Protective immune mechanisms in helminth infection

Abstract

Important insights have recently been gained in our understanding of how host immune responses mediate resistance to parasitic helminths and control associated pathological responses. Although similar cells and cytokines are evoked in response to infection by helminths as diverse as nematodes and schistosomes, the components of the response that mediate protection are dependent on the particular parasite. In this Review, we examine recent findings regarding the mechanisms of protection in helminth infections that have been elucidated in murine models and discuss the implications of these findings in terms of future therapies.More than two billion people are infected with parasitic helminths 1 . Although infections by these pathogens are generally not fatal, they are associated with high rates of morbidity, with chronic infection often leading to anaemia and malnourishment 1 . Developed countries have controlled these infections through primary health-care programmes and effective public sanitation, but helminth diseases are still widespread in developing nations and often drug treatment does not protect against rapid re-infection. The need for effective vaccines to control these infections is compelling and at least a few clinical trials are currently underway 2,3 ; however, one impediment towards development of an effective vaccine is a lack of understanding of the actual components of the immune response that mediate protection against helminths. In this Review, we examine the host protective mechanisms with regard to the cell types and molecules involved in helminth expulsion and in control of pathological inflammation that is associated with infection.Helminth infections and the corresponding host immune responses are products of a prolonged dynamic co-evolution between the host and parasite. For parasites, it is advantageous to trick the host into developing an ineffective immune response, to find a suitable niche for maturation and propagation, and to do so without killing or unduly harming the host. Conversely, the host NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript has to ideally generate an effective immune response to expel the parasite, and minimize its harmful effects, while not sacrificing its ability to effectively respond to other pathogens. The host immune system evolved in the context of a parasite-replete environment, and the balance of immune effector and regulatory cell populations are at least partly a consequence of ongoing responses to infectious organisms that can often simultaneously invade host tissues. Although such dynamic host-pathogen interactions exist throughout much of the world, in industrialized countries infectious diseases are better controlled as a result of increased hygiene, the administration of vaccines at an early age and the widespread use of antibiotics. Although this has resulted in marked reductions in chronic and severe disease, recent studies indicate a possible adverse effect of this enhanced control of infectious diseases that...

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

“…Furthermore, the physiological changes provoked by the worm infection, such as epithelial cell proliferation and goblet cell hyperplasia, were similar in Tregdepleted and control mice. Thus, it seems that H. p. bakeri, which generally leads to chronic infections, tolerates a broad spectrum of Th2-mediated immune and physiological reactions compared with other intestinal nematodes such as Nippostrongylus brasiliensis, T. muris or T. spiralis, which are more efficiently expelled in acute infections [37,38].In conclusion, our data show that Treg are crucial for the control of helminth-induced pathological changes in the intestine and for limiting Th2 responses. Further studies will have to show whether Treg are involved in mediating the general immunosuppression seen in chronic intestinal nematode infections.…”

“…The general view suggests that expulsion of adult intestinal nematodes is critically dependent on CD4 1 T cells secreting the Th2 effector cytokines and that these cytokines lead to an inhospitable environment, possibly enabling the expulsion of the parasites in the chronic phase of infection [37,38]. It has also been shown that the application of high doses of recombinant IL-4 abrogates primary infections with H. p. bakeri [39].…”

“…Furthermore, the physiological changes provoked by the worm infection, such as epithelial cell proliferation and goblet cell hyperplasia, were similar in Tregdepleted and control mice. Thus, it seems that H. p. bakeri, which generally leads to chronic infections, tolerates a broad spectrum of Th2-mediated immune and physiological reactions compared with other intestinal nematodes such as Nippostrongylus brasiliensis, T. muris or T. spiralis, which are more efficiently expelled in acute infections [37,38].…”

“…However, the release of a broad spectrum of Th2 cytokines was impaired after anti-CD25 Ab treatment, arguing for the side-by-side depletion of Th2 effector cells [23]. In contrast, our model showed that the selective Treg depletion strongly promoted the Th2 response to H. p. bakeri antigen.The general view suggests that expulsion of adult intestinal nematodes is critically dependent on CD4 1 T cells secreting the Th2 effector cytokines and that these cytokines lead to an inhospitable environment, possibly enabling the expulsion of the parasites in the chronic phase of infection [37,38]. It has also been shown that the application of high doses of recombinant IL-4 abrogates primary infections with H. p. bakeri [39].…”

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

“…Much less is known about the factors that induce such Th2-instructing DC. Helminth infections such as Schistosoma mansoni or Nippostrongylus brasiliensis (reviewed in [19,20]) give rise to Th2-cell polarizing DCs, which appear largely immature or only partially mature. Helminth-derived secretory products seem to evoke only mild transcriptional programming and maturation of DCs [21,22].…”