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On the hunt for helminths: Innate immune cells in the recognition and response to helminth parasites


The generation of protective immunity to helminth parasites is critically dependent upon the development of a CD4 T helper type 2 cytokine response. However, the host-parasite interactions responsible for initiating this response are poorly understood. This review will discuss recent advances in our understanding of how helminth-derived products are recognized by innate immune cells. Specifically, interactions between helminth excretory/secretory products and host Toll-like receptors and lectins will be discussed as well as the putative functions of helminth proteases and chitin in activating and recruiting innate immune cells. In addition, the functional significance of pattern recognition by epithelial cells, granulocytes, dendritic cells, and macrophages including expression of alarmins, thymic stromal lymphopoetin (TSLP), interleukin (IL)-25, IL-33, and Notch ligands in the development of adaptive anti-parasite Th2 cytokine responses and the future research challenges in this area will be examined.


While protective immunity to some parasitic helminths can be conferred by either T helper type 1 (Th1) or Th2 cytokine responses, the expulsion of gastrointestinal helminths is critically dependent upon the ability of the host to generate a polarized Th2 immune response (Finkelman et al., 2004; Maizels and Yazdanbakhsh, 2003). The Th2-associated cytokines IL-4, IL-9, IL-13, IL-25 and IL-33 are known to play important roles in mediating the effector mechanisms that contribute to worm expulsion such as goblet cell hyperplasia and mucin production, eosinophilia, mastocytosis, recruitment of alternatively activated macrophages (AAMacs), increased epithelial cell turnover, and muscle hyper-contractility (Anthony et al., 2007; Nair et al., 2006). However, much less is known about the nature of the initiating events upstream of the adaptive immune response against helminth parasites. This review will first examine the current models of how innate immune cells recognize helminth parasites, with a specific emphasis on the recent advances in our understanding of the mechanisms underlying the sensing of helminth-derived excretory/secretory (ES) products by innate immune cells. Second, we will discuss the functional outcome of these interactions and recent studies that have identified key roles for macrophages, dendritic cells (DC), granulocytes, and epithelial cells in the generation and maintenance of adaptive CD4 Th2 cytokine responses.

Mechanisms of innate recognition of helminth parasites

Specific recognition of conserved molecular motifs associated with different classes of pathogens by antigen presenting cells (APC) can be mediated by pattern recognition receptors (PRR) such as Toll-like receptors (TLR), C-type lectins (C-TL), and intracellular Nod-like receptors (NLR) (Medzhitov, 2007). Signaling via PRR on innate immune cells is critical for recognition of viruses, bacteria, fungi and protozoa and can influence the subsequent development of anti-pathogen immune responses. Recent evidence suggests that stimulation through TLR on T cells can also directly influence their function (LaRosa et al., 2008). In contrast, there are no apparent uniformly-expressed pathogen-associated molecular patterns (PAMP) for helminth parasites and, more generally, there are no known PRR that are associated exclusively with the promotion of Th2 responses. Notwithstanding this, there are a number of helminth-derived products that are known to interact with innate immune cells and modulate their function. In this section, the interaction between helminths and TLRs or C-TL on DC and macrophages will be examined followed by a discussion of recent studies demonstrating that two helminth – derived products, secreted proteases and the structural polymer chitin, play a role in innate immune cell activation following exposure to infection.

