Abstract
Numerous species of nematodes have evolved to inhabit the gastrointestinal tract of animals and humans, with over a billion of the world’s population infected with at least one species. These large multicellular pathogens present a considerable and complex challenge to the host immune system given that individuals are continually exposed to infective stages, as well as the high prevalence in endemic areas. This review summarizes our current understanding of host–parasite interactions, detailing induction of protective immunity, mechanisms of resistance, and resolution of the response. It is clear from studies of well-defined laboratory model systems that these responses are dominated by innate and adaptive type 2 cytokine responses, regulating cellular and soluble effectors that serve to disrupt the niche in which the parasites live by strengthening the physical mucosal barrier and ultimately promoting tissue repair.
Similar content being viewed by others
Helminths and humans
Nature is rife with parasitism, and it has been estimated that one fifth of all humans are hosting one or more species of gastrointestinal nematode.1 As with many other pathogens, parasitic worm infections are prevalent among children in developing countries where hygienic conditions are poor, with symptoms ranging from abdominal pain and mild anemia to diarrhea, stunted growth, and impaired cognitive development; a tragedy given that most nematodes are easily avoided by improvements in basic hygiene, such as access to clean drinking water. Efforts to treat infected individuals with antihelminthic drugs are thus rendered relatively ineffective in the long term because of continued exposure to infective eggs and larvae in the immediate environment, frequently resulting in reinfection.
With that being said, some parasites might incur benefits as well. Epidemiological data demonstrate that over the past decades there has been a steady rise in both the prevalence and incidence of various immune-associated disorders,2, 3, 4 whereas the occurrence of parasite infections has decreased dramatically.5 This inverse correlation has given rise to the hygiene hypothesis that, as the name implies, proposes that excessive cleanliness alters the balance of the immune system (in part because of the lack of parasite exposure), thus resulting in aberrant reactions to harmless environmental molecules, food antigens, or the body itself. Given that our species evolved in close contact with a diverse array of pathogens, this explanation is certainly plausible,6, 7 so much so that some have considered using worm infections as treatment, notably for inflammatory bowel disease.8, 9 Regardless, it is clear that parasites have had, and will continue to have, a significant impact on our species in the foreseeable future. Hence, understanding the complex interaction between gastrointestinal parasites and the mucosal immune system is of crucial importance, not just for the development of improved antihelminthic therapies, but also for potential treatments targeting inflammatory and autoimmune disorders.
Here we describe the cellular and molecular mechanisms that promote protective immunity to enteric roundworm infection. Much of our current understanding comes from wild rodent parasites that have been adopted for laboratory use, including Heligmosomoides polygyrus,10 Nippostrongylus brasiliensis,11 Trichinella spiralis,12 and Trichuris muris,13 that closely mimic human helminth infections. Although the life cycles of these nematodes vary greatly, a crucial part of their lifespans is spent in the intestinal tract where a distinct form of protective immunity is elicited, namely type 2 immunity.
Type 2 immunity
Nematode infections are fundamentally different from other pathogen encounters. Whereas the average bacterium is ∼2 μm in length, adult worms can be several hundred times larger than the typical immune cell. As a consequence, the essential physiological and immunological mechanisms required for the expulsion of parasitic worms are altogether different from those elicited in response to bacterial, fungal, or viral infections. The type 2 response entails several biological processes that serve to disrupt the parasite niche by strengthening the physical barrier and promoting tissue repair. These mechanisms are highly coordinated and involve several different cell types and effector molecules that have been implicated at various stages of the response (Figure 1).
DETECTION
Although the early events after gastrointestinal nematode infection are poorly understood, epithelial cells are clearly the first host cells to come in contact with parasite larvae once the mucus barrier has been breached (Figure 1a). Whether or not these cells survive the assault and are capable of responding to infection is unknown. Alternatively, healthy epithelial cells adjacent to infected ones might sense secreted parasite-derived molecules and/or tissue-derived damage-associated molecules to initiate the inflammatory cascade. Regardless, mice in which nuclear factor-κB signaling is abrogated specifically in epithelial cells are incapable of generating protective immunity upon T. muris infection and thus cannot expel the worms,14 strongly indicating that there is need for epithelial activation before immune engagement. Indeed, recent evidence from H. polygyrus, N. brasiliensis, and T. spiralis infections demonstrates that specialized chemosensory epithelial cells called tuft cells expand upon infection and are critical for providing the early signals that drive type 2 immunity.15, 16, 17 It is unclear whether the larvae are sensed directly by tuft cells or indirectly via signals from other epithelial cell subsets before activation. Nevertheless, mice that lack intestinal tuft cells do not expel N. brasiliensis,15 thus implicating the epithelium in the generation of protective immunity.
The precise parasite-derived antigens being recognized by epithelial cells are largely unknown. A possible candidate is the polysaccharide chitin; one of the main components of the nematode egg, and expressed in the secretory apparatus of larvae and during molting. Chitin elicits strong type 2 immunity in the lung mucosa,18, 19 and acidic mammalian chitinase, which is predominantly expressed by certain pulmonary20 and gastrointestinal21 epithelial cells, is required for optimal protection against both N. brasiliensis and H. polygyrus infections.22 However, as chitin is also a major part of the fungal cell wall, it alone is an insufficient explanation for the induction of antiparasitic immunity. Given that intestinal nematodes tend to cause more tissue destruction than other pathogens (because of their sheer size and invasiveness), it is perhaps more plausible that type 2 immunity results from combined recognition of both endogenous damage-associated alarmins and worm-derived molecules that become available for uptake after larval molting (including chitin), as well as parasite-derived antigens that are continuously secreted throughout infection. Cholinergic neurons, which innervate the mucosal tissue, were recently shown to promote type 2 immunity in response to secreted products from N. brasiliensis,23 lending credence to this hypothesis. However, the exact mechanisms of detection remain to be elucidated.
TRANSMISSION
Once a parasite has been detected by the epithelium and/or other nonhematopoietic cells, the signal is transmitted to cells of the innate immune system so that an appropriate inflammatory cascade can be initiated (Figure 1a). Whereas neurons relay their signals via the neurotransmitter neuromedin U,23, 24 the main epithelial-derived cytokines implicated in the early generation of type 2 immunity are interleukin (IL)-25,25, 26, 27, 28 IL-33,29, 30, 31 and thymic stromal lymphopoietin (TSLP)14, 32, 33 that strongly synergize and prompt the release of IL-4, IL-5, IL-9, and IL-13 from various sources, notably type 2 innate lymphoid cells (ILC2).15, 16, 17, 25, 34, 35, 36, 37, 38 Epithelium-derived IL-25 and IL-33, in particular, are important for driving IL-5 and IL-13 production from ILC2, the latter of which induces a number of responses, including goblet and tuft cell expansion, resulting in a strong positive feedback loop with increased production of IL-25 by epithelial cells.15, 16, 17, 31, 34, 35, 36, 37 As a consequence, mice lacking IL-25 have less efficient expulsion of T. muris,26 T. spiralis,39 N. brasiliensis,25, 27, 40 and H. polygyrus28 worms. Furthermore, exogenous administration of IL-25 fails to restore expulsion in il13−/− mice,25, 27 whereas the reverse is true,15, 17 illustrating that IL-25 acts upstream of IL-13 rather than directly on expulsion. Strikingly, exogenous administration of IL-25 in the early stages of N. brasiliensis infection results in worm clearance in both wild-type and rag1–/– mice,25 strongly suggesting that at high enough concentrations of IL-25, ILC2 activation can overcome T- and B-cell deficiency (which normally is associated with chronicity). It should also be noted that although epithelial tuft cells appear to be the main producers of IL-25 in mice,15, 17 human eosinophils and basophils are capable of secreting this cytokine as well.41 Nevertheless, mice that lack the IL-25-regulating protein Act1 specifically in epithelial cells cannot expel N. brasiliensis,42 further emphasizing the importance of epithelial-derived IL-25 in mediating type 2 immunity.
