the enduring hypoxic response of mycobacterium tuberculosis结核分枝杆菌的持久的缺氧反应.pdfVIP

The Enduring Hypoxic Response of Mycobacterium tuberculosis 1,2 2,3 1 1,2 Tige R. Rustad , Maria I. Harrell , Reiling Liao , David R. Sherman * 1 Seattle Biomedical Research Institute, Seattle, Washington, United States of America, 2 Department of Pathobiology, University of Washington, Seattle, Washington, United States of America, 3 Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America Background. A significant body of evidence accumulated over the last century suggests a link between hypoxic microenvironments within the infected host and the latent phase of tuberculosis. Studies to test this correlation have identified the M. tuberculosis initial hypoxic response, controlled by the two-component response regulator DosR. The initial hypoxic response is completely blocked in a dosR deletion mutant. Methodology/Principal Findings. We show here that a dosR deletion mutant enters bacteriostasis in response to in vitro hypoxia with only a relatively mild decrease in viability. In the murine infection model, the phenotype of the mutant was indistinguishable from that of the parent strain. These results suggested that additional genes may be essential for entry into and maintenance of bacteriostasis. Detailed microarray analysis of oxygen starved cultures revealed that DosR regulon induction is transient, with induction of nearly half the genes returning to baseline within 24 hours. In addition, a larger, sustained wave of gene expression follows the DosR-mediated initial hypoxic response. This Enduring Hypoxic Response (EHR) consists of 230 genes significantly induced at four and seven days of hypoxia but not at initial time points. These genes include a surprising number of transcriptional regulators that