The quorum-sensing peptidic inhibitor rescues host immune system eradication: A novel infectivity mechanism

Avishag Yehuda, Einav Malach, Shahar Vanunu Ofri, Leyla Slamti, Shanny Hsuan Kuo, Jonathan Z. Lau, Myung Whan Oh, John Adeoye, Neta Shlezinger, Didier Lereclus, Gee W. Lau, Zvi Hayouka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Subverting the host immune system is a major task for any given pathogen to assure its survival and proliferation. For the opportunistic human pathogen Bacillus cereus (Bc), immune evasion enables the establishment of potent infections. In various species of the Bc group, the pleiotropic regulator PlcR and its cognate cell-cell signaling peptide PapR7 regulate virulence gene expression in response to fluctuations in population density, i.e., a quorum-sensing (QS) system. However, how QS exerts its effects during infections and whether PlcR confers the immune evading ability remain unclear. Herein, we report how interception of the QS communication in Bc obliterates the ability to affect the host immune system. Here, we designed a peptide-based QS inhibitor that suppresses PlcR-dependent virulence factor expression and attenuates Bc infectivity in mouse models. We demonstrate that the QS peptidic inhibitor blocks host immune system-mediated eradication by reducing the expression of PlcR-regulated major toxins similarly to the profile that was observed for isogenic strains. Our findings provide evidence that Bc infectivity is regulated by QS circuit-mediated destruction of host immunity, thus reveal a interesting strategy to limit Bc virulence and enhance host defense. This peptidic quorum-quenching agent constitutes a readily accessible chemical tool for studying how other pathogen QS systems modulate host immunity and forms a basis for development of anti-infective therapeutics.

Original languageAmerican English
Article numbere2301045120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number35
DOIs
StatePublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 the Author(s).

Keywords

  • host-pathogen interaction
  • neutrophils
  • peptides
  • quorum quenching
  • quorum sensing

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