in IL-4-deficient mice (23) suggesting this is not simply due to the actions of Th2 cells or cytokines. Indeed, the parasites produce a large range of excretory/secretory (ES) molecules that help them to mediate tissue invasion, feeding and immunomodulation (24) including the suppression of IFNγ responses (25).

Bovine tuberculosis (BTB), caused by infection with the bacterium M. bovis is an important pathogen of cattle worldwide and has zoonotic potential. Although some countries have reduced or eliminated BTB, wildlife M. bovis reservoirs and the limitations of diagnostic tests have hindered successful eradication in other regions. The single intradermal comparative cervical tuberculin test (SICCT) and the in vitro IFNγ assay are commonly used to identify M. bovis infected cattle. However, certain parasite co-infections can reduce the sensitivity of these assays. A large-scale epidemiological study in England and Wales showed that in dairy herds with a high incidence of F. hepatica fewer animals were detected as positive reactors against BTB (26). Experiments in cattle confirmed that infection with F. hepatica reduces the sensitivity of the standard BTB tests (SICCT test and IFNγ test) through reduced M. bovis-specific Th1 immune responses (27). However, F. hepatica co-infection did not influence the detection of visible lesions in BTB infected cows (28). These data clearly show how the immunomodulatory effects of F. hepatica on the bovine host can reduce the sensitivity of current pre-mortem BTB tests. This may significantly influence the ability of practical measures to eliminate BTB infections in regions with high prevalence of F. hepatica.

Despite the reduced M. bovis-specific Th1 immunity in cows co-infected with F. hepatica, mycobacterial burdens were shown to be reduced (29). The mechanisms responsible for this are uncertain, but the authors proposed that the actions of alternatively-activated macrophages induced in response to F. hepatica infection may act to limit the proliferation of M. bovis.

In sheep, infections with the liver flukes Dicrocoelium dentriticum or F. hepatica can predispose the ewes to mastitis in the immediate post-partum period (30). Abnormal metabolism of carbohydrates during the later stages of pregnancy in ewes can cause pregnancy toxemia. This disease is associated with hyperketonaeimia, and blood concentrations of the ketone body β-hydroxybutyrate can help detect ewes at risk of developing pregnancy toxemia. Higher concentrations of β-hydroxybutyrate were recorded in trematode-infected ewes (30). Since β-hydroxybutyrate may have immunomodulatory effects, the authors hypothesized that its increased levels in infected ewes may suppress immunity in the udder enhancing the risk of infection at this site (30). This has raised the hypothesis that the use of anthelmintic drugs may also help reduce the incidence of mastitis in trematode-affected flocks.

Finally, infection with the human liver fluke Opisthorchis viverrini is endemic in the Greater Mekong sub-region. This fluke is classified as a group 1 carcinogen by the International Agency for Research on Cancer because chronic infections with O. viverrini can lead to the development of cholangiocarcinoma, a malignant cancer of the bile ducts. In areas of Thailand where flukes are endemic, the Gram-negative bacterium Helicobacter pylori was found in 66.7% of the patients studied that had cholangiocarcinoma (31). This raised the hypothesis that co-infections with H. pylori and with O. viverrini synergistically increases the severity of hepatobiliary abnormalities. Indeed, in an experimental hamster model the severity of the hepatobiliary abnormalities was increased in those that were co-infected with O. viverrini (32).

Infections with schistosomes cause chronic inflammatory disease in humans and animals. The diseases they cause can lead to the development of severe pathology, significant morbidity, and economic loss. Schistosomes are transmitted through the skin via contact with infected water sources inhabited by the snail vector. The parasites establish chronic infections in the mammalian host's bloodstream where they mature, mate, and produce substantial quantities of eggs. The eggs enter the intestines and bladder where they are excreted via feces and urine. Deposition of the eggs in host tissues can cause chronic inflammation, tissue damage and fibrosis. Schistosomes typically induce a Th2-polarized immune response in the mammalian host that enables them to establish chronic infections where they can persist for years (33).

