Functional Characterization and Proteomic Assessment of Thioredoxin-mediated Alteration of Outer Membrane Vesicles in Acinetobacter Baumannii




Shrihari, Swathi

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Acinetobacter baumannii is an emerging multidrug resistant, Gram-negative bacterium which causes ventilator associated pneumonia, wound infection, and sepsis. Outer membrane vesicles (OMVs) are produced by Gram-negative bacteria and play an important role in pathogenesis. OMVs are composed primarily of outer membrane and periplasmic proteins. Some cytosolic and inner membrane proteins, RNA, DNA, peptidoglycan, and lipopolysaccharide (endotoxin) also may be present. OMVs have been evaluated as vaccine candidates against various bacterial infections due to their antigenic nature and involvement in immune modulation. Previously, our laboratory has shown that deletion of the thioredoxin A (TrxA) gene in A. baumannii reduced bacterial virulence, and that vaccination with trxA was protective against wild type (WT) A. baumannii systemic infection. To further evaluate trxA OMVs as a vaccine candidate, we first assessed OMV cytotoxicity and observed that trxA OMVs exhibited greater cytotoxicity compared to WT OMV preparations. Because thioredoxins have been shown to provide a favorable reducing environment for protein folding and subsequent activation, we postulate that TrxA deletion can lead to alteration of OMV proteins, thus influencing OMV-mediated function(s). We therefore compared the protein content of WT and mutant OMVs by proteomic analysis. We observed that upregulated and unique trxA OMV proteins consisted of many membranes bound proteins involved in small molecule transport, as well as proteolytic activity. Bacterial OmpA, metalloprotease, and fimbrial protein have been shown to enhance mammalian cell apoptosis through various mechanisms. Upregulation of these proteins in trxA OMVs may contribute to the increase of cytotoxicity observed in this study.


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Integrative Biology