The focus of the studies proposed in this application is to dissect the effects of modulation of anti-malarial immunity by nematode co-infection and the underlying mechanisms involved. Modulation of immune responses to unrelated antigens or infections, including malaria, by helminth parasites has been documented in clinical and experimental studies. A striking feature of human helminthiases, which occur primarily in developing countries, is that their geographic distribution largely overlaps that of malaria. One of the factors responsible for the disappointing results of recent human trials with recombinant subunit malaria vaccines has recently been suggested to be concurrent helminth infection. The proposed studies will test the hypothesis that concurrent nematode infection alters anti-malarial immunity via counter-regulatory, immunomodulatory cytokines produced during the Th2 type immune response characteristic of helminth infection. It is postulated that the anti-helminth Th2 immune response antagonizes Th1 type immunity required for control of primary and challenge infections with malaria. Alternatively, helminth parasites or their products may directly inhibit anti-malarial immunity via a more generalized immunosuppressive mechanism. The murine models of blood-stage Plasmodium chabaudi AS malaria and of Heligmosomoides polygyrus, a gastrointestinal nematode parasite, which is a model of human hookworm, will be used.
Four specific aims are proposed to: a) determine if protective immunity to primary blood-stage malaria is impaired by concurrent nematode infection; b) determine the effect of concurrent nematode infection on the efficacy of vaccine-induced anti-malarial immunity; c) determine (i) if anti-malarial immunity is restored after deworming nematode infected mice and (ii) if novel vaccine adjuvants can correct impaired vaccine-induced immunity in co-infected mice; and d) determine the cellular and molecular mechanisms involved in modulation of anti-malarial immunity by nematode co-infection. The approaches to be used include animal models of co-infection, immunology, molecular immunology, and cell-culture. The scientific knowledge derived from this study will be useful in designing rational and innovative strategies to overcome the effects of co-infection with helminth parasites in malaria endemic areas.
| Segura, M; Matte, C; Thawani, N et al. (2009) Modulation of malaria-induced immunopathology by concurrent gastrointestinal nematode infection in mice. Int J Parasitol 39:1525-32 |
| Segura, Mariela; Su, Zhong; Piccirillo, Ciriaco et al. (2007) Impairment of dendritic cell function by excretory-secretory products: a potential mechanism for nematode-induced immunosuppression. Eur J Immunol 37:1887-904 |
| Su, Zhong; Segura, Mariela; Stevenson, Mary M (2006) Reduced protective efficacy of a blood-stage malaria vaccine by concurrent nematode infection. Infect Immun 74:2138-44 |
| Su, Zhong; Segura, Mariela; Morgan, Kenneth et al. (2005) Impairment of protective immunity to blood-stage malaria by concurrent nematode infection. Infect Immun 73:3531-9 |