Experiments in mice have shown that a gastrointestinal nematode infection can influence the pathogenesis of a subsequent schistosome infection. A chronic Trichuris muris infection within the large intestine enhanced the survival and migration of S. mansoni schistosomula to the portal system. Consequently, schistosome worm and egg burdens and associated pathology were enhanced when compared to mice infected with S. mansoni alone (34). This suggests that the immunomodulatory effects elicited in the mucosa of the large intestine to enable the gastrointestinal helminth to establish chronic infection can extend to other host tissues. This may exacerbate host susceptibility to subsequent co-infection with other helminth parasites. A similar effect has been reported to occur in a naturally-affected livestock species. A longitudinal study of free-ranging African buffalo reported that animals infected with Cooperia fuelleborni had greater burdens of schistosomes (Schistosoma mattheei) than those where this nematode species was not detected (35). The mechanisms that mediate these effects in the co-infected animals remain to be determined. This could simply represent host variation in susceptibility to gastrointestinal nematodes. However, since infection of cattle with the related gastrointestinal nematode species C. oncophora enhanced their susceptibility to lungworm (Dictyocaulus viviparus) infection (36), it is plausible that nematode-mediated effects on the buffalo immune response may similarly impede the establishment of immunity to schistosomes.

However, it is important to note that data from mouse studies show that differences in the species of the co-infecting parasite may have contrasting effects on schistosome infections (34, 37). The gastrointestinal helminth H. polygyrus establishes infection specifically within the murine duodenum. In mice infected with H. polygyrus a marked reduction in schistosome egg-induced hepatic pathology was observed. This effect appeared to correlate with significant decreases in the expression of pro-inflammatory cytokines responsible for the induction of the egg-induced immunopathology (37). Thus, although co-infection with gastrointestinal helminths may significantly impact on schistosomiasis, the currently available data do not help us to reliably predict whether they are likely to exacerbate or reduce the disease pathogenesis.

African trypanosomes are single-cell extracellular hemoflagellate protozoan parasites and are transmitted between mammalian hosts via blood-feeding tsetse flies of the genus Glossina. The Trypanosoma brucei rhodesiense and T. b. gambiense subspecies cause human African trypanosomiasis in endemic regions within the tsetse fly belt across sub-Saharan Africa. Animal African trypanosomiasis is caused by T. congolense, T. vivax, and T. brucei and inflicts substantial economic strains on the African livestock industry. The parasitic life cycle within the mammalian host is initiated by the intradermal injection of metacyclic trypomastigotes by the tsetse fly vector. The extracellular parasites then reach the draining lymph nodes, presumably via invasion of the afferent lymphatics and then disseminate systemically (38, 39). During this process the metacyclic trypanosome forms differentiate into long slender bloodstream forms that are adapted for survival within the mammalian host. When C57BL/6 mice are infected with T. brucei the initial parasitaemic wave coincides with the expression of high levels of IFNγ by the host in an attempt to control the infection. However, the trypanosomes also cause significant immunosuppression enabling them to establish chronic infections in the hostile environment of the host's bloodstream.

A study has shown that the severity of malaria and trypanosomiasis was exacerbated in mice co-infected with P. berghei and T. brucei (40). In the co-infected mice survival rates were reduced and the parasitaemias were greater, with more severe anemia and hypoglycaemia. Each of these infections induces a strong pro-inflammatory response with high levels of IFNγ. Further studies are necessary to determine whether additive/synergistic effects of each infection on IFNγ expression are responsible for the increased disease severity observed in the co-infected mice.

Trypanosome infections may also modulate host susceptibility to infection with some pathogenic bacteria. For example, in mice chronically-infected with either Brucella melitensis, B. abortus, or B. suis, the burden of bacteria in the spleen was reduced if the mice were also co-infected with T. brucei (41). The effects of T. brucei infection on Brucella burdens in co-infected mice were impeded in the absence of functional IL-12p35/IFNγ signaling. This suggests that the strong pro-inflammatory IFNγ-mediated immune response induced by the T. brucei infection aided the clearance of Brucella. Thus, although infections with T. brucei can induce significant levels of immunosuppression and immunopathology, this study shows that under some circumstances the host's response to T. brucei infection may provide protection against co-infection with other pathogens (41). However, this not true for all pathogenic bacteria. Although Th1 responses are essential for protection against Mycobacterium tuberculosis, T. brucei infection did not ameliorate the susceptibility of mice to co-infection with this pathogenic bacterium (41).

Infection with the obligate intracellular parasite T. cruzi causes Chagas' disease and is an important cause of morbidity and mortality in humans in Central and South America (42). Concurrent infection of mice with S. mansoni can significantly affect disease pathogenesis and susceptibility following infection with T. cruzi (43). The co-infected mice were shown to be unable to effectively control the T. cruzi infection, and the increased parasitic load was accompanied by substantial inflammation in their livers. Infections with T. cruzi are associated with the establishment of a Th1-polarized immune response, and the production of macrophage-derived NO from arginine by inducible NO synthetase (iNOS) is important for parasite clearance. However, during the chronic phase of schistosomiasis high levels of arginase-1 are instead expressed by alternatively activated macrophages. In the S. mansoni co-infected mice, the reduced protection against T. cruzi coincided with the reduced production of IFN-γ and NO (43). This study illustrates how macrophage polarity and the relative expression levels of iNOS and arginase-1 in response to infection with one parasite could influence the host's ability to co-infection with other parasites.

