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

Md Saruar Bhuiyan, Felix Ellett, Gerald L. Murray, Xenia Kostoulias, Gustavo M. Cerqueira, Keith E. Schulze, Mohd Hafidz Mahamad Maifiah, Jian Li, Darren J. Creek, Graham J. Lieschke, Anton Y. Peleg

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Article number1523116113
Pages (from-to)9599-9604
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume113
Issue number34
DOIs
Publication statusPublished - 23 Aug 2016

Keywords

  • Acinetobacter baumannii
  • Chemotaxis
  • Neutrophils
  • Phenylacetate
  • Zebrafish

Cite this

Bhuiyan, Md Saruar ; Ellett, Felix ; Murray, Gerald L. ; Kostoulias, Xenia ; Cerqueira, Gustavo M. ; Schulze, Keith E. ; Mahamad Maifiah, Mohd Hafidz ; Li, Jian ; Creek, Darren J. ; Lieschke, Graham J. ; Peleg, Anton Y. / Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis. In: Proceedings of the National Academy of Sciences. 2016 ; Vol. 113, No. 34. pp. 9599-9604.
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abstract = "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.",
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Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis. / Bhuiyan, Md Saruar; Ellett, Felix; Murray, Gerald L.; Kostoulias, Xenia; Cerqueira, Gustavo M.; Schulze, Keith E.; Mahamad Maifiah, Mohd Hafidz; Li, Jian; Creek, Darren J.; Lieschke, Graham J.; Peleg, Anton Y.

In: Proceedings of the National Academy of Sciences, Vol. 113, No. 34, 1523116113, 23.08.2016, p. 9599-9604.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bhuiyan, Md Saruar

AU - Ellett, Felix

AU - Murray, Gerald L.

AU - Kostoulias, Xenia

AU - Cerqueira, Gustavo M.

AU - Schulze, Keith E.

AU - Mahamad Maifiah, Mohd Hafidz

AU - Li, Jian

AU - Creek, Darren J.

AU - Lieschke, Graham J.

AU - Peleg, Anton Y.

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KW - Chemotaxis

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KW - Phenylacetate

KW - Zebrafish

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