Examination of Mycobacterium tuberculosis sigma factor mutants using low-dose aerosol infection of guinea pigs suggests a role for SigC in pathogenesis

• Published in: Microbiology (Society for General Microbiology) 2006-06, Vol.152 (6), p.1591-1600
• Main Authors: Karls, Russell K, Guarner, Jeannette, McMurray, David N, Birkness, Kristin A, Quinn, Frederick D
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacteriology; Biological and medical sciences; Cell Line; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Fundamental and applied biological sciences. Psychology; Genetics; Guinea Pigs; Humans; Lung - microbiology; Lung - pathology; Macrophages - microbiology; Microbiology; Monocytes - microbiology; Mutation; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - metabolism; Mycobacterium tuberculosis - pathogenicity; Sigma Factor - genetics; Sigma Factor - metabolism; Tuberculosis, Pulmonary - microbiology; Tuberculosis, Pulmonary - pathology; Virulence
• ISSN: 1350-0872; 1465-2080
• DOI: 10.1099/mic.0.28591-0

1 Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA 2 Mycobacteriology Laboratory Branch, Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA 3 Infectious Disease Pathology Activity, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA 4 Department of Medical Microbiology and Immunology, Texas A&M University System Health Science Center, College Station, TX 77845, USA Correspondence Frederick D. Quinn fquinn{at}vet.uga.edu Secondary sigma factors in bacteria direct transcription of defence regulons in response to specific stresses. To identify which sigma factors in the human respiratory pathogen Mycobacterium tuberculosis are important for adaptive survival in vivo , defined null mutations were created in individual sigma factor genes. In this study, in vitro growth virulence and guinea pig pathology of M. tuberculosis mutants lacking functional sigma factors (SigC, SigF, or SigM) were compared to the parent strain, H37Rv. None of the mutant strains exhibited a growth deficiency in Middlebrook 7H9 broth, nor were any impaired for intracellular replication in the human monocytic macrophage cell-line THP-1. Following low-dose aerosol infection of guinea pigs, however, differences could be detected. While a SigM mutant resulted in lung and spleen granulomas of comparable composition to those found in H37Rv-infected animals, a SigF mutant was partially attenuated, exhibiting necrotic spleen granulomas and ill-defined lung granulomas. SigC mutants exhibited attenuation in the lung and spleen; notably, necrotic granulomas were absent. These data suggest that while SigF may be important for survival in the lung, SigC is likely a key regulator of pathogenesis and adaptive survival in the lung and spleen. Understanding how SigC mediates survival in the host should prove useful in the development of anti-tuberculosis therapies. Abbreviations: AFB, acid-fast bacilli; TB, tuberculosis