Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis

Bhuiyan, M.S., Ellett, F., Murray, G.L., Kostoulias, X., Cerqueira, G.M., Schulze, K.E., Mahamad Maifiah, M.H., Li, J., Creek, D.J., Lieschke, G.J., Peleg, A.Y.
Proceedings of the National Academy of Sciences of the United States of America   113(34): 9599-604 (Journal)
Registered Authors
Ellett, Felix, Lieschke, Graham J.
Acinetobacter baumannii, chemotaxis, neutrophils, phenylacetate, zebrafish
MeSH Terms
  • Acinetobacter Infections/immunology*
  • Acinetobacter Infections/microbiology
  • Acinetobacter Infections/pathology
  • Acinetobacter baumannii/genetics*
  • Acinetobacter baumannii/immunology
  • Acinetobacter baumannii/metabolism
  • Acinetobacter baumannii/pathogenicity
  • Animals
  • Animals, Genetically Modified
  • Bacterial Proteins/genetics*
  • Chemotaxis/drug effects*
  • Chemotaxis/immunology
  • Embryo, Nonmammalian
  • Female
  • Gene Expression
  • Immunity, Innate
  • Metabolic Networks and Pathways/genetics
  • Mice
  • Mice, Inbred BALB C
  • Neutrophil Infiltration
  • Neutrophils/drug effects
  • Neutrophils/immunology
  • Neutrophils/microbiology
  • Phenylacetates/metabolism*
  • Phenylacetates/pharmacology
  • Transcription Factors/deficiency
  • Transcription Factors/genetics*
  • Virulence
  • Virulence Factors/deficiency
  • Virulence Factors/genetics*
  • Zebrafish
27506797 Full text @ Proc. Natl. Acad. Sci. USA
Innate cellular immune responses are a critical first-line defense against invading bacterial pathogens. Leukocyte migration from the bloodstream to a site of infection is mediated by chemotactic factors that are often host-derived. More recently, there has been a greater appreciation of the importance of bacterial factors driving neutrophil movement during infection. Here, we describe the development of a zebrafish infection model to study Acinetobacter baumannii pathogenesis. By using isogenic A. baumannii mutants lacking expression of virulence effector proteins, we demonstrated that bacterial drivers of disease severity are conserved between zebrafish and mammals. By using transgenic zebrafish with fluorescent phagocytes, we showed that a mutation of an established A. baumannii global virulence regulator led to marked changes in neutrophil behavior involving rapid neutrophil influx to a localized site of infection, followed by prolonged neutrophil dwelling. This neutrophilic response augmented bacterial clearance and was secondary to an impaired A. baumannii phenylacetic acid catabolism pathway, which led to accumulation of phenylacetate. Purified phenylacetate was confirmed to be a neutrophil chemoattractant. These data identify a previously unknown mechanism of bacterial-guided neutrophil chemotaxis in vivo, providing insight into the role of bacterial metabolism in host innate immune evasion. Furthermore, the work provides a potentially new therapeutic paradigm of targeting a bacterial metabolic pathway to augment host innate immune responses and attenuate disease.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes