Immunopathology of intestinal helminth infection

The relationship between intestinal pathology and immune expulsion of gastrointestinal nematodes remains controversial. Parasite expulsion is associated with intestinal pathology in several model systems and both of these phenomena are T cell dependent. However, while immune expulsion of gastrointestinal helminth parasites is usually associated with Th2 responses, the effector mechanisms directly responsible for parasite loss have not been elucidated. In contrast, the intestinal pathology observed in many other disease models closely resembles that seen in helminth infections, but has been attributed to Th1 cytokines. We have used infection with the nematode Trichinella spiralis in mice defective for cytokines to demonstrate that although parasite expulsion is indeed IL-4 dependent, contrary to expectations, the enteropathy is also regulated by IL-4. Furthermore, abrogation of severe pathology in iNOS deficient and TNF receptor defective animals does not prevent parasite expulsion. TNF and iNOS are therefore involved in intestinal pathology in nematode infections, apparently under regulation by IL-4 and Th2 mediated responses. Therefore, it appears that the IL-4-dependent protective response against the parasite operates by a mechanism other than merely the gross degradation of the parasite's environment brought about by the immune enteropathy. However, it remains important to elucidate the protective mechanisms involved in parasite expulsion, which are still unclear.     

Worms: Pernicious parasites or allies against allergies?

Type 2 immune responses are most commonly associated with allergy and helminth parasite infections. Since the discovery of Th1 and Th2 immune responses more than 30 years ago, models of both allergic disease and helminth infections have been useful in characterizing the development, effector mechanisms and pathological consequences of type 2 immune responses. The observation that some helminth infections negatively correlate with allergic and inflammatory disease led to a large field of research into parasite immunomodulation. However, it is worth noting that helminth parasites are not always benign infections, and that helminth immunomodulation can have stimulatory as well as suppressive effects on allergic responses. In this review, we will discuss how parasitic infections change host responses, the consequences for bystander immunity and how this interaction influences clinical symptoms of allergy.     

Protection and pathology during parasite infection: IL‐10 strikes the balance

The host response to infection requires an immune response to be strong enough to control the pathogen but also restrained, to minimize immune‐mediated pathology. The conflicting pressures of immune activation and immune suppression are particularly apparent in parasite infections, where co‐evolution of host and pathogen has selected many different compromises between protection and pathology. Cytokine signals are critical determinants of both protective immunity and immunopathology, and, in this review, we focus on the regulatory cytokine IL‐10 and its role in protozoan and helminth infections. We discuss the sources and targets of IL‐10 during parasite infection, the signals that initiate and reinforce its action, and its impact on the invading parasite, on the host tissue, and on coincident immune responses.     

Granulocytes: effector cells or immunomodulators in the immune response to helminth infection?

Granulocytes are effector cells in defence against helminth infections. We review the current evidence for the role of granulocytes in protective immunity against different helminth infections and note that for each parasite species the role of granulocytes as effector cells can vary. Emerging evidence also points to granulocytes as immunomodulatory cells able to produce many cytokines, chemokines and modulatory factors which can bias the immune response in a particular direction. Thus, the role of granulocytes in an immunomodulatory context is discussed including the most recent data that points to an important role for basophils under this guise.     

Worms and allergy

Worms and asthma are associated with a type 2 immune response, but evidence has accumulated that helminth infection is negatively associated with atopy, prevalence of allergic diseases and severity of asthma. One important difference between these polarized type 2 responses is that in allergy modulation of the immunological response is not appropriate, whereas in infection with helminths, several host mechanisms down-regulate the host immune response. As a result, patients infected with worms have a decrease in both type 1 and type 2 responses. The main mechanism involved in this down-modulation is increased production of IL-10, but expansion of regulatory T cells and NKT cells may also participate. Regarding the interaction between worms and allergy, a few variables need to be taken in account: phase (acute or chronic) of helminth infection, parasite load and species of helminth. In animals and humans, acute helminth infection may increase manifestations of allergy, whereas chronic infection with parasites decreases atopy. The modulation of the immune response by helminths is dependent on having an adequate parasite load. Moreover, although several helminth species have been shown to modulate immune responses, most in vitro and in vivo studies have focused on the importance of Schistosoma mansoni in down-modulating allergic reactions.     