Whereas IL-25 is predominantly tuft cell derived, IL-33 is expressed by several epithelial cell subsets,17 as well as some hematopoietic cell types.43, 44 It belongs to the IL-1 family of cytokines and is thus translated in a proform that can be further processed. However, in contrast to IL-1β and IL-18, IL-33 is biologically active before cleavage and can localize to the nucleus where it binds chromatin, which is augmented upon T. spiralis infection.45 Its precise role is unclear46 but it appears to be inactivated rather than activated upon cleavage by caspase-1,47 thus preventing its function as an epithelial-derived alarmin under normal conditions. In contrast, once IL-33 is released in the setting of tissue damage, it can be further activated by granulocyte-derived proteases to exert its function.48, 49 Much like IL-25, it is important for driving IL-13 production by ILC2 during infection31, 35 and can also be recognized by other cell types.50, 51, 52, 53 Furthermore, whereas exogenous administration of IL-33 at early time points after T. muris infection promotes worm clearance, injection at later stages of infection does not induce expulsion,29 suggesting that there is an early window of opportunity in which it exerts its effects. The relative importance of IL-33 as compared with IL-25 is not clear, as there is some functional redundancy between the two, and it thus remains to be determined whether both are equally important upon parasite infection.
Another function of IL-33 is to induce the expression of TSLP in the epithelium.29 The data on TSLP during parasite infections are sparse, but unlike IL-25 and IL-33, which are critical for the expulsion of multiple parasites, TSLP appears to be involved only during T. muris but not N. brasiliensis or H. polygyrus infections,14, 32, 33 and this is understandable given that TSLP is mainly expressed in the large intestine.33 TSLP can be directly recognized by dendritic cells54 as well as basophils,55 again suggesting that epithelial-derived cytokines can bypass ILC2. Indeed, although the main target of IL-25, IL-33, and TSLP appear to be ILC2, it should be noted that both murine and human memory T cells are strongly activated by IL-25,41, 53 IL-33,53, 56, 57 and TSLP,53, 58 without the need for T-cell receptor engagement,57, 59 thus being able to respond to antigen nonspecifically. Hence, it remains to be determined what the target cells are for these cytokines, and whether ILCs are truly critical for antiparasitic immunity in previously challenged hosts.
In contrast to epithelial-derived alarmins, the hematopoietic-derived cytokines are involved during both early and late stages of infection, making it difficult to distinguish between their effects on transmission, induction, and expulsion. Nevertheless, IL-13 is by all accounts the most pivotal, being required for protection against most parasitic nematodes,60, 61, 62, 63 perhaps for its role in supporting the migration of dendritic cells that subsequently drive adaptive immunity.64, 65 IL-13 is also critical for inducing many of the expulsion mechanisms in the intestine that will be discussed further on. Although IL-4, IL-5, IL-9, and IL-13 have distinct functions, there is considerable redundancy between them. For instance, although IL-4 deficiency strongly affects the expulsion of T. spiralis in C57BL/6 mice, BALB/c mice are not affected by the lack of this cytokine, whereas IL-13 deficiency is equally debilitating in both strains.63 Similarly, female mice are resistant to T. muris infection in the absence of IL-4 (in contrast to their male counterparts) mostly because of a stronger propensity for IL-13 production.66 Furthermore, with the exception of IL-4 in the skin,67 IL-4 appears to be dispensable for N. brasiliensis expulsion.61, 68 The redundancy between IL-4 and IL-13 likely stems from their shared usage of the IL-4Rα subunit,69, 70, 71 although interestingly, IL-4Rα deficiency in T cells has no impact on worm expulsion during either T. spiralis,72 H. polygyrus,73 or N. brasiliensis61, 62 infections, in contrast to total IL-4Rα ablation.63, 73, 74, 75 Instead, IL-4 might need to be produced rather than recognized by T cells, as it is mostly secreted by follicular helper T cells to promote IgG1 class switching of B cells.68 Nonetheless, IL-4 production by ILC2 has recently been implicated in the generation of protective T cell immunity to H. polygyrus, and interestingly was dependent on leukotriene D4.76 Leukotriene D4 did not induce IL-13 or IL-5 expression that as mentioned is mainly promoted by IL-25 and IL-33, illustrating a compartmentalized activation mechanism. IL-4 is also produced by basophils68, 77, 78 that also is more likely to be important for humoral immunity and thus play a role during challenge infections.
IL-5 has a complicated and context-dependent role in type 2 immunity. As with IL-13, it is secreted mainly by ILC2, but functions predominantly as an eosinophil recruitment and growth factor.79, 80, 81 Eosinophils, which make up only a fraction of circulating leukocytes, are relatively abundant in the intestinal tract82 and have traditionally been associated with combating parasites. There are little data, however, to suggest that deficiency in either IL-5 or eosinophils affects the polarization of protective immunity or by extension the outcome of infection, despite that eosinophil-derived mediators can skew dendritic cells to promote type 2 immunity.83, 84 Thus, eosinophils do not appear to be critical for the generation of T helper cell type 2 (Th2) immunity or clearance of T. muris,85 and blocking IL-5 does not affect H. polygyrus expulsion despite significantly decreasing eosinophil numbers.86 If anything, eosinophils act positively on the fecundity of H. polygyrus worms.87 However, mice that overexpress IL-5 have massive systemic eosinophilia and are less susceptible to N. brasiliensis,88 whereas eosinophil-deficient mice are unimpaired in their ability to expel,89 illustrating that IL-5 has additional unknown functions beyond those associated with eosinophils.
As with the role of IL-5 in promoting eosinophil responses, IL-9 acts mainly as a maturation factor for mucosal mast cells,90, 91, 92 and is largely T cell derived,93, 94, 95 although it can be secreted by ILC2,96 as well as by mast cells themselves97, 98 that in turn promote enhanced secretion of IL-25, IL-33, and TSLP from epithelial cells.99 As a result, T. muris and H. polygyrus expulsion are impaired in mast cell-deficient mice99, 100 as well as upon administration of neutralizing IL-9 antibodies,101, 102 although it should be noted that studies using mast cell-deficient mice (c-kit mutants) suffer from possible confounding factors given the role for c-kit on many other cell types, and thus remain to be clarified. Interestingly, a recent study also found that mast cells not only can respond to IL-33 but might also enhance the transmission of type 2 signals by the production of IL-33 in response to adenosine triphosphate release by dying epithelial cells.44
INDUCTION
Once the innate immune system has been alerted to the presence of intestinal parasites, it must propagate the signal to the mesenteric lymph nodes and engage the adaptive immune system, a task mainly accomplished by conventional dendritic cells (Figure 1b). Intestinal dendritic cells can be classified into at least three distinct subsets based on their sole or combined expression of CD11b and CD103, as well as the dependence on either interferon regulatory factor 4 or 8 (IRF4 or IRF8) for their development and/or survival.103 All three subsets are capable of processing antigens, migrating to mesenteric lymph nodes upon activation, and priming naive T cells.103 However, recent evidence across various infection and allergy models demonstrates a dominant role for IRF4-dependent CD11b+ dendritic cells in the induction of Th2 immunity,52, 104, 105, 106, 107, 108, 109, 110, 111 notably during infection with N. brasiliensis,104, 105 T. muris,106, 107 and the parasitic trematode Schistosoma mansoni.106, 108, 109 Conversely, IRF8-dependent CD103+ dendritic cells are important for the generation of type 1 responses of both helper112, 113 and cytotoxic114, 115 T cells, thus promoting T. muris113 and H. polygyrus116 chronicity. Together, these studies demonstrate that specialized subsets of dendritic cells are responsible for the induction of distinct types of adaptive immunity. Although the precise mechanisms behind this compartmentalization are unclear, they likely involve both cell-intrinsic signals and external factors that actively promote the generation of protective immunity and vice versa. One such example is the phosphatase SHIP-1 that, if specifically deleted from dendritic cells, results in impaired T. muris expulsion, likely because of enhanced production of IL-12.117 Similarly, the expression of CD40,118 OX40 ligand,119 and nuclear factor-κB120 have all been implicated in the ability of dendritic cells to generate optimal Th2 immunity in response to S. mansoni egg-derived antigens, suggesting that levels of costimulation might be a critical factor in determining the outcome of priming. In contrast, expression of the transforming growth factor-β-activating integrin αvβ8 promotes chronicity, with mice becoming resistant to T. muris infection when αvβ8 is lacking on dendritic cells.121 Similarly, the MAP3 (mitogen-activated protein kinase kinase kinase) kinase TPL-2 was also shown to modulate immunity to H. polygyrus, as its deletion in dendritic cells resulted in enhanced resistance to infection that was attributed to its downstream influence on the homing of leukocytes.122 Indeed, different dendritic cell subsets have divergent expression of certain cytokine and pattern-recognition receptors,123, 124, 125, 126 and might thus be inherently more or less prone to respond to specific pathogens and cytokines to begin with. These types of signals, in combination with cell-extrinsic cues from epithelial and innate immune cells, could determine which type of dendritic cell that gets activated upon parasite infection. Moreover, the nature of the initial stimulus is also likely to have an impact on the resulting response.127 For instance, dendritic cells in the skin of mice that are exposed to N. brasiliensis larvae or the contact sensitizer dibutyl phthalate (both of which induce type 2 immunity) acquire distinct transcriptional profiles, revealing a previously unappreciated role for type I interferons during parasite infection,128 and highlighting the complicated nature of pathogen recognition by the innate immune system.
