Capsule carbohydrate structure determines virulence in Acinetobacter baumannii
Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation...
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| Veröffentlicht in: | PLoS pathogens 2021-02, Vol.17 (2), p.e1009291-e1009291 |
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| creator | Talyansky, Yuli Nielsen, Travis B Yan, Jun Carlino-Macdonald, Ulrike Di Venanzio, Gisela Chakravorty, Somnath Ulhaq, Amber Feldman, Mario F Russo, Thomas A Vinogradov, Evgeny Luna, Brian Wright, Meredith S Adams, Mark D Spellberg, Brad |
| description | Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis. |
| doi_str_mv | 10.1371/journal.ppat.1009291 |
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Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1009291</identifier><identifier>PMID: 33529209</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acinetobacter baumannii - pathogenicity ; Acinetobacter Infections - genetics ; Acinetobacter Infections - metabolism ; Acinetobacter Infections - microbiology ; Animals ; Antibiotics ; Antimicrobial agents ; Bacterial Capsules - physiology ; Biology and Life Sciences ; Carbohydrates ; Depletion ; Gene expression ; Gene loci ; Genotype & phenotype ; Genotypes ; Immune system ; Infections ; Insertion ; Lethality ; Leukocytes (neutrophilic) ; Loci ; Macrophages ; Male ; Medicine and Health Sciences ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mortality ; mRNA ; Neutrophils ; NMR ; Nuclear magnetic resonance ; Phagocytes ; Phagocytes - metabolism ; Phagocytes - virology ; Phagocytosis ; Physical Sciences ; Polysaccharides, Bacterial - chemistry ; Public health ; RAW 264.7 Cells ; Research and Analysis Methods ; Strains (organisms) ; Virulence</subject><ispartof>PLoS pathogens, 2021-02, Vol.17 (2), p.e1009291-e1009291</ispartof><rights>2021 Talyansky et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. 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pathogenicity</topic><topic>Acinetobacter Infections - genetics</topic><topic>Acinetobacter Infections - metabolism</topic><topic>Acinetobacter Infections - microbiology</topic><topic>Animals</topic><topic>Antibiotics</topic><topic>Antimicrobial agents</topic><topic>Bacterial Capsules - physiology</topic><topic>Biology and Life Sciences</topic><topic>Carbohydrates</topic><topic>Depletion</topic><topic>Gene expression</topic><topic>Gene loci</topic><topic>Genotype & phenotype</topic><topic>Genotypes</topic><topic>Immune system</topic><topic>Infections</topic><topic>Insertion</topic><topic>Lethality</topic><topic>Leukocytes (neutrophilic)</topic><topic>Loci</topic><topic>Macrophages</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Mice, Inbred C57BL</topic><topic>Mortality</topic><topic>mRNA</topic><topic>Neutrophils</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Phagocytes</topic><topic>Phagocytes - 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Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. 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| ispartof | PLoS pathogens, 2021-02, Vol.17 (2), p.e1009291-e1009291 |
| issn | 1553-7374 1553-7366 1553-7374 |
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| subjects | Acinetobacter baumannii - pathogenicity Acinetobacter Infections - genetics Acinetobacter Infections - metabolism Acinetobacter Infections - microbiology Animals Antibiotics Antimicrobial agents Bacterial Capsules - physiology Biology and Life Sciences Carbohydrates Depletion Gene expression Gene loci Genotype & phenotype Genotypes Immune system Infections Insertion Lethality Leukocytes (neutrophilic) Loci Macrophages Male Medicine and Health Sciences Mice Mice, Inbred C3H Mice, Inbred C57BL Mortality mRNA Neutrophils NMR Nuclear magnetic resonance Phagocytes Phagocytes - metabolism Phagocytes - virology Phagocytosis Physical Sciences Polysaccharides, Bacterial - chemistry Public health RAW 264.7 Cells Research and Analysis Methods Strains (organisms) Virulence |
| title | Capsule carbohydrate structure determines virulence in Acinetobacter baumannii |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T18%3A34%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Capsule%20carbohydrate%20structure%20determines%20virulence%20in%20Acinetobacter%20baumannii&rft.jtitle=PLoS%20pathogens&rft.au=Talyansky,%20Yuli&rft.date=2021-02-01&rft.volume=17&rft.issue=2&rft.spage=e1009291&rft.epage=e1009291&rft.pages=e1009291-e1009291&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1009291&rft_dat=%3Cproquest_plos_%3E2486145303%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2501883539&rft_id=info:pmid/33529209&rft_doaj_id=oai_doaj_org_article_2e15c8218812402f94d6020b9c41afb5&rfr_iscdi=true |