Harnessing Innate Immunity - Complement and TLR Inhibition in Experimental Models of Gram Positive and Polymicrobial Bacteremia and Sepsis

Abstract

Sepsis is a syndrome of life-threatening organ malfunction caused by a dysregulated host response to infection. The complement, kallikrein/kinin, coagulation and fibrinolysis plasma cascade systems as well as the TLR system recognize and initiate the immediate responses to infection and thus play an important role in the development of sepsis. In this regard, the ubiquitous TLR co-receptor, CD14, as well as C5 have been identified as upstream, bottle-neck targets to attenuate the response to infection. S. aureus is the most common cause of Gram-positive sepsis whereas E. coli is the most common cause of Gram-negative sepsis. Both bacteria activate complement and coagulation, and are recognized by TLRs in human whole blood, triggering the release of inflammatory cytokines, markers of coagulation activation and markers of leukocyte activation. In turn, combined inhibition of complement and CD14 efficiently reduced these responses to S. aureus and E. coli in a human, whole blood model. Furthermore, in a randomized, controlled trial of combined CD14 and C5 inhibition (treatment) versus saline (control) in porcine polymicrobial sepsis, treatment significantly improved survival Preemptive, combined inhibition of CD14 and C5 thus emerges as a potential anti-inflammatory regimen in both S. aureus and E. coli bacteremia.