Interestingly, some studies suggest that ILC,129, 130, 131 basophils,132, 133, 134 and eosinophils135, 136 can express major histocompatibility complex class II and directly prime Th2 responses, notably upon N. brasiliensis131 and T. muris132 infections, with each cell type having been shown to migrate to the mesenteric lymph nodes during infection.85, 87, 137, 138 However, given that protective immunity is abolished in mice where all139, 140 or specific subsets104, 105, 106, 108, 109 of dendritic cells have been depleted, it is perhaps more likely that these other innate cells contribute to local tissue immunity by promoting dendritic cell activation, or by further enhancing the cytokine response of mature T cells that have migrated to the infected tissue.53 Moreover, dendritic cells are responsive not only to cytokines produced by other innate cells, but also to epithelium-derived cytokines, including TSLP,54, 141, 142, 143 IL-25,144 and IL-33,52, 145 thus potentially bypassing ILC2 and granulocytes entirely.
The induction of adaptive immunity is paramount for protection against gastrointestinal nematodes, with T cells no doubt playing a critical role in worm expulsion, as is evident in athymic or lymphopenic mice infected with T. spiralis,146, 147 N. brasiliensis,148, 149 T. muris150, 151 and H. polygyrus.149, 152 Immunity is mediated by helper T cells rather than cytotoxic T cells, as shown by the neutralization of CD4+ but not CD8+ cells153, 154 and by adoptive transfer of CD4+ T cells from previously infected mice that confers protection in normally susceptible lymphopenic mice.155, 156 In contrast, the role of B cells in the immune response to nematode infection is more context dependent. For instance, mice that lack mature B cells appear to have less efficient expulsion of T. muris.157 However, adoptive transfer of B cells alone from previously infected mice is insufficient to confer resistance to T. muris infection,158 whereas transfer of IgA159 or IgG1 (refs. 160, 161) antibodies from resistant mice confers partial resistance to various nematodes, most likely because of their neutralizing effect on secreted parasite antigens, or by trapping larvae.162, 163, 164, 165 Given that adoptive transfer of helper T cells from previously infected mice to lymphopenic mice can confer resistance, these findings suggest that B cells might play a role in promoting the generation and/or polarization of the T-cell response, either by cytokine secretion or antigen presentation166, 167 rather than directly affecting worm expulsion. Antibodies might instead play a role upon secondary challenge, if not during primary infections, as was shown for H. polygyrus.165, 168
Resistance to intestinal nematode infections is clearly dependent on the induction of adaptive immunity, particularly T cells. However, some data suggest that T cell-derived IL-4 and IL-13 are dispensable for parasite expulsion, at least in the case of N. brasiliensis infection,38, 169 and can be provided by innate sources instead. T cells might on the other hand be the more important source of IL-9. As such, Th9 cells have been suggested to be distinct from Th2 cells and mediate expulsion of N. brasiliensis95 and T. spiralis.39 Given that T cells represent a much larger pool of effector cells in most infectious contexts, and can respond in a similar way to innate cells the relative importance of innate and adaptive immunity remains to be established. It is also worth emphasizing that these questions relate to primary infections only, most often given as a large bolus of infectious stages. It must be remembered that naturally occurring infections by these parasites will be through repeated challenge with low numbers of eggs or larvae throughout life, and this may well influence the dynamics of the host response and the relative contributions of the different immune components to the partial resistance that is usually generated.
EXPULSION
Once adaptive immunity has been induced in the local lymph nodes, activated effector cells must home back to the site of infection where expulsion can take place. Ejection of gastrointestinal nematodes relies on a combination of physiological mechanisms that include enhanced mucus secretion by goblet cells, release of neutralizing proteins by granulocytes and epithelial cells, epithelial hyperproliferation, and increased intestinal peristalsis (Figure 1c), perhaps the most important of which is augmented production of mucins. Mucins trap worms by impeding motility, and hence mice lacking mucin 2 (the predominant glycoprotein of the mucus layer) are rendered susceptible to T. muris infection and show delayed worm expulsion,170 illustrating the importance of this barrier. Nonetheless, T. muris and other nematode larvae are still able to penetrate the mucus layer of mucin-proficient mice upon infection, indicating that they have evolved strategies to circumvent this barrier. Indeed, one of the main secreted proteins of T. muris is a serine protease with the capacity to degrade Muc 2.171 The type 2 immune response, however, acts not only to increase goblet cell proliferation and mucus production, but also by modifying existing mucins by sulphation172 and switching to secretion of Muc5ac that is resistant to degradation.171 In addition, the host can produce serine-protease inhibitors that prevent further loss of mucin 2.171 Consistent with these data, Muc5ac is only upregulated in resistant mouse strains170 and Muc5ac-deficient mice have impaired expulsion of T. muris, N. brasiliensis, and T. spiralis.173 Increased mucus production and the mucin switch are largely driven by IL-13,173 IL-4,174 and IL-22,175 but the principle of physical obstruction provided by mucus layers can also be extended to other mucosal sites such as the lungs where the lectin surfactant protein-D, which acts as a lubricant, is needed for optimal protection against the pulmonary stage of N. brasiliensis infection.176
Another expulsion mechanism is the release of various proteins by activated granulocytes and epithelial cells, most of which are toxic to parasites. The relative contribution of each molecule is highly context dependent. For instance, although eosinophils release a plethora of proteins that are potent in killing worms in vitro,177, 178 eosinophils appear to be dispensable during most worm infections given that eosinophil-deficient mice are resistant seemingly despite their thinner mucus layer.179 Mast cells on the other hand contribute to worm expulsion through the release of various proteases that serve to loosen tight junctions between epithelial cells, thus aiding in the shedding of embedded worms, notably during T. spiralis infection.180, 181, 182 However, mast cells appear to be unessential for the expulsion of N. brasiliensis infection,183, 184, 185 illustrating the context-specific nature of these responses. Goblet cells also secrete several molecules in addition to mucins that contribute to expulsion.186, 187, 188 Resistin-like molecule-β (RELMβ), in particular, prevents lumen-dwelling worms from feeding by effectively coating their cuticle, thus hampering growth as well as blocking motility and attachment to the host epithelium.186, 188 RELMβ expression is highly increased in the intestinal epithelium during several parasite infections186 (likely induced by ILC2) and is involved in the expulsion of H. polygyrus.188 It might also be required for efficient expulsion of N. brasiliensis, although the data are conflicting.188, 189 In contrast, there seems to be no role for RELMβ in the expulsion of T. spiralis or T. muris.187, 188 RELMα, on the other hand, is mainly expressed in the pulmonary epithelium and might be important for combating the pulmonary stage of N. brasiliensis.189 RELMα is further implicated in the function of alternatively activated macrophages, highlighting its role in type 2 immune responses.
