Abstract
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.
Highlights
Apoptosis is a major programmed cell death pathway but it is well established that necrosis can be induced via defined signal transduction pathways [1,2]
Following entry into host phagocytic cells, Mycobacterium tuberculosis (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
Summary
Apoptosis is a major programmed cell death pathway but it is well established that necrosis can be induced via defined signal transduction pathways [1,2]. The function of programmed necrosis in host resistance or susceptibility to pathogens is still an open question in many cases and may depend upon the context of the infection and the pathogen [5]. The RIPK1/3 necrosis pathway acts as a back-up mechanism of death induction in cells infected with viruses that are able to inhibit host cell apoptosis [6]. Programmed necrosis is associated with increased host resistance against viral pathogens in the case of vaccinia virus, adenovirus and MCMV [5,6]. For the influenza A virus, programmed necrosis leads to increased pathology and host susceptibility [7]. Enteropathogenic Escherichia coli can inhibit RIPK3-dependent necrosis via the glycosyl transferase NleB and this activity is important for bacterial virulence [8,9]. IRF-3-dependent necrosis induction by Listeria monocytogenes promotes pathogen dissemination and virulence [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
