Assessing the immunomodulatory and haemostatic role of platelets in the type 2 inflammatory response to Schistosoma mansoni

Beyond their role in haemostasis, platelets have been shown to be strongly immunomodulatory, particularly in type 1 inflammatory responses to bacteria and viruses. However, the role of platelets in type 2 inflammation, that characterises helminth infection and allergy is poorly understood. More than 200 million people globally are chronically infected with schistosome parasites which has a massive burden of >3 million disability adjusted life years. Despite large (~1cm long) worms residing in the vasculature for 5-10 years, they do not induce severe inflammation or coagulation. However, infected individuals display a plethora of debilitating symptoms including hepatosplenomegaly and intestinal haemorrhaging due to thousands of schistosome eggs transiting through and lodging within host tissues. This thesis aims to assess the haemostatic alterations and functional consequences of platelet-immune cell cross-talk in schistosomiasis.

We used a murine model of chronic Schistosoma mansoni infection to examine specific platelet-leukocyte interactions and the effect these have on inflammation. Chronic schistosome infection induces thrombocytopenia (~500x10^3/mm^3) that persists after drug-mediated worm clearance. In vivo platelet tracking revealed accelerated hepatic and splenic platelet clearance in schistosome infection, and this occurred in an FcγR-independent manner. Furthermore, there was a significant increase in platelets aggregating with specific hepatic macrophage subsets (Ly6Cˡᵒ MHCIIˡᵒ RELMαʰⁱ). Live cell imaging in vitro experiments revealed that platelets enhanced the phagocytic ability of M2 macrophages without altering MHCII or RELMα expression. Surprisingly, platelets from schistosome-infected mice spontaneously aggregated in the absence of exogenous agonists despite not having an activated platelet phenotype, yet show prolonged clotting time. We used multiple experimental strategies to deplete or increase platelet numbers in schistosome infection, and this highlighted the challenges of separating the haemostatic and immunological roles of platelets in vivo. Work in this thesis demonstrates how schistosome infection disrupts platelet lifespan and functionality, whilst promoting enhanced interactions with immune cells.