After being trapped in mucus and coated by various toxic proteins and neutralizing antibodies, worms are expelled by a combination of increased epithelial proliferation and intestinal peristalsis. The precise contribution of each mechanism likely depends on the parasite in question. For instance, accelerated epithelial turnover might be more important for expulsion of T. muris worms that preferentially infect epithelial cells. Because of its rapid turnover, T. muris worms thus need to continuously burrow through the epithelium in order to remain within their niche. Accordingly, epithelial hyperproliferation serves to shift the epithelium outward from the crypts. In contrast, peristalsis might be of more relevance during H. polygyrus infection, given that the worms enter the lamina propria and resurface to wrap around the villi rather than specifically infecting the epithelium, as is the case for T. muris. Peristalsis could therefore aid in shedding infected cells that the parasite is attached to. Increased epithelial turnover in response to T. muris infection seems to occur mainly in resistant mouse strains, largely driven by IL-13,190 and as such, signaling pathways that regulate the proliferation of epithelial stem cells such as the lysine methyltransferase Setd7 affect the outcome of T. muris infection, but not H. polygyrus infection.191 Intestinal peristalsis is mediated by contraction of smooth muscle cells, and is induced by both IL-9 (ref. 102), IL-4 and IL-13,27, 73, 192 and seems to be controlled mainly by T cells. Thus, the responsiveness of smooth muscle cells to neurotransmitters that control contraction via muscarinic receptors are important for N. brasiliensis expulsion.193 Most of the available data on gut peristalsis during nematode infection are however highly correlative73, 102 and its importance remains to be established. Nevertheless, together these mechanisms effectively expel the invading parasite.
RESOLUTION
When a worm infection has been cleared, inflammation is resolved and the damaged tissue must be repaired. This process is partly orchestrated by type 2 cytokines and involves several cell types, notably macrophages and eosinophils (Figure 1c). Thus, despite being redundant for the expulsion of most nematodes, eosinophils might be important for wound healing and tissue regeneration in which they have been implicated in nonmucosal tissues.194, 195, 196 Eosinophils have also been shown to promote the survival of long-lived plasma cells in the bone marrow197 as well as the generation of IgA-secreting plasma cells in the gastrointestinal tract179, 198 (at least in the small intestine199) via the production of IL-1β, suggesting that they might affect secondary challenge infections where antibodies presumably play a larger role. Indeed, both IL-5 and eosinophil-deficient mice harbor increased numbers of N. brasiliensis larvae after secondary infection,89 with similar results during secondary T. spiralis infection.200 Furthermore, eosinophils negatively regulate Th17 cells201 and promote the expansion of regulatory T cells in the steady state198, 202 that might affect overall inflammation, illustrating their complex contribution to tissue homeostasis. Similarly, whereas resident intestinal macrophages are mostly suppressive in nature and do not act inflammatory to pathogen stimulation, type 2 cytokines give rise to alternatively activated macrophages that might contribute to the expulsion of certain parasites.75, 192, 203, 204 Furthermore, macrophages in the intestinal mucosa are also likely to play an important role in tissue repair, as has been shown in various settings of inflammation.205, 206, 207, 208, 209, 210
Whereas most research on host–parasite interactions has focused on the underlying factors that govern resistance and susceptibility, the long-term consequences of both acute and chronic worm infections are largely unexplored. Given the inverse correlation between parasite exposure and the occurrence of immune-associated disorders, it is quite surprising that so little attention has been devoted to this subject, particularly in the case of Trichuris infections that have been in clinical trial for the treatment of various inflammatory disorders.9, 211 Chronically infected mice do not display any overt symptoms of disease, but are by no means unaffected considering that persistent T. muris infections are lethal in the absence of IL-10,212 indicating that there is ongoing inflammation beyond the spontaneous inflammation inherent to il10–/– mice. Indeed, chronic T. muris infection results in the accumulation of interferon-γ+ T cells in the bone marrow,213 and does not appear to protect against the development of colitis.214, 215 Furthermore, depending on the strain, chronically infected mice gain less weight than their uninfected counterparts,216 and in some cases even acquire colitis-like symptoms, thus losing weight,217 mirroring the malnutrition and wasting of some infected humans. In contrast, lung pathology appears to be decreased in response to papain challenge,218 illustrating that worm-induced protection against inflammatory disorders is highly context specific. Data on the long-term effects of acute T. muris infection are even sparser. Alternatively activated macrophages seem to increase in number after expulsion,219 perhaps contributing to tissue repair, and there are dramatic changes to the epithelial niche, with increased numbers of mucosal mast cells that persist in the epithelium for months after expulsion and appear to affect epithelial barrier integrity.220 However, other potential long-lasting consequences of acute T. muris infection remain unexplored. In contrast, H. polygyrus appears to be protective in several inflammatory models,221, 222 and this has been attributed to its ability to dampen inflammation by promoting the generation and function of regulatory T cells via some of its secreted proteins.223, 224 Hence, the hygiene hypothesis might apply only to a narrow group of nematodes and it is important that we distinguish between general phenomena of parasite infection (such as the importance of IL-13) and more specific ones (such as the contribution of eosinophils) if we are to apply our knowledge to patients in the clinic.
Conclusions and future challenges
Parasitic nematodes are an integral part of the mucosal milieu and have played an important role in the evolution of the intestinal immune system. Their presence leads to the induction of type 2 immunity that involves a vast array of cell types and molecules that work in concert to protect against a wide range of extracellular parasites at mucosal surfaces. Although some worm infections might be beneficial to human health, the long-term effects of infection remain poorly understood and there are many unresolved questions as follows. (i) To what extent are parasites able to directly manipulate the immune system, and with what consequences on subsequent infections? Nematodes clearly have the ability to influence the host as they are often able to survive for extended periods of time without causing pronounced inflammation. Identifying the pathways that are regulated upon infection thus might prove valuable for the development of new anti-inflammatory drugs. (ii) How does early parasite exposure affect the developing immune system? Given that nematode infections mainly afflict children it is not unlikely that their immune system is permanently altered as a consequence. (iii) What is the contribution of the microbiota in regulating immune responses to extracellular parasites? Some, or even many of the observed effects on the host upon nematode infection might be due to changes in bacterial composition. Establishing the causal links in the cross-talk between intestinal bacteria, parasites, and the immune system is notoriously difficult and remains to be resolved. (iv) Can parasite-derived molecules be harnessed for treating immune-associated disorders, and are they sufficient? Answering these and other questions will be important as more and more people are afflicted with various diseases partly attributed to the absence of nematode infections.
References
Pullan, R.L., Smith, J.L., Jasrasaria, R. & Brooker, S.J. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit. Vectors 7, 37 (2014).
Asher, M.I. et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368, 733–743 (2006).
Molodecky, N.A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012).
Zhou, B. et al. Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 387, 1513–1530 (2016).
Hotez, P. & Aksoy, S. PLOS Neglected Tropical Diseases: Ten years of progress in neglected tropical disease control and elimination … more or less. PLoS Negl. Trop. Dis. 11, e0005355 (2017).
Kondrashova, A., Seiskari, T., Ilonen, J., Knip, M. & Hyöty, H. The ‘Hygiene hypothesis’ and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. Acta. Pathol. Microbiol. Immunol. Scand. 121, 478–493 (2013).
Ramanan, D. et al. Helminth infection promotes colonization resistance via type 2 immunity. Science 352, 608–612 (2016).
Broadhurst, M.J. et al. IL-22+ CD4+ T cells are associated with therapeutic Trichuris trichiura Infection in an ulcerative colitis patient. Sci. Transl. Med. 2, 60ra88 (2010).
Garg, S.K., Croft, A.M. & Bager, P. Helminth therapy (worms) for induction of remission in inflammatory bowel disease. Cochrane Database Syst. Rev. (1), CD009400 (2014).
Reynolds, L.A., Filbey, K.J. & Maizels, R.M. Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus. Semin. Immunopathol. 34, 829–846 (2012).
Loukas, A. et al. Hookworm infection. Nat. Rev. Dis. Prim. 2, 16088 (2016).
Mitreva, M. & Jasmer, D.P. In: Worm BookJonathan Hodgkin, (ed) 1–21 (2006) doi:10.1895/wormbook.1.124.1 (wormbook.org).
Klementowicz, J.E., Travis, M.A. & Grencis, R.K. Trichuris muris: a model of gastrointestinal parasite infection. Semin. Immunopathol. 34, 815–828 (2012).
Zaph, C. et al. Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007).
Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).
Howitt, M.R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333 (2016).
von Moltke, J., Ji, M., Liang, H.-E. & Locksley, R.M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225 (2016).
Reese, T.A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007).
Van Dyken, S.J. et al. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity 40, 414–424 (2014).
Zhu, Z. et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304, 1678–1682 (2004).
