Effect of the streptococcus agalactiae virulence regulator CovR on the pathogenesis of urinary tract infection

Sullivan, Matthew J. ORCID: https://orcid.org/0000-0003-2276-3132, Leclercq, Sophie Y., Ipe, Deepak S., Carey, Alison J., Smith, Joshua P., Voller, Nathan, Cripps, Allan W. and Ulett, Glen C. (2017) Effect of the streptococcus agalactiae virulence regulator CovR on the pathogenesis of urinary tract infection. Journal of Infectious Diseases, 215 (3). pp. 475-483. ISSN 0022-1899

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Background. Streptococcus agalactiae can cause urinary tract infection (UTI). The role of the S. agalactiae global virulence regulator, CovR, in UTI pathogenesis is unknown. Methods. We used murine and human bladder uroepithelial cell models of UTI and S. agalactiae mutants in covR and related factors, including β-hemolysin/cytolysin (β-h/c), surface-anchored adhesin HvgA, and capsule to study the role of CovR in UTI. Results. We found that covR-deficient serotype III S. agalactiae 874391 was significantly attenuated for colonization in mice and adhesion to uroepithelial cells. Mice infected with covR-deficient S. agalactiae produced less proinflammatory cytokines than those infected with wild-type 874391. Acute cytotoxicity in uroepithelial cells triggered by covR-deficient but not wild-type 874391 was associated with significant caspase 3 activation. Mechanistically, covR mutation significantly altered the expression of several genes in S. agalactiae 874391 that encode key virulence factors, including β-h/c and HvgA, but not capsule. Subsequent mutational analyses revealed that HvgA and capsule, but not the β-h/c, exerted significant effects on colonization of the murine urinary tract in vivo. Conclusions. S. agalactiae CovR promotes bladder infection and inflammation, as well as adhesion to and viability of uroepithelial cells. The pathogenesis of S. agalactiae UTI is complex, multifactorial, and influenced by virulence effects of CovR, HvgA, and capsule.

Item Type: Article
Additional Information: Financial support: This work was supported by the NHMRC (project grants (APP1005315 and APP1084889 to G. C. U. and the Peter Doherty fellowship [APP1052464] to A. J. C.), the Griffith Health Institute, the Conselho Nacional de Desenvolvimento Científico e Tecnológico–Brazil (S. Y. L.), and the Australian Research Council (Future Fellowship FT110101048 to G. C. U.).
Uncontrolled Keywords: bladder,covr,streptococcus agalactiae,urinary tract infection,uroepithelium,virulence,immunology and allergy,infectious diseases,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700/2723
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Depositing User: LivePure Connector
Date Deposited: 15 Aug 2022 10:31
Last Modified: 24 Oct 2022 16:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/87246
DOI: 10.1093/infdis/jiw589

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