Co-infection of helminths and malaria: modulation of the immune responses to malaria

Chronic helminth infections induce strong type 2 and regulatory immune responses and are known to influence immune activity to other antigens such as allergens and vaccines. Since malaria and helminth infections often coincide geographically in the same tropical regions, the question arises whether helminth infections modulate the immune responses towards the malaria parasite and affect its course of disease. Here, we will review studies on co-infections in both animal models and in human populations, and discuss the changes in the immune system seen. Furthermore, the implications of helminth infection for the efficacy of malaria vaccines will be discussed.     

Mouse mast cell protease-1 is required for the enteropathy induced by gastrointestinal helminth infection in the mouse

BACKGROUND & AIMS: The relationship between intestinal pathology and immune expulsion of gastrointestinal nematodes remains controversial. Immune expulsion of gastrointestinal helminth parasites is usually associated with Th2 responses, but the effector mechanisms directly responsible for parasite loss have not been elucidated. Mast cell hyperplasia is a hallmark of infection with gastrointestinal nematodes, in particular Trichinella spiralis. Although the precise mechanism by which mast cells induce expulsion of these parasites has not been elucidated, it has been proposed that mast cell mediators, including cytokines and granule chymases, act to create an environment inhospitable to the parasite, part of this being the induction of intestinal inflammation. Therefore, the aims of this study were to dissect the role of mast cells and mast cell proteases in the induction of parasite-induced enteropathy. METHODS: Mast cell-deficient W/Wv and mouse mast cell protease-1 (mMCP-1)-deficient mice were infected with T. spiralis, and parasite expulsion, enteropathy, and Th2 responses were determined. RESULTS: Expulsion of the parasite was delayed in both strains of mice compared with wild-type controls; additionally, in both cases, the enteropathy was significantly ameliorated. Although Th2 responses were significantly reduced in mast cell-deficient W/Wv mice, those from mMCP-1-deficient mice were similar to wild-type mice. Additionally, levels of TNF-alpha and nitric oxide were significantly reduced in both W/Wv and mMCP-1 deficient mice. CONCLUSIONS: These results imply that mast cells may contribute to the induction of protective Th2 responses and, importantly, that the intestinal inflammation associated with gastrointestinal helminths is partly mediated by mMCP-1.     

Hookworm infections in human and laboratory animals--differences and similarities in immune responses

Hookworm infection is one of the most important parasitic infections of humans. About 740 million people are infected with Ancylostoma duodenale and Necator americanus in the tropics and subtropics. Unlike most other human helminth infections, neither age nor exposure-related immunity develops in the majority of infected people. This review presents the contemporary knowledge concerning the immune response to this complex eukaryotic parasite, recent findings on the human cellular immune responses to hookworms, as well as mechanisms used by the parasite to modulate the immune response in its favor. Also immunological responses in animal models of hookworm infection are presented. Animals in contrast to humans seem to easily deal with hookworm infections and gain protection during re-exposure.     

Prospects for recombinant vaccines against Babesia bovis and related parasites

Babesial parasites infect cattle in tropical and temperate regions of the world and cause significant morbidity and mortality. Discovery of protective antigens that could be used in a killed vaccine has been slow and to date there are few promising vaccine candidates for cattle Babesia. This review describes mechanisms of protective innate and adaptive immune responses to babesial parasites and different strategies to identify potentially protective protein antigens of B. bovis, B. bigemina, and B. divergens. Successful parasites often cause persistent infection, and this paper also discusses how B. bovis evades and regulates the immune response to promote survival of parasite and host. Development of successful non-living recombinant vaccines will depend on increased understanding of protective immune mechanisms and availability of parasite genomes.