Ohno, M. et al. Acidic mammalian chitinase is a proteases-resistant glycosidase in mouse digestive system. Sci. Rep. 6, 37756 (2016).
Vannella, K.M. et al. Acidic chitinase primes the protective immune response to gastrointestinal nematodes. Nat. Immunol. 17, 538–544 (2016).
Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017).
Klose, C.S.N. et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549, 282–286 (2017).
Fallon, P.G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).
Owyang, A.M. et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J. Exp. Med. 203, 843–849 (2006).
Zhao, A. et al. Critical role of IL-25 in nematode infection-induced alterations in intestinal function. J. Immunol. 185, 6921–6929 (2010).
Pei, C. et al. Critical role for interleukin-25 in host protective Th2 memory response against Heligmosomoides polygyrus bakeri. Infect. Immun. 84, 3328–3337 (2016).
Humphreys, N.E., Xu, D., Hepworth, M.R., Liew, F.Y. & Grencis, R.K. IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 180, 2443–2449 (2008).
Wills-Karp, M. et al. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J. Exp. Med. 209, 607–622 (2012).
Hung, L.-Y. et al. IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms. Proc. Natl. Acad. Sci. USA 110, 282–287 (2013).
Massacand, J.C. et al. Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function. Proc. Natl. Acad. Sci. USA 106, 13968–13973 (2009).
Taylor, B.C. et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J. Exp. Med. 206, 655–667 (2009).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Price, A.E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. USA 107, 11489–11494 (2010).
Saenz, S.A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).
Oeser, K., Schwartz, C. & Voehringer, D. Conditional IL-4/IL-13-deficient mice reveal a critical role of innate immune cells for protective immunity against gastrointestinal helminths. Mucosal Immunol. 8, 672–682 (2015).
Angkasekwinai, P. et al. Interleukin-25 (IL-25) promotes efficient protective immunity against Trichinella spiralis Infection by enhancing the antigen-specific IL-9 response. Infect. Immun. 81, 3731–3741 (2013).
Mearns, H. et al. IL-25 exhibits disparate roles during Th2-cell differentiation versus effector function. Eur. J. Immunol. 44, 1976–1980 (2014).
Wang, Y.-H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204, 1837–1847 (2007).
Kang, Z. et al. Epithelial cell-specific Act1 adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin-c-Kit+ innate cell population. Immunity 36, 821–833 (2012).
Tjota, M.Y. et al. IL-33–dependent induction of allergic lung inflammation by FcγRIII signaling. J. Clin. Invest. 123, 2287–2297 (2013).
Shimokawa, C. et al. Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections. Immunity 46, 863–874 (2017).
Scalfone, L.K. et al. Participation of MyD88 and interleukin-33 as innate drivers of Th2 immunity to Trichinella spiralis. Infect. Immun. 81, 1354–1363 (2013).
Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl. Acad. Sci. USA 104, 282–287 (2007).
Cayrol, C. & Girard, J.-P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl. Acad. Sci. USA 106, 9021–9026 (2009).
Lefrançais, E. et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc. Natl. Acad. Sci. USA 109, 1673–1678 (2012).
Lefrançais, E. et al. Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc. Natl. Acad. Sci. USA 111, 15502–15507 (2014).
Moulin, D. et al. Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine 40, 216–225 (2007).
Cherry, W.B., Yoon, J., Bartemes, K.R., Iijima, K. & Kita, H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J. Allergy Clin. Immunol. 121, 1484–1490 (2008).
Plantinga, M. et al. Conventional and monocyte-derived CD11b+ dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38, 322–335 (2013).
Van Dyken, S.J. et al. A tissue checkpoint regulates type 2 immunity. Nat. Immunol. 17, 1381–1387 (2016).
Soumelis, V. et al. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).
Siracusa, M.C. et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229–233 (2011).
Endo, Y. et al. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 42, 294–308 (2015).
Guo, L. et al. Innate immunological function of TH2 cells in vivo. Nat. Immunol. 16, 1051–1059 (2015).
Wang, Q., Du, J., Zhu, J., Yang, X. & Zhou, B. Thymic stromal lymphopoietin signaling in CD4+ T cells is required for TH2 memory. J. Allergy Clin. Immunol. 135, 781–791 (2015).
Holmkvist, P. et al. A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality. Mucosal Immunol. 8, 545–558 (2015).
Bancroft, A.J., McKenzie, A.N.J. & Grencis, R.K. A critical role for IL-13 in resistance to intestinal nematode infection. J. Immunol. 160, 3453–3461 (1998).
McKenzie, G.J., Bancroft, A.J., Grencis, R.K. & McKenzie, A.N.J. A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Curr. Biol. 8, 339–342 (1998).
Urban, J.F. Jr et al. IL-13, IL-4Rα, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8, 255–264 (1998).
Scales, H.E., Ierna, M.X. & Lawrence, C.E. The role of IL-4, IL-13 and IL-4Rα in the development of protective and pathological responses to Trichinella spiralis. Parasite Immunol. 29, 81–91 (2007).
Halim, T.Y.F. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).
Halim, T.Y.F. et al. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat. Immunol. 17, 57–64 (2016).
Bancroft, A.J., Artis, D., Donaldson, D.D., Sypek, J.P. & Grencis, R.K. Gastrointestinal nematode expulsion in IL-4 knockout mice is IL-13 dependent. Eur. J. Immunol. 30, 2083–2091 (2000).
Obata-Ninomiya, K. et al. The skin is an important bulwark of acquired immunity against intestinal helminths. J. Exp. Med. 210, 2583–2595 (2013).
Liang, H.-E. et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 13, 58–66 (2011).
Lin, J.-X. et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 2, 331–339 (1995).
Smerz-Bertling, C. & Duschl, A. Both interleukin 4 and interleukin 13 induce tyrosine phosphorylation of the 140-kDa subunit of the interleukin 4 receptor. J. Biol. Chem. 270, 966–970 (1995).
Zurawski, S.M. et al. The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor. J. Biol. Chem. 270, 13869–13878 (1995).
Michels, C.E. et al. Neither interleukin-4 receptor α expression on CD4+ T cells, or macrophages and neutrophils is required for protective immunity to Trichinella spiralis. Immunology 128, e385–e394 (2009).
Schmidt, S. et al. Nippostrongylus-induced intestinal hypercontractility requires IL-4 receptor alpha-responsiveness by T cells in mice. PLoS ONE 7, e52211 (2012).
Barner, M., Mohrs, M., Brombacher, F. & Kopf, M. Differences between IL-4Rα-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr. Biol. 8, 669–672 (1998).
Filbey, K.J. et al. Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection. Immunol. Cell Biol. 92, 436–448 (2014).
Pelly, V.S. et al. IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection. Mucosal Immunol. 9, 1407–1417 (2016).
Min, B. et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med. 200, 507–517 (2004).
Motomura, Y. et al. Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 40, 758–771 (2014).
Molofsky, A.B. et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013).
Nussbaum, J.C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).
Griseri, T. et al. Granulocyte macrophage colony-stimulating factor-activated eosinophils promote interleukin-23 driven chronic colitis. Immunity 43, 187–199 (2015).
Carlens, J. et al. Common γ-chain-dependent signals confer selective survival of eosinophils in the murine small intestine. J. Immunol. 183, 5600–5607 (2009).
Yang, D. et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J. Exp. Med. 205, 79–90 (2008).
Chu, D.K. et al. Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo. J. Exp. Med. 211, 1657–1672 (2014).
Svensson, M. et al. Accumulation of eosinophils in intestine-draining mesenteric lymph nodes occurs after Trichuris muris infection. Parasite Immunol. 33, 1–11 (2011).
Urban, J.F. Jr, Katona, I.M., Paul, W.E. & Finkelman, F.D. Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc. Natl. Acad. Sci. USA 88, 5513–5517 (1991).
Strandmark, J. et al. Eosinophils are required to suppress Th2 responses in Peyer’s patches during intestinal infection by nematodes. Mucosal Immunol. 10, 661–672 (2017).
Dent, L.A. et al. Interleukin-5 transgenic mice show enhanced resistance to primary infections with Nippostrongylus brasiliensis but not primary infections with Toxocara canis. Infect. Immun. 67, 989–993 (1999).