T. gondii is an orally-acquired obligate intracellular protozoan parasite affecting ~30% of the human population. Following oral infection, the parasites typically disseminate systemically and convert into dormant stages in muscle tissues and the brain. Infection with T. gondii elicits a strong Th1-polarized immune response characterized by production of IFNγ, IL-12, and parasite specific IgG2a antibodies. Studies in mice suggest these responses are important for host protection. Infections are typically asymptomatic in immunocompetent humans, but can reactivate in immunocompromised individuals and result in the development of a life-threatening encephalitis.

Although a study has shown that gastrointestinal helminth (H. polygyrus) co-infection did not affect the induction of a protective Th1 response to T. gondii infection (44), the Th2-response to the H. polygyrus infection was impeded. Co-infection with T. gondii in these mice was instead accompanied by a shift toward a non-protective helminth-specific Th1 response (44). Conversely, separate studies have shown that H. polygyrus co-infection can negatively impact upon CD8⁺ T cell differentiation and cytokine production in response to T. gondii infection (45, 46). Conventional dendritic cells from the H. polygyrus co-infected mice also had reduced expression of IL-12 (46). The reasons for the contrasting outcomes in these two studies are not immediately apparent, but are perhaps explained by important differences in their experiment design. In the first study (44), the mice were first infected with T. gondii and 14 days later orally co-infected with H. polygyrus. However, in the other studies (45, 46), the mice were first infected with H. polygyrus and subsequently co-infected with T. gondii parasites.

Although further experiments are necessary to confirm the cellular and molecular mechanisms that underpin these effects, these studies suggest that differences in the order and timing of the infections with two distinct oral pathogens, can significantly influence the host's response to the second. In particular these data imply that the presence of a strong Th1-polarized immune response to an ongoing T. gondii infection can impede the development of Th2-polarized immune responses to a subsequent helminth co-infection (44). However, the induction of CD8+ T-cell responses against T. gondii co-infection is impeded in the presence of an existing Th2-polarized immune response to a gastrointestinal helminth infection.

Eimeria tenella is a major pathogen of chickens causing intestinal coccidiosis. Infection with E. tenella is restricted to the caecum and causes significant morbidity and mortality, including diarrhea, mucosal lesions and weight loss. The prevalence of E. tenella and T. gondii is widespread, suggesting co-infections with these two pathogens may be common. The effect of co-infection of chickens with Eimeria and T. gondii has been addressed in an experimental study (47). However, the pathology and immune response following co-infection with these parasites did not differ significantly from that observed in chickens infected with Eimeria alone. Co-infection with Eimeria also did not affect the abundance of T. gondii-positive tissue samples or the clinical course of T. gondii infection. Distinct T. gondii strain types have been characterized in Europe and North America (type I, II, and III) and these can significantly influence the virulence and severity of the disease in different host species (48). For example, chickens are generally considered refractory to infection with type I or II oocysts (49, 50), but they may cause severe disease in other host species such as mice (51). Whereas, co-infection of chickens with two common apicomplexan parasites did not reveal any significant mutual effects on disease pathogenesis (47), a study of wild rabbits in Scotland suggested a link between T. gondii infection and higher burdens of E. stiedae (52). Whether differences in the virulence of T. gondii infection in different host species could have a significant impact on their susceptibility to co-infection with other pathogens remains to be determined. Of course, the possibility also cannot be excluded that the rabbits with high Eimeria burdens had high susceptibility to orally-acquired parasite infections.

Infection with Giardia duodenalis (syn. G. intestinalis, or G. lamblia) is a leading cause of waterborne diarrhoeal disease. The characteristic signs of Giardiasis include diarrhea, abdominal pain, nausea, vomiting, and anorexia, with some individuals also developing extra-intestinal and post-infectious complications. Little is currently known of the effects of parasite co-infections on susceptibility to giardiasis. A study of 3 year old children in the Quininde district of Ecuador has shown that those co-infected with the gastrointestinal helminth A. lumbricoides had plasma cytokine profiles indicative of an increased Th2/Th1 cytokine bias, and significantly lower plasma levels of IL-2 and TNF-α when compared to those infected with G. lamblia alone (53). Studies from mouse models have shown that expression of TNF-α is essential for resistance to G. lamblia infection (54). Little is known of the mechanisms that are essential for protection of humans against Giardia infections. However, it is plausible that the effects of Ascaris infection on TNF-α expression may have negatively affected the ability of the children to eradicate Giardia.

