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Title: Counter-regulatory anti-parasite cytokine responses during concurrent Plasmodium yoelii and intestinal helminth infections in mice

item Urban, Joseph

Submitted to: Experimental Parasitology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/1/2008
Publication Date: 6/15/2008
Citation: Noland, G.S., Urban Jr, J.F., Fried, B., Kumar, N. 2008. Counter-regulatory anti-parasite cytokine responses during concurrent Plasmodium yoelii and intestinal helminth infections in mice. Parasite Immunology. 119(2):272-278.

Interpretive Summary: Mouse models provide systems that can define both genetic and immunological characteristics of complex disease interactions. The current study describes the evaluation of co-infection by parasites that stimulate different arms of the immune system, and inherently counter act the effectiveness of the alternative response. Plasmodium yoelii is a protozoan parasite of mice but is representative of the broader species of malaria parasites that infect humans. Heligmosomoides polygyrus is a worm parasite that represents those that commonly infect many livestock and humans. The study shows that prior worm infection can reduce the intensity of the protective immune response to Plasmodium, and minimize the immune arm that limits the infection. It was also found that another unrelated worm infection could simulate the same alteration of immune function and reduced protection against malaria. The observation could not be reproduced by eliminated a key protective protein called IFN-gamma indicating that the interaction between the co-infections was complex and had multiple targets. This observation not only is relevant to co-infection with malaria parasites, but suggests that other infections that are controlled similarly, such as viral and certain bacterial infections, are also at risk from immune alterations by worm infections and surrogates that reduce immune efficacy and enhance poor disease outcomes. This technology will transfer to members of the scientific community that evaluate co-infections and complex disease interactions where immune modulating activity affects immune function in livestock and man.

Technical Abstract: Malaria and helminth infections are two of the most prevalent parasitic diseases in tropical areas. While concomitant infection is common, mechanisms contributing to altered disease outcomes during co-infection remain poorly defined. We have previously reported exacerbation of normally non-lethal P. yoelii malaria in BALB/c mice chronically infected with the intestinal trematode Echinostoma caproni. Here, we examined whether exacerbation is due to suppression of IFN-gamma, a cytokine critical to the anti-malaria response, and also compared immune responses during malaria co-infection with either E. caproni or the intestinal nematode Heligmosomoides polygyrus. Spleen cells from E. caproni and H. polygyrus infected mice produced significantly lower amounts of IFN-gamma during P. yoelii co-infection than malaria-only infected mice. Furthermore, the magnitude of IFN-gamma suppression appeared to correlate with the relative amounts of IL-4 induced by either helminths (E. caproni = low; H. polygyrus = high), but not IL-10. Concurrent malaria infection also suppressed helminth-associated IL-4 responses, indicating that immunologic counter-regulation occurs during malaria-helminth co-infection. Neutralization of IFN-gamma in mice infected only with P. yoelii did not recapitulate exacerbation observed during co-infection, indicating that helminth infection adversely affects multiple anti-malarial immune pathways.