Knott, M.L. et al. Impaired resistance in early secondary Nippostrongylus brasiliensis infections in mice with defective eosinophilopoeisis. Int. J. Parasitol. 37, 1367–1378 (2007).
Faulkner, H., Humphreys, N.E., Renauld, J.-C., Van Snick, J. & Grencis, R.K. Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur. J. Immunol. 27, 2536–2540 (1997).
Matsuzawa, S. et al. IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J. Immunol. 170, 3461–3467 (2003).
Forbes, E.E. et al. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J. Exp. Med. 205, 897–913 (2008).
Ruitenberg, E.J. & Elgersma, A. Absence of intestinal mast cell response in congenitally athymic mice during Trichinella spiralis infection. Nature 264, 258–260 (1976).
Irani, A.-M. A. et al. Deficiency of the tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa of patients with defective T lymphocyte function. J. Immunol. 138, 4381–4386 (1987).
Licona-Limón, P. et al. Th9 cells drive host immunity against gastrointestinal worm infection. Immunity 39, 744–757 (2013).
Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).
Hültner, L. et al. In activated mast cells, IL-1 up-regulates the production of several Th2-related cytokines including IL-9. J. Immunol. 164, 5556–5563 (2000).
Chen, C.-Y. et al. Induction of interleukin-9-producing mucosal mast cells promotes susceptibility to IgE-mediated experimental food allergy. Immunity 43, 788–802 (2015).
Hepworth, M.R. et al. Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines. Proc. Natl. Acad. Sci. USA 109, 6644–6649 (2012).
Koyama, K. & Ito, Y. Mucosal mast cell responses are not required for protection against infection with the murine nematode parasite Trichuris muris. Parasite Immunol. 22, 21–28 (2000).
Richard, M., Grencis, R.K., Humphreys, N.E., Renauld, J.-C. & Van Snick, J. Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice. Proc. Natl. Acad. Sci. USA 97, 767–772 (2000).
Khan, W.I. et al. Modulation of intestinal muscle contraction by interleukin-9 (IL-9) or IL-9 neutralization: correlation with worm expulsion in murine nematode infections. Infect. Immun. 71, 2430–2438 (2003).
Joeris, T., Müller-Luda, K., Agace, W.W. & Mowat, A.M. Diversity and functions of intestinal mononuclear phagocytes. Mucosal Immunol. 10, 845–864 (2017).
Gao, Y. et al. Control of T helper 2 responses by transcription factor IRF4-dependent dendritic cells. Immunity 39, 722–732 (2013).
Kumamoto, Y. et al. CD301b + dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39, 733–743 (2013).
Mayer, J.U. et al. Different populations of CD11b+ dendritic cells drive Th2 responses in the small intestine and colon. Nat. Commun. 8, 15820 (2017).
Demiri, M., Müller-Luda, K., Agace, W.W. & Svensson-Frej, M. Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection. Parasite Immunol. 39, doi: 10.1111/pim.12458 (2017).
Cook, P.C. et al. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells. Nat. Commun. 6, 6920 (2015).
Tussiwand, R. et al. Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity 42, 916–928 (2015).
Murakami, R. et al. A unique dermal dendritic cell subset that skews the immune response toward Th2. PLoS ONE 8, e73270 (2013).
Williams, J.W. et al. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat. Commun. 4, 2990 (2013).
Martínez-López, M., Iborra, S., Conde-Garrosa, R. & Sancho, D. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice. Eur. J. Immunol. 45, 119–129 (2015).
Luda, K.M. et al. IRF8 transcription-factor-dependent classical dendritic cells are essential for intestinal T cell homeostasis. Immunity 44, 860–874 (2016).
Cerovic, V. et al. Lymph-borne CD8α+ dendritic cells are uniquely able to cross-prime CD8+ T cells with antigen acquired from intestinal epithelial cells. Mucosal Immunol. 8, 38–48 (2015).
Sun, T. et al. Intestinal Batf3-dependent dendritic cells are required for optimal antiviral T-cell responses in adult and neonatal mice. Mucosal Immunol. 10, 775–788 (2017).
Everts, B. et al. Migratory CD103+ dendritic cells suppress helminth-driven type 2 immunity through constitutive expression of IL-12. J. Exp. Med. 213, 35–51 (2015).
Gold, M.J., Antignano, F., Hughes, M.R., Zaph, C. & McNagny, K.M. Dendritic-cell expression of Ship1 regulates Th2 immunity to helminth infection in mice. Eur. J. Immunol. 46, 122–130 (2016).
MacDonald, A.S., Straw, A.D., Dalton, N.M. & Pearce, E.J. Th2 response induction by dendritic cells: a role for CD40. J. Immunol. 168, 537–540 (2002).
Jenkins, S.J., Perona-Wright, G., Worsley, A.G.F., Ishii, N. & MacDonald, A.S. Dendritic cell expression of OX40 Ligand acts as a costimulatory, not polarizing, signal for optimal Th2 priming and memory induction in vivo. J. Immunol. 179, 3515–3523 (2007).
Artis, D. et al. Dendritic cell-intrinsic expression of NF-kB1 is required to promote optimal Th2 cell differentiation. J. Immunol. 174, 7154–7159 (2005).
Worthington, J.J. et al. Loss of the TGFβ-activating integrin αvβ8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity. PLoS Pathog. 9, e1003675 (2013).
Kannan, Y. et al. TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus. PLoS Pathog. 13, e1006536 (2017).
Yrlid, U. et al. A distinct subset of intestinal dendritic cells responds selectively to oral TLR7/8 stimulation. Eur. J. Immunol. 36, 2639–2648 (2006).
Fujimoto, K. et al. A new subset of CD103+CD8α+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces Th1 response and CTL activity. J. Immunol. 186, 6287–6295 (2011).
Watchmaker, P.B. et al. Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat. Immunol. 15, 98–108 (2014).
Liu, H. et al. TLR5 mediates CD172α+ intestinal lamina propria dendritic cell induction of Th17 cells. Sci. Rep 6, 22040 (2016).
Agrawal, S. et al. Different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol. 171, 4984–4989 (2003).
Connor, L.M. et al. Th2 responses are primed by skin dendritic cells with distinct transcriptional profiles. J. Exp. Med. 214, 125–142 (2017).
Hepworth, M.R. et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).
Mirchandani, A.S. et al. Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. J. Immunol. 192, 2442–2448 (2014).
Oliphant, C.J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).
Perrigoue, J.G. et al. MHC class II–dependent basophil–CD4+ T cell interactions promote TH2 cytokine–dependent immunity. Nat. Immunol. 10, 697–705 (2009).
Sokol, C.L. et al. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat. Immunol. 10, 713–720 (2009).
Yoshimoto, T. et al. Basophils contribute to Th2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat. Immunol. 10, 706–712 (2009).
Shi, H.Z., Humbles, A., Gerard, C., Jin, Z. & Weller, P.F. Lymph node trafficking and antigen presentation by endobronchial eosinophils. J. Clin. Invest. 105, 945–953 (2000).
MacKenzie, J.R., Mattes, J., Dent, L.A. & Foster, P.S. Eosinophils promote allergic disease of the lung by regulating CD4+ Th2 lymphocyte function. J. Immunol. 167, 3146–3155 (2001).
Kim, S. et al. Basophils are transiently recruited into the draining lymph nodes during helminth infection via IL-3, but infection-induced Th2 immunity can develop without basophil lymph node recruitment or IL-3. J. Immunol. 184, 1143–1147 (2010).
Mackley, E.C. et al. CCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nat. Commun. 6, 5862 (2015).
Phythian-Adams, A.T. et al. CD11c depletion severely disrupts Th2 induction and development in vivo. J. Exp. Med. 207, 2089–2096 (2010).
Lundie, R.J. et al. A central role for hepatic conventional dendritic cells in supporting Th2 responses during helminth infection. Immunol. Cell Biol. 94, 400–410 (2016).
Melum, G.R. et al. A thymic stromal lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper airway mucosa. J. Allergy Clin. Immunol. 134, 613–621 (2014).
Ochiai, S. et al. CD326lo CD103lo CD11blo dermal dendritic cells are activated by thymic stromal lymphopoietin during contact sensitization in mice. J. Immunol. 193, 2504–2511 (2014).
