Complement C5 inhibition as sepsis therapy

PROJECT SUMMARY Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Sepsis is a leading cause of death in intensive care units. The contact of pathogens with the intravascular compartment of the host leads to systemic inflammation, wherein activation of the complement and coagulation systems plays critical roles. The objectives of this proposal are to investigate the role of complement activation and its crosstalk with inflammation and coagulation to sepsis progression and multiple organ failure (MOF) and, whether blocking complement activation at the C5 level could prevent MOF and improve the outcome of sepsis. We will use clinically relevant models of sepsis caused by two of the most common pathogens, Escherichia coli and Staphylococcus aureus to: (i) determine the contribution of complement and coagulation to pathogenesis of microthrombosis, vascular dysfunction, organ failure and death; (ii) test stage-specific therapies targeting the complement and coagulation cascades to provide organ protection and survival benefit in sepsis-induced progressive MOF. Successful completion of these aims will determine: (i) whether timed complement inhibition at the C5 level could be used as an effective therapy for sepsis-induced MOF; (ii) if inhibition of C5a receptor-1 signaling could attenuate disease progression and provide organ protection; (iii) if combination therapies employing early treatment with an anticoagulant and a delayed treatment with a C5 inhibitor will provide synergistic protection in cases of high septic bacteremia/shock. Altogether, our project will combine basic and preclinical research to verify novel hypotheses on the pathophysiology of both Gram-negative and Gram-positive sepsis, and test innovative approaches, which in the long-term may save lives from this deadly disease with no specific cure.