Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis.
Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis.
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DOI：
10.1371/journal.ppat.1005652
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发表时间：
2016-05
期刊：
影响因子：
6.7
通讯作者：
Briken V
中科院分区：
文献类型：
--
作者：
Srinivasan L;Gurses SA;Hurley BE;Miller JL;Karakousis PC;Briken V
The interaction of Mycobacterium tuberculosis (Mtb) with host cell death signaling pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for host cell exit of the bacteria. The bacterial modulators regulating necrosis induction are poorly understood. Here we describe the identification of a transcriptional repressor, Rv3167c responsible for regulating the escape of Mtb from the phagosome. Increased cytosolic localization of MtbΔRv3167c was accompanied by elevated levels of mitochondrial reactive oxygen species and reduced activation of the protein kinase Akt, and these events were critical for the induction of host cell necrosis and macroautophagy. The increase in necrosis led to an increase in bacterial virulence as reflected in higher bacterial burden and reduced survival of mice infected with MtbΔRv3167c. The regulon of Rv3167c thus contains the bacterial mediators involved in escape from the phagosome and host cell necrosis induction, both of which are crucial steps in the intracellular lifecycle and virulence of Mtb. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a highly successful human pathogen. Following entry into host phagocytic cells, Mtb resides within a modified phagosomal compartment and inhibits apoptotic host cell death. Recent studies have demonstrated that Mtb eventually translocates from the phagosomal compartment to the cytosol. This event is followed by the induction of necrotic host cell death allowing the bacteria to exit the host cell and infect naive cell populations. Our study adds to this relatively unexplored aspect of Mtb pathogenesis by revealing that the transcriptional repressor Rv3167c of Mtb negatively regulates phagosomal escape and host cell necrosis. We furthermore demonstrate that the increased necrosis induction by the Mtb mutant strain deficient in Rv3167c required elevated reactive oxygen species levels within host cell mitochondria and reduced activation of the protein kinase Akt. In addition, the increased virulence of the Mtb mutant strain observed after aerosol infection of mice strengthens the link between the ability of the bacteria to induce host cell necrosis and virulence. The Mtb genes negatively regulated by Rv3167c are thus potential virulence factors that can be targeted for drug and vaccine development.
