Based on data presented here, we would also LEE011 predict that DosR regulon expression would be reduced in lesions that remain Adriamycin hypoxic for extended periods of time. Thus, the DosR regulon is expressed in vivo as the bacilli are increasing in number. This expression pattern suggests that the DosR regulon��s role is not simply as a latency trigger but functions at all times during the early stages of infection. The minimal phenotypic effect of DosR deletion highlighted the question of which genes and mechanisms are used by MTB to enter and maintain bacteriostasis triggered by hypoxia. The response subsequent to the initial hypoxic response mediated by DosR contains a larger number of highly induced genes that remain induced for days after replication stops. This hypoxic response is dominated by a core of stably induced genes we name here the Enduring Hypoxic Response, and is observed in both wild-type and dosR mutant strains. We are currently dissecting this response to better understand the ways in which MTB enters into and survives bacteriostasis. Analysis of the genes of the EHR should offer insights into the hypoxic response of MTB and the resulting bacteriostasis. Not surprisingly, there is considerable overlap with genes induced in the defined hypoxia model and the previously reported Wayne model of hypoxia. Moreover, the fraction of genes induced in the Wayne model that are also part of the EHR increases over the hypoxic time course. We also observe that, unlike the DosR regulon, the EHR shows a substantial overlap with the MTB genes induced by nutrient deprivation. Exploring common themes among the various in vitro models may help identify genes and processes essential for bacteriostasis in general, rather than any specific condition used to trigger replication arrest. The genes repressed during the defined hypoxic time course are primarily well characterized genes involved in normal aerobic growth. Once the shift is made to anaerobiosis, energy generation and the regeneration of NAD + become significant challenges. Surprisingly, many of the genes predicted to be involved these processes are not induced or are even repressed. These include the oxygen-independent NADH dehydrogenase complex, the nitrate and nitrite reductase complexes, lactate dehydrogenase, glycine dehydrogenase, and the isocitrate lyase gene of the glyoxylate shunt. This is surprising given that active transcription and metabolism is occurring in these nonreplicating cells, as evidenced by the production and maintenance of mRNA. This poses an intriguing dilemma- what is the metabolic pathway used to generate energy in hypoxic MTB? We were surprised to find that blocking expression of the DosR regulon had very little effect on subsequent expression of the EHR. The genes disregulated at later time points are almost all members of the DosR regulon that remain induced in wild type and fail to be induced in the mutant.