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S-nitrosylation mediated by Staphylococcus aureus-derived nitric oxide modulates virulence and host local inflammatory response

ABSTRACT: Staphylococcus aureus has become a critical source of community and nosocomial infections. Due to the widespread use of antibiotics, S. aureus has developed resistance to multiple antibiotics, making clinical treatment more difficult. Therefore, it is of significant clinical relevance to investigate the pathogenic mechanism of S. aureus and identify new therapeutic targets. Bacterial endogenous signaling molecule nitric oxide (NO) plays an important role in regulating pathogenicity, but the mechanism remains to be further explored. Our results have shown that S-nitrosylation mediated by S. aureus-derived NO has significant effects on the virulence of bacterial pathogen and the activity of macrophages, and GntR and Hsp90 are the key modification targets in S. aureus and macrophages, respectively. In order to explore the pathogenesis of S. aureus mediated by NO，we hypothesized that endogenous NO regulates exopolysaccharide (EPS) synthesis of S. aureus through mediating S-nitrosylation of GntR, thus enhancing the virulence and regulates endoplasmic reticulum stress (ERS) by mediating Hsp90 S-nitrosylation, thereby modulating M1/M2 polarization of macrophage and host local inflammatory response, and ultimately achieving the pathogenic process of S. aureus. The hypothesis is validated through histological and molecular biology approaches, combining in vitro and in vivo experimental schemes. The research is expected to provide a new perspective for understanding the pathogenic mechanism of S. aureus and potentially new targets for future antimicrobial therapies.

ORGANISM(S): Mus Musculus Staphylococcus Aureus

SUBMITTER: Baolin Sun

PROVIDER: PXD059253 | iProX | Wed Dec 25 00:00:00 GMT 2024

REPOSITORIES: iProX

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Project description:The capacity to sense and transduce temperature signals pervades all aspects of biology, and temperature exerts powerful control over the development and virulence of diverse pathogens. In the leading fungal pathogen of humans, Candida albicans, temperature has a profound impact on morphogenesis, a key virulence trait. Many cues that induce the transition from yeast to filamentous growth are contingent on a minimum temperature of 37ÂºC, while further elevatation to 39ÂºC serves as an independent inducing cue. The molecular chaperone Hsp90 is a key regulator of C. albicans temperature-dependent morphogenesis, as induction of filamentous growth requires relief from Hsp90-mediated repression of the morphogenetic program. Compromise of Hsp90 function genetically, pharmacologically, or by elevated temperature induces filamentation in a manner that depends on protein kinase A (PKA) signaling, but is independent of the terminal transcription factor, Efg1. Here, we determine that despite morphological and regulatory differences, inhibition of Hsp90 induces a transcriptional profile similar to that induced by other filamentation cues, and does so in a manner that is independent of Efg1. Further, we identify Hms1 as a transcriptional regulator required for morphogenesis induced by elevated temperature or compromise of Hsp90 function. Hms1 functions downstream of the cyclin Pcl, and the cyclin-dependent kinase Pho85, both of which are required for temperature-dependent filamentation. Upon Hsp90 inhibition, Hms1 binds to DNA elements involved in filamentous growth, including UME6 and RBT5, and regulates their expression, providing a mechanism through which Pho85, Pcl1, and Hms1 govern morphogenesis. Consistent with the importance of morphogenetic flexibility with virulence, deletion of C. albicans HMS1 attenuates virulence in a metazoan model of infection. Thus, we establish a new mechanism through which Hsp90 orchestrates C. albicans morphogenesis, and define novel regulatory circuitry governing a temperature-dependent developmental program, with broad implications for temperature sensing and virulence of microbial pathogens. Two-color experimental design testing the effect of geldanamycin on wild type of delta-efg1 cells. RNA from each replicate came from independent cultures.

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S-nitrosylation mediated by Staphylococcus aureus-derived nitric oxide modulates virulence and host local inflammatory response

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