Helminth modulation of innate immunity through Toll-like receptors

DC recognition of microbes by TLR ligation typically results in their phenotypic maturation characterized by increased expression of co-stimulatory molecules CD40, CD80, and CD86, up-regulation of surface MHC class II, and the production of pro-inflammatory cytokines such as IL-6, IL-12, IL-23, and TNF (Kapsenberg, 2003). In contrast, helminth-matured DCs are notable for their relatively immature status; they often express low levels of co-stimulatory molecules and pro-inflammatory cytokines (MacDonald and Maizels, 2008) and in some cases are rendered refractory to subsequent stimulation through TLR activation (Kane et al., 2004). While less phenotypically mature, these DC are capable of promoting robust antigen-specific CD4 T cell proliferation and Th2 cell differentiation and there is evidence that TLR signaling can play a role in the promotion of this “DC2” maturation program. Soluble egg antigen (SEA) preparations from the trematode Schistosoma mansoni are perhaps the best-characterized helminth-derived antigens that influence DC responses and contain a number of unique TLR ligands. For example, lacto-N-fucopentaose III (LNFPIII) is a milk sugar containing the Lewisx glycan that is found within SEA and can interact with TLR4 to selectively activate extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling in DC (Thomas et al., 2003). LNFPIII exhibits Th2 adjuvanticity through both the recruitment of suppressor macrophages and the conditioning of DC to promote CD4 T cell IL-4 production. Additionally, the schistosome-derived lysophosphatidylserine (lyso-PS) can interact with TLR2 to induce DC that promote the differentiation of IL-4 and IL-10 producing T cells, similar to what some have observed following TLR2 ligation by Pam-3-cys (Dillon et al., 2004). Dependent upon the number of acyl chains, schistosome PS can differentially condition DC to promote either Th2 polarization or specifically induce IL-10 producing regulatory T cells (Treg) (van der Kleij et al., 2002). It has been suggested that this induction of a Treg program by schistosome PS may be a means by which the parasite co-opts the normal host response to PS on the surface of apoptotic cells to suppress inflammation (van der Kleij et al., 2002).

The filarial nematode ES product ES-62 is a phosphorylcholine-rich glycoprotein able to interact with TLR4 in a way distinct from that of the conventional TLR4 ligand, LPS. In contrast to LPS, binding of ES-62 to TLR4 is independent of its Pro712 residue and ES-62 ligation of TLR4 on DC and macrophages results in the inhibition, rather than promotion, of IL-12 secretion (Goodridge et al., 2005). ES-62 is of particular interest in that it provides not only an innate signal to DC and macrophages to limit pro-inflammatory cytokine production, but can also directly inhibit the effector functions of mast cells (Melendez et al., 2007). Internalization of ES-62-TLR4 complexes by mast cells results in the sequestration and subsequent degradation of protein kinase C α (PKC-α), an important regulator of mast cell responses, leading to defective Fcε RI-mediated mast cell degranulation and the selective inhibition of TNFα, IL-3, and IL-6, but not IL-5 and IL-13 release (Melendez et al., 2007). Given the association of many intestinal helminth infections with the recruitment of large numbers of mast cells within the lamina propria, it is possible that the ability of nematode ES products to influence mast cell function could be a conserved evolutionary pathway to limit parasite-driven inflammation while selectively allowing expression of Th2 cytokines.

Despite the studies discussed above, a direct requirement for TLR signaling in generating anti-helminth immune responses remains controversial. While TLR ligation by helminth-derived antigens is recognized as a mechanism to limit the development of Th1 cytokine-mediated inflammation, it is still unclear whether signals induced by binding of helminth-derived antigens to TLR can directly promote Th2 cell differentiation. In fact, there is substantial evidence to suggest that the signaling pathways downstream of TLR are negatively correlated with the development of Th2 cytokine responses. For example, MyD88-deficient mice exhibit enhanced Th2 cytokine responses following exposure to Trichuris and are resistant to the development of chronic infection (Helmby and Grencis, 2003). These data are consistent with the observation that MyD88−/− mice develop enhanced antigen-specific IL-13 responses following OVA immunization, proposed to be the result of defective Th1 cell differentiation and IFN-γ production (Schnare et al., 2001). The absence of the TLR/IL-1R associated adaptor molecule, TNFR-associated factor 6 (TRAF6) results in a progressive Th2 cytokine-mediated inflammatory disease (Chiffoleau et al., 2003) supporting a negative regulatory role for TLR signaling pathways in Th2 cell differentiation. However, the function of TRAF6 in influencing innate anti-helminth immune responses is unknown at present. It is important to note that these data do not exclude an important role for TLR signaling in the generation of anti-helminth immune responses independently of MyD88 and TRAF6. For example, other TLR-associated adapters including TIRAP, TIRP, TOLLIP, and TRIF can influence multiple aspects of innate and adaptive immune responses although their role in recognition of helminth parasites awaits investigation. Similarly, the functions of intracellular PRRs including NOD proteins, NALPs, and NAIPs in innate responses to helminths are unknown. Given that some helminth parasites including Trichuris muris and Trichinella spiralis can inhabit a partially intracellular niche, these proteins may be biologically significant.

