Gingipains protect Porphyromonas gingivalis from macrophage-mediated phagocytic clearance.
| Title: | Gingipains protect Porphyromonas gingivalis from macrophage-mediated phagocytic clearance. |
|---|---|
| Authors: | Widziolek M; Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.; School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom.; Mieszkowska A; Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.; Marcinkowska M; Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland.; Salamaga B; School of Biosciences, University of Sheffield, Sheffield, United Kingdom.; Folkert J; Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.; Rakus K; Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.; Chadzinska M; Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.; Potempa J; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.; Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, Kentucky, United States of America.; Stafford GP; School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom.; The Florey Institute, University of Sheffield, Sheffield, United Kingdom.; Prajsnar TK; Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland.; Murdoch C; School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom.; The Florey Institute, University of Sheffield, Sheffield, United Kingdom. |
| Source: | PLoS pathogens [PLoS Pathog] 2025 Jan 21; Vol. 21 (1), pp. e1012821. Date of Electronic Publication: 2025 Jan 21 (Print Publication: 2025). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101238921 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7374 (Electronic) Linking ISSN: 15537366 NLM ISO Abbreviation: PLoS Pathog Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science, c2005- |
| MeSH Terms: | Porphyromonas gingivalis*/immunology ; Porphyromonas gingivalis*/pathogenicity ; Adhesins, Bacterial*/immunology ; Adhesins, Bacterial*/metabolism ; Adhesins, Bacterial*/genetics ; Macrophages*/immunology ; Macrophages*/microbiology ; Phagocytosis*/immunology ; Cysteine Endopeptidases*/immunology ; Cysteine Endopeptidases*/metabolism ; Cysteine Endopeptidases*/genetics ; Bacteroidaceae Infections*/immunology ; Bacteroidaceae Infections*/microbiology ; Periodontitis*/immunology ; Periodontitis*/microbiology; Neutrophils/immunology ; Neutrophils/microbiology ; Gingipain Cysteine Endopeptidases ; Animals ; Zebrafish ; Animals, Genetically Modified ; Immunity, Innate |
| Abstract: | Porphyromonas gingivalis (Pg) is a keystone pathogen in periodontitis, a highly prevalent disease manifested by chronic inflammation of the periodontium, alveolar bone resorption and tooth loss. During periodontitis pathobionts such as Pg can enter the bloodstream and growing evidence correlates periodontitis with increased risk of cardiovascular and neurodegenerative diseases. However, the mechanism by which immune cells respond to Pg challenge in vivo remains elusive. Pg produce aggressive proteolytic virulence factors termed gingipains which not only provide nutrients necessary for bacterial growth, but also subvert the host immune response, facilitating bacterial survival. Using transgenic zebrafish with fluorescently labelled macrophages and neutrophils, the role of gingipains in bacterial survival and interaction with phagocytes during systemic and local infection was examined. In contrast to the wild-type (W83) Pg, isogenic gingipain-null (ΔK/R-ab) or wild-type Pg treated with gingipain inhibitors caused less zebrafish mortality, bacteria were rapidly phagocytosed, acidified in phagosomes and eradicated when systemically injected, showing that gingipains are instrumental in preventing phagocytosis and intracellular killing of Pg by innate immune cells. Moreover, Pg were predominantly phagocytosed by macrophages, and gingipain depletion/inactivation increased bacterial phagocytosis when bacteria were injected either systemically or locally in the otic vesicle, with less bacteria internalised by neutrophils. This phenomenon was Pg-specific as Fusobacterium nucleatum caused neutrophil recruitment that then effectively phagocytosed these bacteria. These data demonstrate the important role of phagocytes, especially macrophages, in combating Pg infection and highlight the crucial protective role of gingipains in subverting the innate immune response. This study also emphasizes the advantages of using zebrafish to study interactions of Pg with phagocytes in vivo in real-time, providing a valuable experimental system for testing new therapeutic strategies aimed at reducing periodontal-associated systemic or neurodegenerative disease.; (Copyright: © 2025 Widziolek 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.) |
| Competing Interests: | The authors have declared that no competing interests exist. |
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| Substance Nomenclature: | 0 (Gingipain Cysteine Endopeptidases); 0 (Adhesins, Bacterial); EC 3.4.22.- (Cysteine Endopeptidases) |
| Entry Date(s): | Date Created: 20250121 Date Completed: 20250502 Latest Revision: 20250523 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11801703 |
| DOI: | 10.1371/journal.ppat.1012821 |
| PMID: | 39836688 |
| Database: | MEDLINE |
Journal Article