Acinetobacter baumannii Gastrointestinal Colonization Is Facilitated by Secretory IgA Which Is Reductively Dissociated by Bacterial Thioredoxin A.

Patrick M Ketter,J Seshu,Andrew P Cap,Jieh-Juen Yu,Mark Eppinger,M Neal Guentzel,Rishein Gupta,Bernard P Arulanandam,Karl E Klose,Holly C May,James P Chambers

doi:10.1128/mbio.01298-18

Abstract

ABSTRACTMultidrug-resistant Acinetobacter baumannii is among the most common causes of infectious complications associated with combat-related trauma in military personnel serving overseas. However, little is currently known about its pathogenesis. While the gastrointestinal (GI) tract has been found to be a major reservoir for A. baumannii, as well as to potentially contribute to development of multidrug resistance, no studies have addressed the mechanisms involved in gut colonization. In this study, we address this critical gap in knowledge by first assessing the interaction between secretory IgA (SIgA), the principal humoral immune defense on mucosal surfaces, and the A. baumannii clinical isolate Ci79. Surprisingly, SIgA appeared to enhance A. baumannii GI tract colonization, in a process mediated by bacterial thioredoxin A (TrxA), as evidenced by reduction of bacterial attachment in the presence of TrxA inhibitors. Additionally, a trxA targeted deletion mutant (ΔtrxA) showed reduced bacterial burdens within the GI tract 24 h after oral challenge by in vivo live imaging, along with loss of thiol-reductase activity. Surprisingly, not only was GI tract colonization greatly reduced but the associated 50% lethal dose (LD50) of the ΔtrxA mutant was increased nearly 100-fold in an intraperitoneal sepsis model. These data suggest that TrxA not only mediates A. baumannii GI tract colonization but also may contribute to pathogenesis in A. baumannii sepsis following escape from the GI tract under conditions when the intestinal barrier is compromised, as occurs with cases of severe shock and trauma.

Highlights

Multidrug-resistant Acinetobacter baumannii is among the most common causes of infectious complications associated with combat-related trauma in military personnel serving overseas
We found that secretory IgA (SIgA) contributes to A. baumannii colonization in a murine oral GI challenge model but that the organism reduces the disulfide bonds of SIgA, causing separation of secretory component (SC) from dimeric IgA in a process mediated by secreted bacterial thioredoxin A (TrxA)
Since SIgA is the primary immunoglobulin associated with mucosal surfaces, including the GI tract [22], we set out to determine if it was protective against A. baumannii GI tract colonization and infection

Summary

Introduction

Multidrug-resistant Acinetobacter baumannii is among the most common causes of infectious complications associated with combat-related trauma in military personnel serving overseas. IMPORTANCE Acinetobacter baumannii is an emerging bacterial pathogen recently classified as a serious threat to U.S and global health by both the Centers for Disease Control and Prevention and the World Health Organization It is one of the leading causes of combat-related infections associated with injured military personnel serving overseas. Bacterial colonization and mortality were significantly reduced in animals challenged with a thioredoxin A-deficient A. baumannii mutant Combined, these data suggest that thioredoxin A is a novel virulence factor, for which antithioredoxin therapies could be developed, for this important multidrug-resistant pathogen. We found that SIgA contributes to A. baumannii colonization in a murine oral GI challenge model but that the organism reduces the disulfide bonds of SIgA, causing separation of SC from dimeric IgA in a process mediated by secreted bacterial thioredoxin A (TrxA)

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