Group A Streptococcus AdcR Regulon Participates in Bacterial Defense against Host-Mediated Zinc Sequestration and Contributes to Virulence
| Autor: | John D. Helmann, Brian M. Wendel, Nishanth Makthal, Hackwon Do, Randall J. Olsen, James M. Musser, Muthiah Kumaraswami |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Streptococcus pyogenes 030106 microbiology Immunology Mutant Virulence Human pathogen Biology medicine.disease_cause Binding Competitive Regulon Microbiology Mice 03 medical and health sciences Bacterial Proteins Streptococcal Infections medicine Animals Calgranulin B Humans Gene Mice Knockout Regulation of gene expression Binding Sites Ion Transport Pathogenic bacteria Bacterial Infections Survival Analysis In vitro Zinc 030104 developmental biology Infectious Diseases Gene Expression Regulation Host-Pathogen Interactions Parasitology Leukocyte L1 Antigen Complex Protein Binding |
| Zdroj: | Infect Immun |
| ISSN: | 1098-5522 0019-9567 |
| DOI: | 10.1128/iai.00097-20 |
| Popis: | Colonization by pathogenic bacteria depends on their ability to overcome host nutritional defenses and acquire nutrients. The human pathogen group A streptococcus (GAS) encounters the host defense factor calprotectin (CP) during infection. CP inhibits GAS growth in vitro by imposing zinc (Zn) limitation. However, GAS counterstrategies to combat CP-mediated Zn limitation and the in vivo relevance of CP-GAS interactions to bacterial pathogenesis remain unknown. Here, we report that GAS upregulates the AdcR regulon in response to CP-mediated Zn limitation. The AdcR regulon includes genes encoding Zn import (adcABC), Zn sparing (rpsN.2), and Zn scavenging systems (adcAII, phtD, and phtY). Each gene in the AdcR regulon contributes to GAS Zn acquisition and CP resistance. The ΔadcC and ΔrpsN.2 mutant strains were the most susceptible to CP, whereas the ΔadcA, ΔadcAII, and ΔphtD mutant strains displayed less CP sensitivity during growth in vitro. However, the ΔphtY mutant strain did not display an increased CP sensitivity. The varied sensitivity of the mutant strains to CP-mediated Zn limitation suggests distinct roles for individual AdcR regulon genes in GAS Zn acquisition. GAS upregulates the AdcR regulon during necrotizing fasciitis infection in WT mice but not in S100a9(−/−) mice lacking CP. This suggests that CP induces Zn deficiency in the host. Finally, consistent with the in vitro results, several of the AdcR regulon genes are critical for GAS virulence in WT mice, whereas they are dispensable for virulence in S100a9(−/−) mice, indicating the direct competition for Zn between CP and proteins encoded by the GAS AdcR regulon during infection. |
| Databáze: | OpenAIRE |
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