Metal sensing and regulation of adaptive responses to manganese limitation by MtsR is critical for group A streptococcus virulence

Do, Hackwon; Makthal, Nishanth; Chandrangsu, Pete; Olsen, Randall J.; Helmann, John D.; Musser, James M.; Kumaraswami, Muthiah

doi:10.1093/nar/gkz524

Title: Metal sensing and regulation of adaptive responses to manganese limitation by MtsR is critical for group A streptococcus virulence

Journal Article · 11 June 2019 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkz524 · OSTI ID:1525909

Do, Hackwon ^[1]; Makthal, Nishanth ^[1]; Chandrangsu, Pete ^[2]; Olsen, Randall J. ^[3]; Helmann, John D. ^[4]; Musser, James M. ^[3];

^[1]

Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
Department of Microbiology, Cornell University, Ithaca, NY 14853-8101, USA, W.M. Keck Science Department, Claremont McKenna, Pitzer and Scripps College, Claremont, CA 91711, USA
Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA
Department of Microbiology, Cornell University, Ithaca, NY 14853-8101, USA

Abstract Pathogenic bacteria encounter host-imposed manganese (Mn) limitation during infection. Herein we report that in the human pathogen Streptococcus pyogenes, the adaptive response to Mn limitation is controlled by a DtxR family metalloregulator, MtsR. Genes upregulated by MtsR during Mn limitation include Mn (mtsABC) and Fe acquisition systems (sia operon), and a metal-independent DNA synthesis enzyme (nrdFEI.2). To elucidate the mechanism of metal sensing and gene regulation by MtsR, we determined the crystal structure of MtsR. MtsR employs two Mn-sensing sites to monitor metal availability, and metal occupancy at each site influences MtsR regulatory activity. The site 1 acts as the primary Mn sensing site, and loss of metal at site 1 causes robust upregulation of mtsABC. The vacant site 2 causes partial induction of mtsABC, indicating that site 2 functions as secondary Mn sensing site. Furthermore, we show that the C-terminal FeoA domains of adjacent dimers participate in the oligomerization of MtsR on DNA, and multimerization is critical for MtsR regulatory activity. Finally, the mtsR mutant strains defective in metal sensing and oligomerization are attenuated for virulence in a mouse model of invasive infection, indicating that Mn sensing and gene regulation by MtsR are critical processes during S. pyogenes infection.

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Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: Fondren Foundation; National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC02-05CH11231; AC03-76SF00098

OSTI ID:: 1525909

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 14 Vol. 47; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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