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bioRxiv · 10.1101/2022.07.19.497369

Battle for the histones: a secreted bacterial sirtuin from Campylobacter jejuni activates neutrophils and induces inflammation during infection

Callahan, S. M.·Hancock, T. J.·Doster, R. S.·Parker, C. B.·Wakim, M. E.·Gaddy, J. A.·Johnson, J. G.
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Abstract

Histone modifications alter numerous cornerstone processes in eukaryotes, including metabolism, physiology, and immunity. Numerous bacterial pathogens can alter expression of host-derived sirtuins to deacetylate histones in order to promote infection, yet, a bacterial-derived sirtuin has yet to be investigated to deacetylate host histones. Using Campylobacter jejuni, the leading cause of bacterial-derived gastroenteritis, we found a secreted sirtuin, SliP, which binds to and deacetylates neutrophil histones. We found neutrophil activation and extrusion of neutrophil extracellular traps was SliP dependent, whereby sliP mutants are unable to activate neutrophils or promote NETosis. Leveraging the mouse model of campylobacteriosis, we further demonstrate the sliP mutant can efficiently infect IL-10-/- mice, but induction of proinflammatory cytokine production and gastrointestinal pathology is SliP-dependent. In conclusion, we investigate a unique bacterial effector which targets host histones and is responsible for the inflammatory response and tissue pathology observed during campylobacteriosis. HighlightsO_LIC. jejuni encodes a secreted effector, SliP, which functions as a canonical sirtuin C_LIO_LISliP binds to and deacetylates neutrophil histone H3 during bacterial infection C_LIO_LIC. jejuni-induced neutrophil activation and NETosis are SliP-dependent C_LIO_LIInflammation and tissue pathology during C. jejuni infection is SliP-dependent C_LI

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Callahan, S. M., Hancock, T. J., Doster, R. S., Parker, C. B., Wakim, M. E., Gaddy, J. A., Johnson, J. G.. 2022-07-20. Battle for the histones: a secreted bacterial sirtuin from Campylobacter jejuni activates neutrophils and induces inflammation during infection. https://doi.org/10.1101/2022.07.19.497369

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