Toward Resolving the Paradox of the Critical Role of the DosR Regulon in Mycobacterium tuberculosis Persistence and Active Disease.
Toward Resolving the Paradox of the Critical Role of the DosR Regulon in Mycobacterium tuberculosis Persistence and Active Disease.
复制标题
解决 DosR 调节子在结核分枝杆菌持续存在和活动性疾病中的关键作用的悖论。
DOI：
10.1164/rccm.201503-0424ed
复制
发表时间：
2015
影响因子：
24.7
通讯作者：
Schlesinger,LarryS
中科院分区：
文献类型：
--
作者：
Voskuil,MartinI;Schlesinger,LarryS
The DosR regulon was first described in 2003 as a set of 48 DosR-activated genes highly induced by hypoxia and nitric oxide, conditions that inhibit respiration and growth of Mycobacterium tuberculosis (Mtb)(1, 2). DosR is phosphorylated by two hemecontaining sensor histidine kinases, DosS and DosT, which directly respond to hypoxia, nitric oxide, and carbon monoxide (2). The DosR regulon has arguably been the most intensely studied group of Mtb genes. Interest in the regulon has largely been fueled by its high expression during the infection of macrophages and animals, and during latent infection and active disease in humans (2). In vitro studies demonstrate that it is critical for both survival and maintenance of metabolism during anaerobic models of in vitro dormancy (2-4).The DosR regulon is most often associated with latent tuberculosis (TB). This association reflects expression of the regulon during in vitro conditions of nonreplicating persistence (eg, anaerobic dormancy) that are believed to reproduce aspects of Mtb physiology in latent infection (2). It is generally accepted that Mtb during latent infection is in a low metabolic state, and bacilli replication is infrequent or absent. The nonreplicating status of bacilli during latent infection is best exemplified by studies that document the stability of DNA restriction fragment length polymorphism banding patterns during decades of latency (5) and the fact that the standard monotherapy for latent TB does not result in the emergence of drug-resistant strains. Several studies suggest that the DosR regulon is involved in latency. The first found that latently infected persons are more likely than those with active infection to bear T cells specific for DosR regulon antigens (6). High in vivo expression of the DosR regulon also indicates it is likely involved in active disease. Once pulmonary tissue becomes the site of inflammatory TB granulomas, access to oxygen
