Mycobacterium tuberculosis ECF sigma factor sigC is required for lethality in mice and for the conditional expression of a defined gene set

Abstract

SummaryBacterial alternative RNA polymerase sigma factors are key global adaptive response regulators with a likely role in Mycobacterium tuberculosis pathogenesis. We constructed a mutant lacking the sigma factor gene, sigC , by allelic exchange, in the virulent CDC1551 strain of M. tuberculosis and compared the resulting mutant with the isogenic wild-type strain and complemented mutant strain. In vitro , compared to the wild-type and complemented strains, the mutant was found to have similar ability to survive in both murine bone marrow-derived macrophages and activated J774 macrophages.

Inactivation of the ilvB1 gene in Mycobacterium tuberculosis leads to branched-chain amino acid auxotrophy and attenuation of virulence in mice

“…in both organs. Small differences in the initial bacterial loads in the organs of mice have been observed previously, and this is not expected to influence the outcome of infection (Ewann et al, 2002;Sun et al, 2004). In contrast to the wild-type bacteria, which increased in numbers in the lungs of infected animals over a period of 4 weeks (from 1.3610 4 to 2.6610 5 c.f.u.…”

Differential regulation of the two-component regulatory system senX3-regX3 in Mycobacterium tuberculosis

“…In addition, much remains to be determined regarding regulation of Mtb senX3-regX3 coexpression. This operon has been shown to be a member of the sigma factor SigC regulon, since these genes are downregulated in a sigC-deficient mutant (Sun et al, 2004), although their regulation may be indirect. Recent data indicate that expression of this 2CRS is negatively regulated by the Pst system component PstA1, since a pstA1 deletion mutant exhibited increased expression of regX3, which was responsible for sensitization of Mtb to nitric oxide synthase (NOS2)-dependent killing mechanisms in the lungs of mice (Tischler et al, 2013).…”

Evolution of the Mycobacterial SigK Regulon

“…This capacity to persist in the host, despite the dynamic alterations effected by the host immune response, testifies to an evolved capacity of the organism to regulate its genetic expression to the conditions encountered during infection. Indeed, a number of studies have demonstrated that disruption of M. tuberculosis regulatory elements, such as sigma factors, results in reduced virulence in experimental models (21,28,30).The determination of genomic sequences for a number of nonpathogenic mycobacteria has revealed that homologues of many genes, including regulatory elements, are often present in organisms that are not virulent to humans. For instance, comparative analysis has demonstrated conservation of biochemical pathways and a secretory system important for full virulence of M. tuberculosis (7,10).…”

“…This capacity to persist in the host, despite the dynamic alterations effected by the host immune response, testifies to an evolved capacity of the organism to regulate its genetic expression to the conditions encountered during infection. Indeed, a number of studies have demonstrated that disruption of M. tuberculosis regulatory elements, such as sigma factors, results in reduced virulence in experimental models (21,28,30).…”