Helminth-associated glycans and C-type lectins in host-parasite interactions

The surfaces of helminths, as well as their ES products, are rich in glycoproteins. Recognition of these carbohydrate domains is thought to be mediated by the calcium-dependent carbohydrate binding protein family of receptors, known as C-type lectins (C-TL), that are expressed by a number of innate cells including DC, macrophages, and epithelial cells. The C-TL family consists of soluble and trans-membrane receptors that demonstrate unique specificity for carbohydrate residues via distinct clustering of carbohydrate recognition domains (CRD) and are able to distinguish between sialylated and sulphated forms of the same carbohydrate (Cambi et al., 2005). Trans-membrane members of the C-type lectin family include collectins, the mannose receptor family, selectins, and dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and ligand engagement of these receptors is involved in processes ranging from cellular trafficking to cell signaling and pathogen recognition (Cambi et al., 2005). Interaction between the peanut glycan allergen Ara h 1 and DC-SIGN has recently been shown to activate ERK MAPK signaling in DC and contribute to DC-mediated Th2 cell differentiation (Shreffler et al., 2006). While glycans from schistosomes (Meyer et al., 2005) and Toxocara canis (Schabussova et al., 2007) have also been shown to interact with DC-SIGN, the functional consequences of these host-parasite interactions remains to be interrogated. The calcium-dependent galactose-binding proteins, intelectins, are expressed by paneth cells and goblet cells and have also been implicated in the recognition of gastrointestinal helminths. Although their functions in innate immunity remain largely unknown, intelectins are highly induced in the intestine following exposure to both T. muris and T. spiralis and have been proposed to interact with the surface of parasites to impede attachment to host surfaces (Artis, 2006; Pemberton et al., 2004). The secretory glycoprotein, IPSE/alpha-1, found in SEA is an example of a helminth glycan that does not appear to associate with a classical C-TL for signaling but acts through IgE to induce the production of IL-4 from basophils in an antigen-independent way (Schramm et al., 2007). This ability to elicit IL-4 production in vivo in the absence of antigen-specific IgE offers a potential mechanism for helminth induction of innate IL-4 that can contribute to Th2 cell differentiation.

Lectins also provide a link to the lectin pathway of complement activation, a highly conserved component of innate immunity (Fujita, 2002). Recognition of pathogen-associated carbohydrate residues by the soluble mannose binding lectin (MBL) triggers the serine protease-mediated cleavage of complement components C4 and C2 resulting in the generation of C3 convertase that carries out the rest of the complement cascade (Fujita, 2002). Recognition by MBL is an integral part of the first line of defense against a large number of microbial pathogens including bacteria, fungi, protozoa, and viruses and a recent study using MBL-A knockout mice has identified a role for MBL in regulating resistance to the filarial nematode Brugia malayi (Carter et al., 2007). While MBL expression has been detected in intestinal epithelial cells (Uemura et al., 2002) and MBL can bind and initiate complement activation in response to S. mansoni (Klabunde et al., 2000) and T. spiralis (Gruden-Movsesijan et al., 2003), its function in vivo during intestinal helminth infection has not yet been determined.

Interestingly, helminths not only provide a source of ligands for host C-TLs but a number of ascarid and strongylid nematodes, including Necator americanus, Nippostrongylus brasiliensis, Ancylostoma ceylanicum, Ascaris suum, Haemonchus contortus, and Toxocaris canis encode their own C-TL-like proteins (Loukas and Maizels, 2000). The function of these helminth-derived lectins is as yet unknown but the highly glycosylated nature of the mucin barrier in the gastrointestinal tract and airway epithelium would suggest a potential role for parasite C-TLs in immune evasion or tissue recognition (Loukas and Maizels, 2000). Significant heterogeneity exists in the structure and composition of mucins along the gastrointestinal tract (Moncada et al., 2003) and given the specificity of C-TL binding, these host-parasite interactions could provide necessary signals for host species-restricted establishment of helminth parasites.

