Elucidating the Role of Inherited Complement System Defects in the Molecular Pathophysiology of Sepsis and Purpura Fulminans

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PROJECT SUMMARY Purpura fulminans (PF) is a rare but devastating complication of sepsis in which patients develop a highly thrombotic subtype of disseminated intravascular coagulation (DIC), leading to dismemberment, end organ damage, and death. PF can be triggered by a range of bacterial infections and is distinguished by extremely high levels of circulating cytokines and failure of key anti-inflammatory pathways which cause a marked upregulation of procoagulant tissue factor (TF) expression by activated monocytes. Because PF represents an extreme disease phenotype, leveraging our findings in this disorder could yield key insights into the broader problem of septic DIC. However, at present almost nothing is known about the molecular pathophysiology and genetic predisposition underlying PF. Utilizing germline whole exome sequencing (WES) and a targeted gene discovery approach, we have found a significant enrichment in rare, deleterious coding variants in the complement systems of patients with PF compared to unselected patients with sepsis (P<0.0001). Intriguingly, we also found that these variants may be associated with increased mortality in unselected sepsis patients despite the absence of overt PF. We hypothesize that complement system defects lead to heightened systemic inflammation and procoagulant activity, resulting in the development of coagulopathy. In Aim 1 of this project, we will follow up on our preliminary results by performing WES on clinically well-annotated specimens in the NHLBI BioLINCC repository from septic patients without overt PF. We will correlate complement mutational status to plasma biomarkers of thrombosis and inflammation after adjusting for age, sex, ethnicity, and comorbidities in order to understand if complement system defects are associated with worsened thrombo-inflammation in sepsis. In Aim 2, we will functionally characterize a novel class of rare PF-associated variants in complement receptors 3 and 4 (CR3/4) with respect to their impact on monocyte-driven inflammation and thrombosis. The proposed work will provide important new insights into the relationship between innate immunity and dysregulated coagulation and generate a foundational WES dataset with biological correlates for studying the widespread problem of coagulopathy in sepsis.