Reduced immunopathology and mortality despite tissue persistence in aMycobacterium tuberculosismutant lacking alternative σ factor, SigH

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 C57BL͞6 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.T uberculosis is one of the leading infectious causes of death and claims Ϸ2 million lives annually (1). There is controversy over whether the disease is primarily a dysfunctional immunologic reaction to a persistent microbe or whether the bacteria themselves produce tissue damage; there is evidence that both host and bacterial factors play key roles in disease severity. In susceptible mouse strains, such as C3H, the pathogen elicits a dysregulated, necrotizing host immune response leading to tissue destruction and further bacterial replication. In resistant mice such as C57BL͞6, Mycobacterium tuberculosis survives in high numbers for many months and is contained in organized granulomatous lesions in the lung without progressive lung damage. Thus whereas mycobacteria survive in both genetic backgrounds, disease progression is delayed in resistant animals (2-4).On the bacterial side, M. tuberculosis virulence has been associated with its initial survival within macrophages and resistance to reactive oxygen and nitrogen intermediates (ROIs and RNIs) (5-8). Tubercle bacilli demonstrate inducible responses to oxidative stresses, and several M. tuberculosis genes, including katG (catalase peroxidase), ahpC (alkylhydroperoxide reductase), and sodA and sodC (superoxide dismutases) have been implicated in protection from the macrophage oxidative burst (9-11). Another potential ...

MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

“…The mycobacterial growth rate in guinea pigs is not the only indicator of virulence, and studies have shown that strains with no differences in in vivo growth rates can produce infections that differ significantly by histopathological analysis 46,47 . Despite the reduced bacterial loads, histopathological assessments revealed that lung sections from guinea pigs infected with DmazF3D9D6 exhibited higher degrees of granulomatous inflammation than guinea pigs infected with the parental strain (Fig.…”

The stress‐responsive chaperone α‐crystallin 2 is required for pathogenesis of Mycobacterium tuberculosis

“…Reduced pathology in the absence of any detectable change in bacterial load has previously been reported for M. tuberculosis mutants lacking the sigH (Kaushal et al, 2002) and whiB3 (Steyn et al, 2002) genes, and differences in the rate of progression of pathology have been observed between clinical isolates of M. tuberculosis that differ in their ability to elicit a proinflammatory immune response (Manca et al, 2001). One possible explanation for the reduced pathology phenotype of the Dacr2 mutant is that the Acr2 protein itself elicits some detrimental form of immune response that promotes tissue destruction without affecting the bacterial population.…”

Mycobacterium tuberculosis Rv1395 Is a Class III Transcriptional Regulator of the AraC Family Involved in Cytochrome P450 Regulation

“…Indeed, the Ϫ10 and Ϫ35 boxes identified to date vary largely, and the Ϫ35 region in particular tolerates a high level of sequence diversity (75). Recently, the consensus sequences for SigH (17,18) and SigE (16) have been described. However, Rv1394c and Rv1395 promoters do not fit with these elements, suggesting that they are probably recognized by other sigma factors.…”