Distinct mechanisms of type 3 secretion system recognition control LTB4 synthesis in neutrophils and macrophages.

Autor: Brady A; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America., Mora Martinez LC; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America., Hammond B; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America., Whitefoot-Keliin KM; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America., Haribabu B; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.; Center for Microbiomics, Inflammation and Pathogenicity, Louisville, Kentucky, United States of America., Uriarte SM; Deptartment of Oral Immunology & Infectious Diseases, University of Louisville, Louisville, Kentucky, United States of America.; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Louisville, Kentucky, United States of America., Lawrenz MB; Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, Louisville, Kentucky, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2024 Oct 18; Vol. 20 (10), pp. e1012651. Date of Electronic Publication: 2024 Oct 18 (Print Publication: 2024).
DOI: 10.1371/journal.ppat.1012651
Abstrakt: Leukotriene B4 (LTB4) is an inflammatory lipid produced in response to pathogens that is critical for initiating the inflammatory cascade needed to control infection. However, during plague, Yersinia pestis inhibits the timely synthesis of LTB4 and subsequent inflammation. Using bacterial mutants, we previously determined that Y. pestis inhibits LTB4 synthesis via the action of the Yop effector proteins that are directly secreted into host cells through a type 3 secretion system (T3SS). Here, we show that the T3SS is the primary pathogen associated molecular pattern (PAMP) required for production of LTB4 in response to both Yersinia and Salmonella. However, we also unexpectantly discovered that T3SS-mediated LTB4 synthesis by neutrophils and macrophages require the activation of two distinctly different host signaling pathways. We identified that phagocytosis and the NLRP3/CASP1 inflammasome significantly impact LTB4 synthesis by macrophages but not neutrophils. Instead, the SKAP2/PLC signaling pathway is required for T3SS-mediated LTB4 production by neutrophils. Finally, while recognition of the T3SS is required for LTB4 production, we also discovered that a second unrelated PAMP-mediated signal activates the MAP kinase pathway needed for synthesis. Together, these data demonstrate significant differences in the host factors and signaling pathways required by macrophages and neutrophils to quickly produce LTB4 in response to bacteria. Moreover, while macrophages and neutrophils might rely on different signaling pathways for T3SS-dependent LTB4 synthesis, Y. pestis has evolved virulence mechanisms to counteract this response by either leukocyte to inhibit LTB4 synthesis and colonize the host.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Brady et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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