Innate recognition of proteases

The natural life cycle of many helminths involves extensive migration through host tissues such as the skin, lung, and intestine. Traversing these tissues as larvae and establishing permanent residence in host tissues as adults is facilitated by the secretion of a number of parasite-derived proteases that allow the digestion of structural proteins like fibronectin, collagen, and laminin (McKerrow et al., 2006; Falcone et al., 2004). For a number of years it has been recognized that many protein allergens, such as house dust mite-derived Der p 1, Fel d1 from domestic cats, and fungal allergens, also possess intrinsic protease activity (Falcone et al., 2004). Similar to helminth parasites, these allergens most often gain access to host tissues at mucosal sites and in some individuals elicit potent Th2 cytokine responses with many of the hallmarks of helminth infection including eosinophilia, goblet cell hyperplasia, and elevated serum IgE levels. While the link between protease activity and type 2 inflammation is well documented, the mechanistic basis for these observations has been unclear.

Basophils, innate immune cells able to rapidly secrete IL-4 in vitro following stimulation with anti-IgE (Gessner et al., 2005) as well as in response to allergens and helminth antigens (Phillips et al., 2003), are poised at the interface between the innate sensing of antigens and the initiation of adaptive Th2 cytokine responses. Medzhitov and colleagues recently demonstrated that protease-mediated activation of basophils might be a shared link between allergens and helminth infection. Immunization with the cysteine protease allergen, papain, resulted in the transient recruitment of basophils to lymph nodes that peaked one day prior to the peak of IL-4 producing CD4 T cells (Sokol et al., 2008). These papain-elicited basophils within the lymph node were shown to express thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine produced predominantly by epithelial cells and implicated in CD4 Th2 cell differentiation (Zhou et al., 2005). In vivo depletion of TSLP or basophils correlated with impaired Th2 cell differentiation following papain immunization, suggesting a role for basophil-derived TSLP in papain-mediated Th2 cytokine responses. Interestingly, TSLP-TSLPR interactions are critical for immunity to T. muris, although the dominant cellular source of TSLP was intestinal epithelial cells (Zaph et al., 2007). Whether conserved mechanisms exist to promote expression of TSLP in multiple cell lineages is unclear at present. Of note, treatment of basophils with papain in vitro also resulted in the production of IL-4, IL-6, and TNF but not histamine, reminiscent of the ability of helminth products, like ES-62, to selectively induce cytokine production while limiting release of pro-inflammatory mediators from innate effectors (Sokol et al., 2008). While these data are consistent with a role for secreted proteases in the direct activation of basophils, the mechanism of host recognition remains unknown. Given their multiple roles in regulating inflammation, cellular trafficking, and epithelial barrier function members of the protease-activated receptor (PAR) family (Amadesi and Bunnett, 2004) are appealing potential molecular targets for helminth proteases. Recent work from Shea-Donohue and colleagues demonstrated that Nippostrongylus brasiliensis infection induced an IL-13-dependent increase in PAR-1 expression in the small intestine and that PAR-1 expression was associated with increased smooth muscle hypercontractility (Zhao et al., 2005) though whether innate activation of other PAR family members can occur in the absence of IL-13 remains unknown.

Another potential mechanism by which protease allergens may influence Th2 cytokine responses is via the degradation of IL-13Rα2. It was recently demonstrated that prolonged exposure to house dust mite or mold allergens in vitro resulted in the cleavage and degradation of the soluble IL-13Rα2 (Daines et al., 2007), a decoy receptor proposed to modulate IL-13R signaling (Chiaramonte et al., 2003). Degradation of IL-13Rα2 resulted in enhanced IL-13R-dependent STAT6 activation and was dependent upon the protease activity of the allergens as protease inhibitor treatment abrogated the effect. Whether this mechanism is conserved between allergens and nematode ES protease products however is unknown.

