Parasitic helminths exhibit the remarkable ability to establish chronic, often lifelong, infections by triggering multiple mechanisms to dampen the host immune response. These immunoregulatory pathways protect the host from excessive infection-induced tissue damage, and can be exploited for new therapies to treat inflammation. Using transgenic mice that express human resistin (hRetn) and Nippostrongylus brasiliensis as a mouse model of geohelminth infection, we identified hRetn as an immunomodulatory protein that impaired helminth expulsion but was critically protective in a mouse model of sepsis involving injection of a fatal dose of LPS. Mechanistically, hRetn bound the LPS receptor TLR4 and inhibited LPS binding and signaling. Based on these results, we hypothesize that the function of helminth-induced resistin is to dampen excessive LPS-induced inflammatory responses, which may arise from helminth- induced tissue damage or sepsis. We propose to elucidate the mechanism by which helminth- induced hRetn protects against sepsis and generate new hRetn fusion proteins to treat LPS- induced inflammation.
In Aim 1, we will examine how helminth-induced hRetn regulates LPS- induced pathogenesis and if this regulatory pathway is dependent on TLR4.
In Aim 2, we will generate new hRetn proteins fused with human Fc immunoglobulin and hRetn peptides that can be used therapeutically to treat sepsis.
Parasitic helminths trigger multiple immunoregulatory pathways to prevent their own expulsion that can be harnessed to treat inflammation. We identify human resistin as a helminth-induced protein that prevents endotoxic shock, and will elucidate this anti- inflammatory pathway and test new resistin reagents to treat endotoxic shock. Identifying new regulators of LPS-induced inflammation has therapeutic implications for several inflammatory diseases beyond helminth infection, including sepsis.
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