Doster, R. S. | Search bioRxiv

bioRxiv2022

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

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

microbiology↗

bioRxiv2018

Streptococcus agalactiae induces placental macrophages to release extracellular traps loaded with tissue remodeling enzymes via an oxidative-burst-dependent mechanism

Streptococcus agalactiae, or Group B Streptococcus (GBS), is a common perinatal pathogen. GBS colonization of the vaginal mucosa during pregnancy is a risk factor for invasive infection of the fetal membranes (chorioamnionitis) and its consequences such as membrane rupture, preterm labor, stillbirth, and neonatal sepsis. Placental macrophages, or Hofbauer cells, are fetally-derived macrophages present within placental and fetal membrane tissues that perform vital functions for fetal and placental development, including supporting angiogenesis, tissue remodeling, and regulation of maternal-fetal tolerance. Although placental macrophages, as tissue-resident innate phagocytes, are likely to engage invasive bacteria such as GBS, there is limited information regarding how these cells respond to bacterial infection. Here, we demonstrate in vitro that placental macrophages release macrophage extracellular traps (METs) in response to bacterial infection. Placental macrophage METs contain proteins including histones, myeloperoxidase, and neutrophil elastase similar to neutrophil extracellular traps and are capable of killing GBS cells. MET release from these cells occurs by a process that depends on the production of reactive oxygen species. Placental macrophage METs also contain matrix metalloproteases that are released in response to GBS and could contribute to fetal membrane weakening during infection. MET structures were identified within human fetal membrane tissues infected ex vivo, suggesting that placental macrophages release METs in response to bacterial infection during chorioamnionitis.\n\nImportanceStreptococcus agalactiae, also known as Group B Streptococcus (GBS), is a common pathogen during pregnancy where infection can result in chorioamnionitis, preterm premature rupture of membranes (PPROM), preterm labor, stillbirth, and neonatal sepsis. Mechanisms by which GBS infection results in adverse pregnancy outcomes are still incompletely understood. This study evaluated interactions between GBS and placental macrophages. The data demonstrate that in response to infection, placental macrophages release extracellular traps capable of killing GBS. Additionally, this work establishes that proteins associated with extracellular trap fibers include several matrix metalloproteinases that have been associated with chorioamnionitis. In the context of pregnancy, placental macrophage responses to bacterial infection might have beneficial and adverse consequences, including protective effects against bacterial invasion but also releasing important mediators of membrane breakdown that could contribute to membrane rupture or preterm labor.

microbiology↗