Dataset Information

The chemorepellent, SLIT2, bolsters innate immunity against Staphylococcus aureus.

ABSTRACT: Neutrophils are essential for host defense against Staphylococcus aureus (S. aureus). The neuro-repellent, SLIT2, potently inhibits neutrophil chemotaxis, and might, therefore, be expected to impair antibacterial responses. We report here that, unexpectedly, neutrophils exposed to the N-terminal SLIT2 (N-SLIT2) fragment kill extracellular S. aureus more efficiently. N-SLIT2 amplifies reactive oxygen species production in response to the bacteria by activating p38 mitogen-activated protein kinase that in turn phosphorylates NCF1, an essential subunit of the NADPH oxidase complex. N-SLIT2 also enhances the exocytosis of neutrophil secondary granules. In a murine model of S. aureus skin and soft tissue infection (SSTI), local SLIT2 levels fall initially but increase subsequently, peaking at 3 days after infection. Of note, the neutralization of endogenous SLIT2 worsens SSTI. Temporal fluctuations in local SLIT2 levels may promote neutrophil recruitment and retention at the infection site and hasten bacterial clearance by augmenting neutrophil oxidative burst and degranulation. Collectively, these actions of SLIT2 coordinate innate immune responses to limit susceptibility to S. aureus.

SUBMITTER: Bhosle VK

PROVIDER: S-EPMC10541174 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The chemorepellent, SLIT2, bolsters innate immunity against Staphylococcus aureus.

Bhosle Vikrant K VK Sun Chunxiang C Patel Sajedabanu S Ho Tse Wing Winnie TWW Westman Johannes J Ammendolia Dustin A DA Langari Fatemeh Mirshafiei FM Fine Noah N Toepfner Nicole N Li Zhubing Z Sharma Manraj M Glogauer Judah J Capurro Mariana I MI Jones Nicola L NL Maynes Jason T JT Lee Warren L WL Glogauer Michael M Grinstein Sergio S Robinson Lisa A LA

eLife 20230929

Neutrophils are essential for host defense against Staphylococcus aureus (S. aureus). The neuro-repellent, SLIT2, potently inhibits neutrophil chemotaxis, and might, therefore, be expected to impair antibacterial responses. We report here that, unexpectedly, neutrophils exposed to the N-terminal SLIT2 (N-SLIT2) fragment kill extracellular S. aureus more efficiently. N-SLIT2 amplifies reactive oxygen species production in response to the bacteria by activating p38 mitogen-act ...[more]

PMID: 37773612

Similar Datasets

Project description:A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3-5% of cases, infections can develop, most caused by Staphylococcus aureus biofilm formation on the skull surface. Medical management of this infection is difficult, as biofilm properties confer immune and antimicrobial recalcitrance to the infection and necessitate additional surgical procedures. Furthermore, treatment failure rates can be appreciably high. These factors, compounded with rapidly expanding rates of antimicrobial resistance, highlight the need to develop alternative treatment strategies to target and reverse the immune dysfunction that occurs during biofilm infection. Our recent work has identified CD4+ Th1 and Th17 cells as potent regulators of innate immune cell activation during craniotomy infection. Here, we report the role of IFN-γ, versus other Th1- and Th17-derived cytokines, in programing the immune response to biofilm infection using both global and cell type-specific IFN-γR1-deficient (Ifngr1-/-) mice. Bacterial burdens were significantly higher in Ifngr1-/- relative to WT animals despite few changes in immune cell abundance. Single-cell transcriptomics identified candidate explanations for this phenotype as alterations in cell death pathways, innate immune cell activation, MHC-II expression, and T cell responses were significantly reduced in Ifngr1-/- mice. While caspase-1 activation in PMNs and macrophage/microglial MHC-II expression were regulated by IFN-γ signaling, no phenotypes were observed with either granulocyte- or macrophage/microglia Ifngr1-/- conditional knockout mice, suggestive of redundancy. Instead, a decreased Th1/Th17 ratio was identified in Ifngr1-/- animals that was corroborated by elevated IL-17 levels and correlated with dysfunctional T cell-innate immune communication. Further, Th17 cells were less effective than Th1 cells in promoting S. aureus bactericidal activity in microglia and macrophages. Collectively, this work identifies a key protective role for IFN-γ during craniotomy infection by enhancing macrophage and microglial antibacterial activity. Therefore, controlled programming of IFN-γ responses may represent a novel therapeutic strategy for chronic craniotomy infections.

Dataset Information

The chemorepellent, SLIT2, bolsters innate immunity against Staphylococcus aureus.

Publications

The chemorepellent, SLIT2, bolsters innate immunity against <i>Staphylococcus aureus</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets