Acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis
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 imp...
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National Academy of Sciences
2016
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| Online Access: | http://irep.iium.edu.my/65203/ http://irep.iium.edu.my/65203/ http://irep.iium.edu.my/65203/ http://irep.iium.edu.my/65203/7/65203%20Acinetobacter%20baumannii%20phenylacetic%20acid%20metabolism.pdf |
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iium-652032018-10-05T03:09:40Z http://irep.iium.edu.my/65203/ Acinetobacter baumanniiphenylacetic 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. QR Microbiology 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 National Academy of Sciences 2016-08 Article PeerReviewed application/pdf en http://irep.iium.edu.my/65203/7/65203%20Acinetobacter%20baumannii%20phenylacetic%20acid%20metabolism.pdf Bhuiyan, Md Saruar and Ellett, Felix and Murray, Gerald L. and Kostoulias, Xenia and Cerqueira, Gustavo M. and Schulze, Keith E. and Mahamad Maifiah, Mohd Hafidz and Li, Jian and Creek, Darren J. and Lieschke, Graham J. and Peleg, Anton Y. (2016) Acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis. Proceedings of the National Academy of Sciences (PNAS), 113 (34). pp. 9599-9604. ISSN 0027-8424 http://www.pnas.org/content/pnas/113/34/9599.full.pdf 10.1073/pnas.1523116113 |
| repository_type |
Digital Repository |
| institution_category |
Local University |
| institution |
International Islamic University Malaysia |
| building |
IIUM Repository |
| collection |
Online Access |
| language |
English |
| topic |
QR Microbiology |
| spellingShingle |
QR Microbiology 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 baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis |
| description |
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 |
| format |
Article |
| author |
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. |
| author_facet |
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. |
| author_sort |
Bhuiyan, Md Saruar |
| title |
Acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis |
| title_short |
Acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis |
| title_full |
Acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis |
| title_fullStr |
Acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis |
| title_full_unstemmed |
Acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis |
| title_sort |
acinetobacter baumanniiphenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis |
| publisher |
National Academy of Sciences |
| publishDate |
2016 |
| url |
http://irep.iium.edu.my/65203/ http://irep.iium.edu.my/65203/ http://irep.iium.edu.my/65203/ http://irep.iium.edu.my/65203/7/65203%20Acinetobacter%20baumannii%20phenylacetic%20acid%20metabolism.pdf |
| first_indexed |
2023-09-18T21:32:31Z |
| last_indexed |
2023-09-18T21:32:31Z |
| _version_ |
1777412605223108608 |