Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha-crystallin

Unlike many pathogens that are overtly toxic to their hosts, the primary vi rulence determinant of Mycobacterium tuberculosis appears to be its ability to persist for years or decades within humans in a clinically latent state . Since early in the 20th century latency has been linked to hypoxic condit ions within the host, but the response of M. tuberculosis to a hypoxic sign al remains poorly characterized. The M. tuberculosis alpha -crystallin (acr ) gene is powerfully and rapidly induced at reduced oxygen tensions, provid ing us with a means to identify regulators of the hypoxic response. Using a whole genome microarray, we identified > 100 genes whose expression is rap idly altered by defined hypoxic conditions. Numerous genes involved in bios ynthesis and aerobic metabolism are repressed, whereas a high proportion of the induced genes have no known function. Among the induced genes is an ap parent operon that includes the putative two-component response regulator p air Rv3133c/Rv3132c. When we interrupted expression of this operon by targe ted disruption of the upstream gene Rv3134c, the hypoxic regulation of acr was eliminated. These results suggest a possible role for Rv3132c/3133c/313 4e in mycobacterial latency.