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Regulation of Innate Immune Responses is Required for S. mansoni Development
Uniformed Services University Of The Health Sciences Bethesda United States
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Helminth blood flukes of the genus Schistosoma infect over 200 million people. As a result of host-parasite co-evolution, S. mansoni evolved to exploit host immune factors as signals to coordinate its own development. Worms fail to develop normally in RAG-- mice, lacking T and B cells, while development is restored by adoptive transfer of CD4 T cells, suggesting that CD4 T cells play a central role in regulating parasite development. Recent findings suggest the role of CD4 T cells in this process is indirect, being limited to provision of non-cognate T cell help for innate responses which, in turn, facilitate parasite development. In support of this hypothesis, we have found that long-term stimulation of TLR4 by LPS, a pathogen associated molecular pattern PAMP, in RAG-- mice, in the absence of CD4 T cells, also restores worm development, indicating that innate immune signals are sufficient for parasite development to proceed normally. We have also found that chronic TLR stimulation via other PAMPs that utilize MyD88 dependent signaling, as well as chronic inflammasome signaling were also sufficient to restore worm development in RAG-- mice. Chronic stimulation of both of these pathways resulted in down-regulated proinflammatory responses leading us to hypothesize that regulation of innate immune responses are necessary for restoration of S. mansoni development. In support of this hypothesis we found blocking TNF- or administering IL-4 also led to the regulation of pro-inflammatory immune responses that favored parasite development as well. Administering IL-4 to immunodeficient mice also resulted in the establishment of Th2 like immune environment. This suggests that in immunologically intact animals it is the establishment of Th2 responses that promote parasite development. Elucidation of the innate immune signals that control schistosome development could provide leads for the development of new drug targets and vaccine strategies.
APPROVED FOR PUBLIC RELEASE