Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative sigma factor, SigH.
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.
Kaushal
Deepak
D
Department of Medicine, Center for Tuberculosis Research, Johns Hopkins School of Medicine, 424 North Bond Street, Baltimore, MD 21231, USA.
Schroeder
Benjamin G
BG
Tyagi
Sandeep
S
Yoshimatsu
Tetsuyuki
T
Scott
Cherise
C
Ko
Chiew
C
Carpenter
Liane
L
Mehrotra
Jyoti
J
Manabe
Yukari C
YC
Fleischmann
Robert D
RD
Bishai
William R
WR
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D003001:Cloning, Molecular; D016384:Consensus Sequence; D016207:Cytokines / Q000032:analysis*; D003643:Death; D005434:Flow Cytometry; D017353:Gene Deletion; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000472:pathogenicity*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012808:Sigma Factor / Q000235:genetics*; D013154:Spleen / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000473:pathology*; D014774:Virulence
D001426:Bacterial Proteins; D016207:Cytokines; C120328:SigH protein, bacteria; D012808:Sigma Factor