OC 78.1 - Immunomodulatory and hemostatic role of platelets in the type 2 inflammatory response to Schistosoma mansoni

Background: Beyond their role in hemostasis, platelets are strong immunomodulators in type 1 inflammatory responses to bacteria and viruses. However, the role of platelets in type 2 responses, characteristic of helminth infection, is poorly understood. Schistosome worms infect more than 200 million people, with an annual cost of >3 million disability adjusted life years. Despite their large size (~1cm long), adult worms within the vasculature do not cause coagulation. Nevertheless, infected individuals develop hepatosplenomegaly and intestinal hemorrhaging as eggs transit and lodge within host tissues.

Aims: To assess hemostatic alterations and platelet-immune cell crosstalk in schistosomiasis.

Methods: A novel in vivo platelet-tracking technique was used in a murine model of chronic Schistosoma mansoni infection to examine platelet turnover, platelet-leukocyte interactions and their effect on immune cells. Hemostatic functions were assessed by whole blood aggregometry and platelet phenotyping.

Results: Chronic schistosome infection induces thrombocytopenia (500x10_3/µl) that persists even after drug-mediated worm clearance. Surprisingly, whole blood aggregometry showed platelets from schistosome-infected mice spontaneously aggregate in the absence of exogenous agonists. Whilst platelets lack an activated phenotype, analysis of transcriptomic datasets from schistosome-infected livers revealed multiple pro-coagulation genes are elevated, suggesting a hypercoaguable phenotype. In vivo platelet-tracking showed a 1.3-fold acceleration of hepatic and splenic platelet clearance in schistosome infection, in an FcγR-independent manner. Platelets preferentially interacted with an expanded immature liver macrophage subset (Ly6C(lo)MHCII(lo)RELMα(+)). A series of robust in vitro experiments, using state-of-the-art live-cell imaging, showed platelets enhance the phagocytic ability of type 2 macrophages without impacting the expression of anti-inflammatory molecules (RELMα, Ym1). Platelet depletion led to animal death, highlighting the essential role of platelets in this inflammatory context.

Conclusion(s): Our studies reveal two sides to platelets in type 2 inflammation, with schistosome-induced hemostatic disruption and platelet-mediated immunomodulation. We are now examining infection-induced changes to coagulation and determining the downstream consequences of targeting platelet-immune cell interactions.