Establishment of chronic infection is an important feature of many parasitic diseases. The immune regulatory mechanisms that support the long-term survival of parasites in infected hosts remain poorly understood. Chronic infection by the nematode Trichinella spiralis is established when first-stage larvae infect skeletal muscle cells. We have discovered that eosinophils contribute to the ensuing myositis while simultaneously promoting protection of larvae against immune-mediated destruction. Specifically, we find that muscle larvae are killed in large numbers in two mouse strains that are deficient in eosinophils. These novel observations prompt a re-evaluation of the long-standing paradigm for eosinophil function during nematode infection. Our hypothesis is that eosinophils prevent classical activation of macrophages in order to preserve larvae in muscle. This may be accomplished directly or indirectly and our goal is to elucidate the influence of eosinophils on cells that infiltrate sites of infection. The significance of these effects will be tested by manipulating the relevant mediators in assays of parasite survival. We have identified the developmental stage at which larvae are susceptible to killing, and our specific aims are to discern the functional deviation of infiltrates in eosinophil deficient mice and to rescue larvae with adoptively transferred eosinophils. The studies proposed will advance our long-term goal to define mechanisms of immune regulation during chronic nematode infection. These mechanisms strike a delicate balance by controlling the intensity of disease in infected hosts while simultaneously promoting parasite survival within the host population.
Chronic infections are important causes of human disease and suffering. Pathogens must evade the immune system in order to survive in their hosts for long periods. Parasitic nematodes are particularly adept at establishing chronic infections, yet the mechanisms of immune evasion they deploy remain poorly understood. Importantly, nematode infection engages the immune system in a way that parallels allergic disease. Thus, our studies are likely to generate insight into chronic allergy as well as chronic infection.
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| Gebreselassie, Nebiat G; Moorhead, Andrew R; Fabre, Valeria et al. (2012) Eosinophils preserve parasitic nematode larvae by regulating local immunity. J Immunol 188:417-25 |
