The Brucella abortus General Stress Response System Regulates Chronic Mammalian Infection and Is Controlled by Phosphorylation and Proteolysis

• Published in: The Journal of biological chemistry Vol. 288; no. 19; pp. 13906 - 13916
• Main Authors: Kim, Hye-Sook, Caswell, Clayton C., Foreman, Robert, Roop, R. Martin, Crosson, Sean
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.05.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Bacterial Pathogenesis; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacterial Signal Transduction; Bacterial Transcription; Base Sequence; Binding Sites; Brucella; Brucella abortus - genetics; Brucella abortus - physiology; Brucellosis - microbiology; Chronic Disease; Conserved Sequence; Female; Gene Expression Regulation, Bacterial; General Stress Response; Genes, Bacterial; Genetic Loci; Host-Pathogen Interactions; Infectious Diseases; Mice; Mice, Inbred BALB C; Microbial Viability; Microbiology; Oxidative Stress; Phosphorylation; PhyR; Protein Binding; Protein Processing, Post-Translational; Proteolysis; Stress Response; Stress, Physiological; Transcriptome; PhyR; Bacterial Signal Transduction; Stress Response; Bacterial Pathogenesis; Brucella; Bacterial Transcription; Infectious Diseases; General Stress Response
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.459305

Brucella spp. are adept at establishing a chronic infection in mammals. We demonstrate that core components of the α-proteobacterial general stress response (GSR) system, PhyR and σE1, are required for Brucella abortus stress survival in vitro and maintenance of chronic murine infection in vivo. ΔphyR and ΔrpoE1 null mutants exhibit decreased survival under acute oxidative and acid stress but are not defective in infection of primary murine macrophages or in initial colonization of BALB/c mouse spleens. However, ΔphyR and ΔrpoE1 mutants are attenuated in spleens beginning 1 month postinfection. Thus, the B. abortus GSR system is dispensable for colonization but is required to maintain chronic infection. A genome-scale analysis of the B. abortus GSR regulon identified stress response genes previously linked to virulence and genes that affect immunomodulatory components of the cell envelope. These data support a model in which the GSR system affects both stress survival and the interface between B. abortus and the host immune system. We further demonstrate that PhyR proteolysis is a unique feature of GSR control in B. abortus. Proteolysis of PhyR provides a mechanism to avoid spurious PhyR protein interactions that inappropriately activate GSR-dependent transcription. We conclude that the B. abortus GSR system regulates acute stress adaptation and long term survival within a mammalian host and that PhyR proteolysis is a novel regulatory feature in B. abortus that ensures proper control of GSR transcription. Background: Virulence of pathogenic bacteria is often determined by their ability to adapt to stress. Results: The Brucella abortus general stress response (GSR) system is required for chronic mammalian infection and is regulated by phosphorylation and proteolysis. Conclusion: The B. abortus GSR signaling pathway has multiple layers of post-translational control and is a determinant of chronic infection. Significance: This study provides new, molecular level insight into chronic Brucella infection.