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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
National Academy of Sciences
2016
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| Subjects: | |
| 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 |
| Summary: | 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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