Joo, S. et al. Critical role of TSLP-responsive mucosal dendritic cells in the induction of nasal antigen-specific IgA response. Mucosal Immunol. 10, 901–911 (2016).
Claudio, E. et al. IL-25 targets dendritic cells to attract IL-9–producing T cells in acute allergic lung inflammation. J. Immunol. 195, 3525–3529 (2015).
Besnard, A.-G. et al. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur. J. Immunol. 41, 1675–1686 (2011).
Walls, R.S., Carter, R.L., Leuchars, E. & Davies, A.J.S. The immunopathology of trichiniasis in T-cell deficient mice. Clin. Exp. Immunol. 13, 231–242 (1973).
Ruitenberg, E.J., Elgersma, A., Kruizinga, W. & Leenstra, F. Trichinella spiralis infection in congenitally athymic (nude) mice. Parasitological, serological and haematological studies with observations on intestinal pathology. Immunology 33, 581–587 (1977).
Jacobson, R.H. & Reed, N.D. The immune response of congenitally athymic (nude) mice to the intestinal nematode Nippostrongylus brasiliensis. Proc. Soc. Exp. Biol. Med. 147, 667–670 (1974).
Urban, J.F. Jr, Maliszewski, C.R., Madden, K.B., Katona, I.M. & Finkelman, F.D. IL-4 treatment can cure established gastrointestinal nematode infections in immunocompetent and immunodeficient mice. J. Immunol. 154, 4675–4684 (1995).
Wakelin, D. & Selby, G.R. Thymus-dependency of the immune response of mice to a primary infection with the nematode Trichuris muris. Int. J. Parasitol. 4, 657–661 (1974).
Ito, Y. The absence of resistance in congenitally athymic nude mice toward infection with the intestinal nematode, Trichuris muris: resistance restored by lymphoid cell transfer. Int. J. Parasitol. 21, 65–69 (1991).
Hashimoto, K. et al. Depleted intestinal goblet cells and severe pathological changes in SCID mice infected with Heligmosomoides polygyrus. Parasite Immunol. 31, 457–465 (2009).
Urban, J.F. Jr, Katona, I.M. & Finkelman, F.D. Heligmosomoides polygyrus: CD4+ but not CD8+ T cells regulate the IgE response and protective immunity in mice. Exp. Parasitol. 73, 500–511 (1991).
Koyama, K., Tamauchi, H. & Ito, Y. The role of CD4+ and CD8+ T cells in protective immunity to the murine nematode parasite Trichuris muris. Parasite Immunol. 17, 161–165 (1995).
Else, K.J. & Grencis, R.K. Antibody-independent effector mechanisms in resistance to the intestinal nematode parasite Trichuris muris. Infect. Immun. 64, 2950–2954 (1996).
Rausch, S. et al. Functional analysis of effector and regulatory T cells in a parasitic nematode infection. Infect. Immun. 76, 1908–1919 (2008).
Blackwell, N.M. & Else, K.J. B cells and antibodies are required for resistance to the parasitic gastrointestinal Nematode Trichuris muris. Infect. Immun. 69, 3860–3868 (2001).
Lee, T.D.G., Wakelin, D. & Grencis, R.K. Cellular mechanisms of immunity to the nematode Trichuris muris. Int. J. Parasitol. 13, 349–353 (1983).
Roach, T.I.A., Else, K.J., Wakelin, D., McLaren, D.J. & Grencis, R.K. Trichuris muris: antigen recognition and transfer of immunity in mice by IgA monoclonal antibodies. Parasite Immunol. 13, 1–12 (1991).
Harris, N.L. et al. Mechanisms of neonatal mucosal antibody protection. J. Immunol. 177, 6256–6262 (2006).
Else, K.J., Wakelin, D., Wassom, D.L. & Hauda, K.M. MHC-restricted antibody responses to Trichuris muris excretory/secretory (E/S) antigen. Parasite Immunol. 12, 509–527 (1990).
Esser-von Bieren, J. et al. Antibodies trap tissue migrating helminth larvae and prevent tissue damage by driving IL-4Rα-independent alternative differentiation of macrophages. PLoS Pathog. 9, e1003771 (2013).
Ramalho-Pinto, F.J., De Rossi, R. & Smithers, S.R. Murine schistosomiasis mansoni: anti-schistosomula antibodies and the IgG subclasses involved in the complement- and eosinophil-mediated killing of schistosomula in vitro. Parasite Immunol. 1, 295–308 (1979).
Pritchard, D.I., Williams, D.J.L., Behnke, J.M. & Lee, T.D.G. The role of IgG1 hypergammaglobulinaemia in immunity to the gastrointestinal nematode Nematospiroides dubius. The immunochemical purification, antigen-specificity and in vivo anti-parasite effect of IgG1 from immune serum. Immunology 49, 353–365 (1983).
Hewitson, J.P. et al. Concerted activity of IgG1 antibodies and IL-4/IL-25-dependent effector cells trap helminth larvae in the tissues following vaccination with defined secreted antigens, providing sterile immunity to challenge infection. PLoS Pathog. 11, e1004676 (2015).
Liu, Q. et al. The role of B cells in the development of CD4 effector T cells during a polarized Th2 immune response. J. Immunol. 179, 3821–3830 (2007).
Horsnell, W.G.C. et al. IL-4Rα-associated antigen processing by B cells promotes immunity in Nippostrongylus brasiliensis infection. PLoS Pathog. 9, e1003662 (2013).
McCoy, K.D. et al. Polyclonal and specific antibodies mediate protective immunity against enteric helminth infection. Cell Host Microbe 4, 362–373 (2008).
Voehringer, D., Reese, T.A., Huang, X., Shinkai, K. & Locksley, R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp. Med. 203, 1435–1446 (2006).
Hasnain, S.Z. et al. Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Gastroenterology 138, 1763–1771 (2010).
Hasnain, S.Z., McGuckin, M.A., Grencis, R.K. & Thornton, D.J. Serine protease(s) secreted by the nematode Trichuris muris degrade the mucus barrier. PLoS Negl. Trop. Dis. 6, e1856 (2012).
Hasnain, S.Z. et al. Immune-driven alterations in mucin sulphation is an important mediator of Trichuris muris helminth expulsion. PLoS Pathog. 13, e1006218 (2017).
Hasnain, S.Z. et al. Muc5ac: a critical component mediating the rejection of enteric nematodes. J. Exp. Med. 208, 893–900 (2011).
Dabbagh, K. et al. IL-4 induces mucin gene experession and goblet cell metaplasia in vitro and in vivo. J. Immunol. 162, 6233–6237 (1999).
Turner, J.E., Stockinger, B. & Helmby, H. IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS Pathog. 9, e1003698 (2013).
Thawer, S. et al. Surfactant protein-D is essential for immunity to helminth infection. PLoS Pathog. 12, e1005461 (2016).
Glauert, A.M., Butterworth, A.E., Sturrock, R.F. & Houba, V. The mechanism of antibody-dependent, eosinophil-mediated damage to schistosomula of Schistosoma mansoni in vitro: a study by phase-contrast and electron microscopy. J. Cell Sci. 34, 173–192 (1978).
Hamann, K.J. et al. In vitro killing of microfilariae of Brugia pahangi and Brugia malayi by eosinophil granule proteins. J. Immunol. 144, 3166–3173 (1990).
Jung, Y. et al. IL-1β in eosinophil-mediated small intestinal homeostasis and IgA production. Mucosal Immunol. 8, 930–942 (2015).
Knight, P.A., Wright, S.H., Lawrence, C.E., Paterson, Y.Y.W. & Miller, H.R.P. Delayed expulsion of the nematode Trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase, mouse mast cell protease-1. J. Exp. Med. 192, 1849–1856 (2000).
McDermott, J.R. et al. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc. Natl. Acad. Sci. USA 100, 7761–7766 (2003).
Lawrence, C.E., Paterson, Y.Y.W., Wright, S.H., Knight, P.A. & Miller, H.R.P. Mouse mast cell protease-1 is required for the enteropathy induced by gastrointestinal helminth infection in the mouse. Gastroenterology 127, 155–165 (2004).
