Not surprisingly, given the aerobic conditions under which gene function is typically GDC-0199 Bcl-2 inhibitor assessed, the EHR includes a high proportion of genes of unknown function. There are also more genes than expected by chance annotated as involved in virulence, detoxification, and adaptation, including a number of heat shock proteins. RelA, regulator of the stringent response, is induced as part of the EHR. This response has been implicated in the survival of MTB under nutrient deprivation and anaerobic growth conditions. Genes annotated as oxidoreductases and cytochromes are also prominent in the EHR, and these genes are likely involved in anaerobic metabolism. There are also several induced genes putatively involved in sulfur metabolism. These include the atypical sulfur transporter sse1, the APS synthase complex cysD/cysN, the methionine synthase gene cysM, and several potentially unrelated genes involved in synthesis of sulfurcontaining compounds such as thioredoxin and ferrodoxin. We sought to define the link between the initial hypoxic response controlled by DosR and the EHR. Accordingly, three paired H37Rv and H37Rv:DdosR hypoxic time courses were conducted. Samples were taken at four, eight, twelve, and 24 hours of exposure to hypoxia. As before, microarrays were used to compare RNA from each strain at each hypoxic time point to log phase expression. To avoid threshold effects caused when modestly induced genes wobble across the two-fold threshold, we applied a more stringent criterion to define the set of genes induced at each time-point. The genes induced at each time-point were divided into three classes: induced in both H37Rv and the dosR mutant, the DosR regulon genes, which are not induced in the dosR mutant, and the genes outside the DosR regulon that are induced in H37Rv but not the mutant. If EHR expression depends significantly on the DosR response, we would GSK212 expect a large number of genes in that final category. The DosR-regulated response to hypoxia has been suggested to play a major role in mycobacterial dormancy, as is apparent from the name DosR, Dormancy survival Regulator. However, the data presented here suggest a more modest role for DosR in survival of hypoxia-mediated bacteriostasis. In vitro, MTB lacking DosR show no survival defect in the defined hypoxic model and only a modest effect in the standing culture hypoxic model. However MTB are somewhat impaired for survival in the Wayne model. Wayne model bacilli are likely to experience stresses in addition to hypoxia, such as nutrient depletion and toxic waste accumulation. In the Wayne model oxygen is slowly depleted as it is consumed, allowing the bacilli to adapt to hypoxia in a gradual manner.