Abstract
Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis.
Highlights
For the past two decades, Acinetobacter baumannii clinical infections have been on the rise due to its facile antimicrobial resistance repertoire, catapulting the organism into the public health spotlight
We found that a highly virulent strain contained a mobile piece of DNA in one of its capsule assembly genes which rendered the gene inactive and removed a single sugar from the bacterium’s complex outer carbohydrate capsule
When we inactivated the same gene in a nonvirulent related strain, it became virulent, and when we repaired the non-functional gene the virulent strain became non-virulent. We determined that this single sugar was critical for innate immune cells to recognize and phagocytose bacteria, and that the cells depended on the deposition of host complement proteins on the capsule to recognize the strains with this extra sugar
Summary
For the past two decades, Acinetobacter baumannii clinical infections have been on the rise due to its facile antimicrobial resistance repertoire, catapulting the organism into the public health spotlight. A. baumannii is the top priority listed on the World Health Organization list of pathogens requiring new therapeutic strategies [1]. A. baumannii isolates exhibit resistance to multiple classes of antimicrobials, leaving certain strains treatable by few antimicrobial therapies and others altogether untreatable [4,5,6]. Together, these factors have made A. baumannii an intractable public health issue refractory to traditional infectious disease therapies and requiring further research into its interaction with the host immune system
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