971. The Role of Inflammation and Innate Effectors in Passive Immunization for Acinetobacter baumannii Infections

Abstract

BackgroundWe have previously demonstrated that A. baumannii virulence is driven by avoidance of innate effector clearance, resulting in LPS-TLR4 triggering of excess inflammation in the host. We also raised a monoclonal antibody (MAb) that improved survival of mice lethally infected with A. baumannii.MethodsMice were selectively depleted of innate effectors (macrophages with liposomal clodronate, neutrophils with cyclophosphamide, and/or complement with cobra venom factor), infected with an XDR clinical blood isolate of A. baumannii, and treated with placebo or anti-A. baumannii MAb.ResultsSingle disruption of macrophages or neutrophils did not enhance lethality but complement deficiency did. In contrast, singly disrupting complement or neutrophils did not impact bacterial density but macrophage disruption markedly increased it. Thus, a dissociation of bacterial density and survival was observed. MAb therapy was completely protective in mice depleted of a single effector. While dual depletion resulted in diminished MAb efficacy in terms of survival, mice retaining neutrophils had marked improvements in survival with MAb therapy compared with other dual-depletion groups. The dissociation of bacterial density and survival suggested that inflammation was a primary driver of host outcome. Levels of IL-10 and TNFα had a reciprocal relationship in mice across effector depletion groups and were lower in mouse groups with higher survival when adjusted for bacterial density. IL-10 disruption completely abrogated the survival benefit of MAb therapy without altering bacterial clearance mediated by MAb. In contrast, TNFα disruption enhanced MAb efficacy for survival, and the presence of TNFα was antagonistic to MAb efficacy.ConclusionThese results confirm that host outcomes from A. baumannii infection are driven by host inflammatory response rather than bacterial density alone. Furthermore, novel therapeutic approaches seeking to improve outcomes from such infections must seek to shift the balance of pro-/anti-inflammatory cytokines to favor a down-modulated inflammatory response.Disclosures All Authors: No reported Disclosures.