Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative σ factor, SigH

Deepak Kaushal, Benjamin G. Schroeder, Sandeep Tyagi, Tetsuyuki Yoshimatsu, Cherise Scott, Chiew Ko, Liane Carpenter, Jyoti Mehrotra, Yukari C Manabe, Robert D. Fleischmann, William Ramses Bishai

Research output: Contribution to journalArticle

Abstract

The pathogenesis of tuberculosis involves multiple phases and is believed to involve both a carefully deployed series of adaptive bacterial virulence factors and inappropriate host immune responses that lead to tissue damage. A defined Mycobacterium tuberculosis mutant strain lacking the sigH-encoded transcription factor showed a distinctive infection phenotype. In resistant C57BL/6 mice, the mutant achieved high bacterial counts in lung and spleen that persisted in tissues in a pattern identical to those of wild-type bacteria. Despite a high bacterial burden, the mutant produced a blunted, delayed pulmonary inflammatory response, and recruited fewer CD4+ and CD8+ T cells to the lung in the early stages of infection. In susceptible C3H mice, the mutant again showed diminished immunopathology and was nonlethal at over 170 days after intravenous infection, in contrast to isogenic wild-type bacilli, which killed with a median time to death of 52 days. Complete genomic microarray analysis revealed that M. tuberculosis sigH may mediate the transcription of at least 31 genes directly and that it modulates the expression of about 150 others; the SigH regulon governs thioredoxin recycling and may be involved in the maintenance of intrabacterial reducing capacity. These data show that the M. tuberculosis sigH gene is dispensable for bacterial growth and survival within the host, but is required for the production of immunopathology and lethality. This phenotype demonstrates that beyond an ability to grow and persist within the host, M. tuberculosis has distinct virulence mechanisms that elicit deleterious host responses and progressive pulmonary disease.

Original languageEnglish (US)
Pages (from-to)8330-8335
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number12
DOIs
StatePublished - Jun 11 2002

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Mycobacterium tuberculosis
Mortality
Lung
Infection
Phenotype
Regulon
Thioredoxins
Inbred C3H Mouse
Bacterial Load
Recycling
Virulence Factors
Microarray Analysis
Inbred C57BL Mouse
Bacillus
Lung Diseases
Genes
Virulence
Tuberculosis
Transcription Factors
Spleen

ASJC Scopus subject areas

  • Genetics
  • General

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Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative σ factor, SigH. / Kaushal, Deepak; Schroeder, Benjamin G.; Tyagi, Sandeep; Yoshimatsu, Tetsuyuki; Scott, Cherise; Ko, Chiew; Carpenter, Liane; Mehrotra, Jyoti; Manabe, Yukari C; Fleischmann, Robert D.; Bishai, William Ramses.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 12, 11.06.2002, p. 8330-8335.

Research output: Contribution to journalArticle

Kaushal, Deepak ; Schroeder, Benjamin G. ; Tyagi, Sandeep ; Yoshimatsu, Tetsuyuki ; Scott, Cherise ; Ko, Chiew ; Carpenter, Liane ; Mehrotra, Jyoti ; Manabe, Yukari C ; Fleischmann, Robert D. ; Bishai, William Ramses. / Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative σ factor, SigH. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 12. pp. 8330-8335.
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