Crosstalk of macrophages and eosinophils in helminth-mediated protection during experimental sepsis

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Sepsis occurs when bacteria enter the blood stream. Accompanying, excessive immune activation during sepsis causes pathology and eventual death by multi-organ failure. The ultimate goal of this project is to identify mechanisms to suppress this excess inflammation without impeding clearance of the bacterial infection. We postulate that investigating the effects helminth infections have on the immune response that develops during sepsis will enable us to identify such mechanisms. In contrast to bacteria, filarial helminth species release up to millions of microfilariae (progeny of filaria) per milliliter of blood without inducing inflammation. To avoid inflammation, helminths modulate the hosts immune system and induce an anti-inflammatory, suppressive milieu. Experimental studies showed that immunomodulation by helminths prevent or improve allergies and autoimmune diseases. However, the impact of chronic helminth infections on acute systemic pro-inflammatory immune responses like sepsis is scarcely understood. Using the only mouse model of filariasis that allows chronic filarial infection, we were able to show that chronic infection of mice with the filarial nematode Litomosoides sigmodontis (Ls) improves clearance of i.p. injected E. coli bacteria and ameliorates hypothermia. Chronic infection with Ls results in eosinophilia, induction of anti-inflammatory, alternatively activated macrophages (AAM) and reduces E. coli mediated pro-inflammatory immune responses. Depletion of macrophages, eosinophils and anti-inflammatory TGF beta reduces the Ls mediated protective effect against an E. coli challenge.This grant proposal will focus on the role of Ls-modulated macrophages from liver, spleen, and peritoneum as well as eosinophils during an E. coli challenge. Analyzes will include phenotypic and functional characterization as well as gene expression. Transfer and depletion experiments will investigate the role of AAM and TGF beta and unravel which macrophage and eosinophil derived mediators are crucial for the protection against E. coli. The crosstalk of macrophages and eosinophils with neutrophils and mast cells will be analyzed in this context.Following sepsis, a compensatory anti-inflammatory response syndrome (CARS) develops and results in T-cell paralysis that increases the risk for superinfections. As Ls infection efficiently modulates the acute immune response to E. coli, experiments are proposed to test the impact of chronic Ls infection on the adaptive immune response and specific in vivo CD8 T-cell lysis after an E. coli challenge. Further experiments will investigate whether administration of known immunomodulatory filarial antigens protect against E. coli sepsis and CARS. Results of these studies may lead to insights for the development of novel treatments which suppress the excessive inflammation that occurs in sepsis without compromising the bodys ability to clear bacterial infections.