Mycobacterium tuberculosis, an obligate mammalian pathogen, adapts to its host during the course of infection via the regulation of gene expression. Of the regulators of transcription that play a role in this response, several alternative sigma factors of M. tuberculosis have been shown to control gene expression in response to stresses, and some of these are required for virulence or persistence in vivo. For this study, we examined the role of the alternative sigma factor SigD in M. tuberculosis gene expression and virulence. Using microarray analysis, we identified several genes whose expression was altered in a strain with a sigD deletion. A small number of these genes, including sigD itself, the gene encoding the autocrine growth factor RpfC, and a gene of unknown function, Rv1815, appear to be directly regulated by this sigma factor. By identifying the in vivo promoters of these genes, we have determined a consensus promoter sequence that is putatively recognized by SigD. The expression of several genes encoding PE-PGRS proteins, part of a large family of related genes of unknown function, was significantly increased in the sigD mutant. We found that the expression of sigD is stable throughout log phase and stationary phase but that it declines rapidly with oxygen depletion. In a mouse infection model, the sigD mutant strain was attenuated, with differences in survival and the inflammatory response in the lung between mice infected with the mutant and those infected with the wild type.Mycobacterium tuberculosis is an obligate mammalian pathogen that is believed to infect roughly one-third of the world's population (33). While capable of causing disease in a substantial proportion of those infected, resulting in approximately eight million cases of active tuberculosis in the world each year, this bacillus causes an asymptomatic infection in most individuals. After an initial period of rapid replication, the infection is typically contained by the host immune system, resulting in the apparent eradication of the infection in some individuals but in the persistence of small numbers of bacteria in others, resulting in asymptomatic chronic infections. These latent infections may subsequently become active, often in the setting of decreased host immunity, with increased bacterial replication and extensive tissue damage.During these several stages of infection, M. tuberculosis encounters a changing host environment, in response to which the bacillus must activate defense and repair mechanisms and reprogram its physiology to ensure survival. The large number of putative transcription regulators identified in the M. tuberculosis genome sequence indicate that much of the regulation required for these adaptations by M. tuberculosis occurs at the level of transcription (6). Among the transcription regulators that have been implicated in these processes are the alternative sigma factors of this organism, 12 of which are encoded in the M. tuberculosis genome. In previous work, our laboratory and others have implicated sev...