Crowle, P.K. & Reed, N.D. Rejection of the intestinal parasite Nippostrongylus brasiliensis by mast cell-deficient W/Wv anemic mice. Infect. Immun. 33, 54–58 (1981).
Crowle, P.K. Mucosal mast cell reconstitution and Nippostrongylus brasiliensis rejection by W/Wv mice. J. Parasitol. 69, 66–69 (1983).
Townsend, M.J. et al. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13, 573–583 (2000).
Artis, D. et al. RELMβ/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc. Natl. Acad. Sci. USA 101, 13596–13600 (2004).
Nair, M.G. et al. Goblet cell-derived resistin-like molecule β augments CD4+ T cell production of IFN-γ and infection-induced intestinal inflammation. J. Immunol. 181, 4709–4715 (2008).
Herbert, D.R. et al. Intestinal epithelial cell secretion of RELM-β protects against gastrointestinal worm infection. J. Exp. Med. 206, 2947–2957 (2009).
Chen, G., Wang, S.H., Jang, J.C., Odegaard, J.I. & Nair, M.G. Comparison of RELMα and RELMβ single- and double-gene-deficient mice reveals that RELMα expression dictates inflammation and worm expulsion in hookworm infection. Infect. Immun. 84, 1100–1111 (2016).
Cliffe, L.J. et al. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308, 1463–1465 (2005).
Oudhoff, M.J. et al. Intestinal epithelial cell-intrinsic deletion of Setd7 identifies role for developmental pathways in immunity to helminth infection. PLoS Pathog. 12, e1005876 (2016).
Zhao, A. et al. Th2 cytokine-induced alterations in intestinal smooth muscle function depend on alternatively activated macrophages. Gastroenterology 135, 217–225 (2008).
McLean, L.P. et al. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G130–G141 (2016).
Yamada, T. et al. Eosinophils promote resolution of acute peritonitis by producing proresolving mediators in mice. FASEB J. 25, 561–568 (2011).
Goh, Y.P.S. et al. Eosinophils secrete IL-4 to facilitate liver regeneration. Proc. Natl. Acad. Sci. USA 110, 9914–9919 (2013).
Heredia, J.E. et al. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153, 376–388 (2013).
Chu, V.T. et al. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat. Immunol. 12, 151–159 (2011).
Chu, V.T. et al. Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity 40, 582–593 (2014).
Forman, R. et al. Eosinophils may play regionally disparate roles in influencing IgA+ plasma cell numbers during large and small intestinal inflammation. BMC Immunol. 17, 12 (2016).
Huang, L. et al. Eosinophils mediate protective immunity against secondary nematode infection. J. Immunol. 194, 283–290 (2015).
Sugawara, R. et al. Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist. J. Exp. Med. 213, 555–567 (2016).
Chen, H.-H. et al. Eosinophils from murine lamina propria induce differentiation of naïve T cells into regulatory T cells via TGF-β1 and retinoic acid. PLoS ONE 10, e0142881 (2015).
Anthony, R.M. et al. Memory TH2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat. Med. 12, 955–960 (2006).
Bowcutt, R. et al. Arginase-1-expressing macrophages are dispensable for resistance to infection with the gastrointestinal helminth Trichuris muris. Parasite Immunol. 33, 411–420 (2011).
Qualls, J.E., Kaplan, A.M., van Rooijen, N. & Cohen, D.A. Suppression of experimental colitis by intestinal mononuclear phagocytes. J. Leukoc. Biol. 80, 802–815 (2006).
Herbert, D.R. et al. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J. Immunol. 184, 6438–6446 (2010).
Chen, F. et al. An essential role for Th2-type responses in limiting tissue damage during experimental helminth infection. Nat. Med. 18, 260–266 (2012).
Malvin, N.P., Seno, H. & Stappenbeck, T.S. Colonic epithelial response to injury requires Myd88 signaling in myeloid cells. Mucosal Immunol. 5, 194–206 (2012).
Esser-von Bieren, J. et al. Immune antibodies and helminth products drive CXCR2-dependent macrophage-myofibroblast crosstalk to promote intestinal repair. PLoS Pathog. 11, e1004778 (2015).
Cosín-Roger, J. et al. The activation of Wnt signaling by a STAT6-dependent macrophage phenotype promotes mucosal repair in murine IBD. Mucosal Immunol. 9, 986–998 (2015).
Croft, A.M., Bager, P. & Kumar, S. Helminth therapy (worms) for allergic rhinitis. Cochrane Database Syst. Rev. (4), CD009238 (2012).
Schopf, L.R., Hoffmann, K.F., Cheever, A.W., Urban, J.F. Jr & Wynn, T.A. IL-10 is critical for host resistance and survival during gastrointestinal helminth infection. J. Immunol. 168, 2383–2392 (2002).
Chenery, A.L. et al. Chronic Trichuris muris infection alters hematopoiesis and causes IFN-γ-expressing T-cell accumulation in the mouse bone marrow. Eur. J. Immunol. 46, 2587–2596 (2016).
Levison, S.E. et al. Genetic analysis of the Trichuris muris-induced model of colitis reveals QTL overlap and a novel gene cluster for establishing colonic inflammation. BMC Genomics 14, 127 (2013).
Bhardwaj, E.K., Else, K.J., Rogan, M.T. & Warhurst, G. Increased susceptibility to Trichuris muris infection and exacerbation of colitis in Mdr1a-/- mice. World J. Gastroenterol. 20, 1797–1806 (2014).
Houlden, A. et al. Chronic Trichuris muris infection in C57BL/6 mice causes significant changes in host microbiota and metabolome: effects reversed by pathogen clearance. PLoS ONE 10, e0125945 (2015).
Levison, S.E. et al. Colonic transcriptional profiling in resistance bility to trichuriasis: phenotyping a chronic colitis and lessons for iatrogenic helminthosis. Inflamm. Bowel Dis. 16, 2065–2079 (2010).
Chenery, A.L. et al. Low-dose intestinal Trichuris muris infection alters the lung immune microenvironment and can suppress allergic airway inflammation. Infect. Immun. 84, 491–501 (2015).
Little, M.C., Hurst, R.J.M. & Else, K.J. Dynamic changes in macrophage activation and proliferation during the development and resolution of intestinal inflammation. J. Immunol. 193, 4684–4695 (2014).
Sorobetea, D., Holm, J.B., Henningsson, H., Kristiansen, K. & Svensson-Frej, M. Acute infection with the intestinal parasite Trichuris muris has long-term consequences on mucosal mast cell homeostasis and epithelial integrity. Eur. J. Immunol. 47, 257–268 (2017).
Saunders, K.A., Raine, T., Cooke, A. & Lawrence, C.E. Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect. Immun. 75, 397–407 (2007).
McSorley, H.J. et al. Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. Eur. J. Immunol. 42, 2667–2682 (2012).
Grainger, J.R. et al. Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. J. Exp. Med. 207, 2331–2341 (2010).
Hang, L. et al. Heligmosomoides polygyrus bakeri infection activates colonic Foxp3+ T cells enhancing their capacity to prevent colitis. J. Immunol. 191, 1927–1934 (2013).
Acknowledgements
R.K.G. acknowledges the support from the Wellcome Trust Investigator Award (083620Z) and Wellcome Trust Centre for Cell Matrix Research Centre Award (203128/Z/16/Z).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declared no conflict of interest.
PowerPoint slides
Rights and permissions
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
About this article
Cite this article
Sorobetea, D., Svensson-Frej, M. & Grencis, R. Immunity to gastrointestinal nematode infections. Mucosal Immunol 11, 304–315 (2018). https://doi.org/10.1038/mi.2017.113
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mi.2017.113
This article is cited by
-
Moniezia benedeni drives the SNAP-25 expression of the enteric nerves in sheep's small intestine
BMC Veterinary Research (2024)
-
Pumpkin seed oil: unveiling its potential in controlling inflammation and pathogenicity during experimental trichinellosis
BMC Veterinary Research (2024)
-
Immune response, oxidative stress, and histological changes of Wistar rats after being administered with Parascaris equorum antigen
Scientific Reports (2024)
-
Dietary non-starch polysaccharides impair immunity to enteric nematode infection
BMC Biology (2023)
-
Regulation and function of adiponectin in the intestinal epithelial cells in response to Trichinella spiralis infection
Scientific Reports (2023)