Recruitment of innate effector cells by chitin

Chitin is one of the most abundant natural polymers on earth and is found in fungi, protozoa, insects, crustaceans, and parasitic nematodes. Recent studies have implicated chitin, as well as the enzymes involved in its degradation, in the etiology of airway inflammation and regulation of Th2 cytokine responses (Reese et al., 2007; Zhu et al., 2004). In nematodes, chitin provides support for structures such as the pharynx and is a key component of parasitic and free-living nematode egg shells; H. polygyrus eggs for example are composed of nearly 5% chitin by weight (Arnold et al., 1993). Recently, it was demonstrated that the intranasal administration of chitin induced an accumulation of eosinophils and basophils, innate immune cells competent to produce IL-4, in the lung (Reese et al., 2007), identifying a novel mechanism by which helminth-derived antigens may drive type 2 inflammation. Exposure to chitin also induced the alternative activation of macrophages as indicated by the presence of arginase-expressing cells in the lung as early as 6 hours post-intranasal administration of chitin. The recruitment of innate immune cells was dependent upon both expression of the high affinity receptor for leukotriene B4, BLT1, and upon the presence of macrophages as clodronate liposome depletion of macrophages prior to i.p. injection of chitin efficiently abrogated eosinophil recruitment to the peritoneum (Reese et al., 2007), suggesting that macrophages may be an early cellular target for chitin recognition. The role of chitin in innate immune cell recruitment in the context of helminth infection models and the mechanism of chitin recognition are still unclear but represent exciting avenues of future research.

Influence of innate immune cells on the development of protective Th2 cytokine responses against helminth parasites

Activation of intestinal epithelial cells

Intestinal epithelial cells (IEC) express a broad range of PRR including TLR, intracellular Nod proteins, and C-TL, as well as classical and non-classical MHC molecules involved in antigen processing and presentation (Shao et al., 2005). The intimate association of intestinal dwelling nematodes with IEC, T. muris for example lives partially embedded within IEC-derived syncytial tunnels (Tilney et al., 2005), coupled with their expression of PRR and antigen-presenting machinery situate them as sentinels in recognition of helminth parasites in the intestine. Using IEC-specific knockout mice, our lab recently demonstrated that IEC-intrinsic NF-κB activation is critical in the development of anti-helminth Th2 cytokine responses (Zaph et al., 2007). In that study, loss of NF-κB-dependent TSLP expression in IEC was correlated with exaggerated production of IL-12/23p40 and TNF by intestinal DC, consistent with the development of an inappropriate Th1 response following T. muris infection. TSLP can also act directly on mast cells (Allakhverdi et al., 2007b) although the role of IEC-mast cell interactions in innate responses to helminth parasites is unclear at present. In addition to TSLP, IEC are a major source of IL-25 and IL-33, two cytokines associated with the promotion of Th2 cytokine responses at mucosal sites. IL-25 appears to act directly on either CD4 T cells (Angkasekwinai et al., 2007) or mast cells (Fallon et al., 2006) to augment expression of Th2 cytokines and is critical for protective immunity following intestinal helminth infection (Owyang et al., 2006). IL-33 can also directly promote Th2 cytokine production from CD4 T cells (Schmitz et al., 2005) and activate mast cells (Allakhverdi et al., 2007a). Recently IL-33 has been shown to accelerate worm expulsion when administered during T. muris infection as well as mediate lymphocyte-independent pathological changes in the intestine (Humphreys et al., 2008). A critical question is how IECs are activated following exposure to helminth parasites and what molecular pathways control expression of cytokines as diverse as TSLP, IL-25 and IL-33.