Oral infections with the Gram negative bacterium Salmonella, through consumption of contaminated food such as meat, eggs, or milk are amongst the most common causes of diarrhea. Co-infections with distinct parasites, helminths, and malaria parasites, have each been shown to exacerbate susceptibility to, or the pathogenesis of, salmonellosis.

Many of the examples discussed above have suggested a link between the induction of a Th2-polarized immune response to helminth infection and the reduced development of Th1-polarized immunity to co-infection with other pathogens. However, co-infection of mice with the gastrointestinal helminth H. polygyrus has also been shown to enhance the pathogenesis of infection with Salmonella enterica serovar Typhimurium independently of the actions of Th2 cells and regulatory T cells (55). Here, co-infection with H. polygyrus has been reported to disrupt the metabolic profile within the small intestine, and by doing so, directly affect the invasive capacity of S. typhimurium. This helminth infection was shown to mediate this effect through the enhancement of bacterial expression of Salmonella pathogenicity island 1 (SPI-1) genes (55). This study reveals a novel immune system-independent mechanism by which a helminth-modified metabolome in the host's intestine can promote susceptibility to bacterial co-infection.

Invasive nontyphoid Salmonella (NTS) bacteraemia is a common cause of community-acquired bacteraemia in the human populations of several regions of sub-Saharan Africa (56). Associations between NTS co-infection and high malaria mortality have been reported (57), and a study of hospitalized children in north-eastern Tanzania showed that a decline in malaria cases was associated with a similar decline in the incidence of NTS and other forms of bacteraemia (58).

Since malaria parasites establish infection within erythrocytes, the daily rounds of parasite replication within these cells can cause high levels of erythrocyte lysis and haemolysis, resulting in anemia. The association of NTS infection with haemolysis is well-established in humans with malaria, especially in patients with severe malarial anemia (59). This haemolysis releases large quantities of cell-free haeme which is toxic to the host. To counter this cytotoxicity, haeme oxygenase 1 (HO-1) expression is induced to degrade the haeme and provide tolerance toward some of the pathological consequences of malaria infection. The actions of HO-1 also provide an additional cytoprotective role by limiting the production of reactive oxygen species (60). However, data from mice (61) and from the analysis of neutrophils from malaria-infected children (62) show that the actions of HO-1 in granulocytes in response to haemolysis during malaria infection impedes their oxidative burst activity and production of reactive oxygen species. This leads to dysfunctional granulocyte mobilization and long-term neutrophil dysfunction. As a consequence, Salmonella are able to survive and proliferate within neutrophils during malaria infection due to their decreased oxidative burst activity, leading to increased NTS susceptibility (61, 62). These data clearly show how a host-induced cytoprotective response to one of the pathological consequences of malaria infection (haemolysis) can significantly impair neutrophil-mediated resistance to co-infection with another pathogen.

Infection with the obligate intracellular bacterium M. tuberculosis causes tuberculosis (TB), a chronic disease affecting ~2 billion people worldwide. This infection typically affects the lungs, and the majority of individuals infected with M. tuberculosis have latent infections and are asymptomatic. However, data from various clinical studies in humans have raised the hypothesis that helminth co-infections may affect TB susceptibility and the risk of developing latent M. tuberculosis infection, as co-infected patients often displayed more advanced disease (63, 64). Gastrointestinal helminth infections may also modulate susceptibility and/or disease pathogenesis to co-infection with other pathogenic Mycobacteria spp. Infection with M. leprae or M. lepromatis causes leprosy, a chronic granulomatous infectious disease. A study of Indonesian patients infected with M. lepromatis reported that those with gastrointestinal helminth infections (e.g., T. trichiura, Stongyloides sterocalis) similarly presented with more severe types of leprosy (65).

