Immunomodulatory role of platelets ITAM receptors in systemic inflammation and sepsis associated with cardiovascular diseases (360G-Wellcome-220106_Z_20_Z)

Sepsis is a dysregulated response to infection that has a high mortality. It is associated with low platelet count, a dysfunctional inflammatory response and multiple organ failure. Patients with cardiovascular disease have a higher risk of developing sepsis with worse outcomes, particularly in the elderly. In this project we will investigate whether cardiovascular diseases and ageing induce a pro-inflammatory and prothrombotic state during sepsis that is mediated by upregulation of platelet activity. We will determine whether this is ameliorated by inhibition of platelet immune receptors GPVI, CLEC-2 and FcγRIIa, which modulate inflammation and pathogenic thrombosis but have a minimal role in haemostasis. We will investigate these mechanisms in platelets and immune cells from patients with cardiovascular disease and validate these observations in clinically relevant experimental sepsis models associated with chronic cardiovascular diseases (e.g. atherosclerosis and heart failure). We will inhibit the platelet receptors GPVI, CLEC-2 and FcγRIIa using a range of different approaches and determine effects on sepsis progression and outcome. This work will help understanding the influence of cardiovascular disease and age on sepsis and provides a novel approach for targeting platelet-immune cell interactions in sepsis using new drugs that target platelet immune receptors.