Granulocytes respond to helminth products by release of inflammatory mediators

As discussed above, granulocytes such as basophils, eosinophils, and mast cells are recruited early to sites of helminth infection and draining lymph nodes and are postulated to contribute to the generation and maintenance of CD4 Th2 cells through the rapid release of Th2-associated cytokines IL-4, IL-13, and, in the case of basophils, TSLP (Sokol et al., 2008; Gessner et al., 2005). In addition to cytokine production, recent studies have highlighted a novel group of endogenous inflammatory mediators derived from granulocytes, macrophages, and epithelial cells, called “alarmins” that can serve both as chemoattractants and provide maturation signals to DC (Oppenheim and Yang, 2005). Among this group of mediators that includes defensins, cathelicidins, and high-mobility group box protein 1, the RNase A superfamily member eosinophil-derived neurotoxin (EDN) has recently been shown to augment the capacity to DC to promote Th2 cell differentiation in a TLR2-dependent manner (Yang et al., 2008). The recruitment of eosinophils to mucosal sites following infection with several species of helminth parasites and during allergic responses suggests a potential role for EDN in initiating or maintaining Th2 cytokine responses. However, in most helminth infection models depletion of eosinophils via anti-IL-5 or anti-CCR3 treatment or genetic deletion has demonstrated that eosinophils are not critical for the generation of anti-helminth Th2 cytokine responses (Anthony et al., 2007).

DC and macrophages in immunity to helminths

DC are a critical APC in the priming of naïve CD4 T cells and, as discussed above, can respond to helminth-derived products by promoting CD4 Th2 cell differentiation both in vitro and in vivo. However, the precise signals that DC may provide T cells to promote Th2 cell differentiation are still unclear. Amsen and colleagues have proposed that differential expression of Notch ligands Delta and Jagged by DC may dictate Th1 and Th2 differentiation respectively (Amsen et al., 2004). The defective Th2 polarization of antigen-specific T cells following co-culture with ovalbumin-pulsed jagged2−/− DC support these observations, though the requirement for jagged2 was not replicated in vivo (Worsley et al., 2008). Notwithstanding this, recent studies have demonstrated that T cell-intrinsic Notch activation is critical for optimal Th2 cell differentiation and cytokine production in vivo following T. muris infection (Tu et al., 2005) likely via direct activation of the Th2 transcription factor GATA3 (Amsen et al., 2007; Fang et al., 2007). In addition to the expression of Notch ligands, DC may directly influence Th2 differentiation through expression of co-stimulatory molecules, OX40L and CD40, which have been implicated in the generation of optimal Th2 responses (Jenkins et al., 2007; MacDonald et al., 2002).

While in vitro stimulation with IFN-γ induces the generation of “classically activated” macrophages that produce IL-12 and inducible nitric oxide synthase (iNOS), exposure to Th2 cytokines is associated with the alternative activation of macrophages that express high levels of arginase (Gordon, 2003). As such, AAMacs are hallmarks of helminth-mediated inflammation and are abundant in schistosome egg-induced granulomas and in the lamina propria during intestinal helminth infection. These macrophages have a unique transcriptional profile characterized by expression of the mannose receptor, resistin-like molecule alpha (RELMα), and the chitinase-like molecule YM-1 (Nair et al., 2003). While an essential role in mediating immunity during H. polygyrus challenge (Anthony et al., 2006) and in limiting pathogenic inflammation in S. mansoni infection (Herbert et al., 2004) have been attributed to AAMacs, their ability to influence the generation and/or function of Th2 cells is unknown and is an area of intense research.


Significant advances have been made in delineating the cellular and molecular aspects of the innate immune response that can contribute to Th2 cell differentiation following helminth infection. In this review, we have highlighted recent studies aimed at the identification of conserved features of helminth products that interact with innate immune cells to coordinate adaptive anti-parasite responses (Figure 1). However, key challenges for the future include further defining the nature of helminth-derived factors and the cell types and signaling pathways that orchestrate the early immune responses required for host protective immunity.

Figure 1
The orchestration of CD4 Th2 cell differentiation following innate immune cell recognition and response to helminth-derived products


The authors would like to thank Meera Nair and Paul Giacomin for critical reading of the manuscript. Research in the Artis lab is supported by the National Institutes of Health (NIH), AI61570, AI 074878 (D. Artis), NIH T32 Training Grant AI 007532-08 (J. Perrigoue), the Pilot Feasibility Program of the National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) DK50306, the Crohn’s and Colitis Foundation of America’s William and Shelby Modell Family Foundation Research Award (D. Artis), the UPenn Research Foundation Award and the UPenn Center for Infectious Diseases Pilot Grant. We apologize to colleagues whose work could not be discussed due to space constraints.


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