Studies from animal models, especially mice, indicate that protection against TB infection is dependent upon the induction of a strong pro-inflammatory Th1-polarized immune response and production of IFNγ, IL-12, and TNF-α, as well as contribution from Th17 cells and IL-17 and IL-23 (66, 67). The immune response induced by co-infection with gastrointestinal helminths may affect immunity to M. tuberculosis through a range of distinct mechanisms, including the induction of regulatory T cell responses (68), modulation of Th1 and Th17 responses to the bacterial infection and reduced expression of effector cytokines (69–71). The increased expression of Th2 cytokines, especially IL-4, in mice co-infected with helminths also promotes the induction of alternatively activated macrophages. These cells have been shown to be less effective than pro-inflammatory IFNγ-stimulated macrophages in controlling M. tuberculosis (72, 73). Indeed, antigens from helminths such as T. muris and Hymenolepis diminuta (tapeworms) can induce an alternatively activated phenotype in human macrophages, reducing their ability to control M. tuberculosis infection in vitro (74). However, mouse studies show that under some circumstances the acute host response to helminth infection might enhance the early control of M. tuberculosis infection by alveolar macrophages (75).

Although the induction of T cell responses is considered essential for protective immunity against TB infection, B cells, and the production of mycobacterial-specific antibodies have also been proposed to play an important role (76). However, helminth infections can also influence B cell responses to M. tuberculosis infection. Co-infection of humans with Strongyloides stercoralis has been shown to affect B cell responses during latent tuberculosis infection, significantly reducing B cell numbers, the induction of mycobacterial-specific IgM and IgG resopnses and expression levels of the B-cell growth factors APRIL and BAFF (77). These helminth-associated impairments to mycobacteria-specific B cell responses could have significant implications for the efficacy of vaccine-induced immune responses to TB in affected regions. However, a clinical trial study in healthy, previously BCG vaccinated adolescents reported that helminth co-infection (S. mansoni did not impact on the efficacy of a candidate viral vector-based TB vaccine (78).

A study of goats in Nigeria revealed that the incidence of pneumonia corresponded with the presence of gastrointestinal parasitism in the same animals (79). Furthermore, a strong association was observed between the occurrence of helminth infections and granulomatous pneumonia. In this study the affected goats were often hydrated, implying that the gastrointestinal helminth infections may have caused pulmonary oedema due to increased fluid accumulation in the lung. The authors suggested that may this have reduced the efficacy of immunity in the lung, enabling other pathogenic microorganisms (bacteria and/or viruses) to establish infection and the subsequent development of pneumonia (79).

The zoonotic bacterium E. coli O157 is a worldwide problem for public health causing haemorrhagic diarrhea in infected humans. Cattle are considered the major reservoir for human infection, and infection in these animals is usually asymptomatic. A study of 14 British farms suggested that co-infection with the liver fluke F. hepatica may increase the risk of E. coli O157 shedding (80). This implies that strategies aimed at controlling F. hepatica infection may have additional benefit by reducing the shedding of E. coli O157.

Giardia lamblia and enteroaggregative E. coli are two of the most commonly isolated pathogens in malnourished children. Mice fed on a protein-deficient diet were used to model the pathogenesis of co-infection with these pathogens in malnourished individuals (81). The malnourished mice fed a protein-deficient diet exhibited significantly greater weight loss following co-infection with G. lamblia and enteroaggregative E. coli when compared to co-infected mice that received a normal diet. This study reveals how the combined effects of the composition of the host's diet and pathogen infection can affect disease pathogenicity. Studies using a laboratory biofilm system to mimic the human gut microbiota have revealed that G. duodenalis can cause significant dysbiosis. These effects were mediated in part through the actions of secretory-excretory Giardia cysteine proteases, and these could promote gut epithelial cell apoptosis, tight junction disruption, and bacterial translocation across the gut epithelium (82).

Despite the ability of Giardia infection to cause intestinal dysbiosis, in countries with poor standards of sanitation Giardia infection has been associated with decreased incidence of diarrhoeal disease. This raised the hypothesis that infection with Giardia spp. might modulate host responses to co-infection with attaching and effacing enteropathogens. Weight loss, pathological signs of colitis and bacterial colonization and translocation were significantly attenuated in mice co-infected with G. muris and the attaching and effacing enteropathogen Citrobacter rodentium (83). These effects coincided with enhanced secretion of the antimicrobial factors β-defensin 2 and trefoil factor 3 by gut epithelial cells during co-infection (83). This suggests that components of the host response to infection with Giardia spp. (e.g., production of antimicrobial factors) may reduce susceptibility to gastrointestinal co-infection with certain pathogenic bacteria. These studies also highlight how differences in the anatomical niches that the parasites inhabit may also have a significant influence on the disease pathogenesis of a bacterial co-infection. When pathogens infect the same niche such as the gastrointestinal tract, infection with Giardia spp. may provide protection against bacterial co-infection (83). Conversely, infection with F. hepatica in the liver was associated with the enhanced pathogenesis of a bacterial co-infection in the intestine (80).

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.