Mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism

Jamwal, Shilpa; Mehrotra, Parul; Singh, Archana; Siddiqui, Zaved; Basu, Atanu; Rao, Kanury V. S.

doi:10.1038/srep23089

Cited by 100 publications

(87 citation statements)

References 45 publications

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“…Whereas mycobacterial phospholipases are not involved in Mtb's phagosomal permeabilization (50), some hemolytic activity is attributed to a mycobacterial sphingomyelinase (33). In addition, a host phospholipase A2 may be involved in phagosomal permeabilization (51). Such findings leave open the possibility that ESX-1 regulates the activities of bacterial and host lipolytic enzymes to disrupt membranes.…”

Section: Discussionmentioning

confidence: 81%

Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions

Conrad

Osman

Shanahan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

228

273

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Mycobacterium tuberculosis and Mycobacterium marinum are thought to exert virulence, in part, through their ability to lyse host cell membranes. The type VII secretion system ESX-1 [6-kDa early secretory antigenic target (ESAT-6) secretion system 1] is required for both virulence and host cell membrane lysis. Both activities are attributed to the pore-forming activity of the ESX-1-secreted substrate ESAT-6 because multiple studies have reported that recombinant ESAT-6 lyses eukaryotic membranes. We too find ESX-1 of M. tuberculosis and M. marinum lyses host cell membranes. However, we find that recombinant ESAT-6 does not lyse cell membranes. The lytic activity previously attributed to ESAT-6 is due to residual detergent in the preparations. We report here that ESX-1-dependent cell membrane lysis is contact dependent and accompanied by gross membrane disruptions rather than discrete pores. ESX-1-mediated lysis is also morphologically distinct from the contact-dependent lysis of other bacterial secretion systems. Our findings suggest redirection of research to understand the mechanism of ESX-1-mediated lysis.Mycobacterium tuberculosis | Mycobacterium marinum | ESAT-6 | ESX-1 secretion system | cell membrane lysis

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Section: Discussionmentioning

confidence: 81%

Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions

Conrad

Osman

Shanahan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

228

273

View full text Add to dashboard Cite

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“…However, BCG and ESX‐1‐deficient Mtb mutants also displayed a defect in their capacity to escape from phagosomes (Houben et al, ; Simeone et al . , ; van der Wel et al, ), another strategy exploited by Mtb for survival in the host macrophage (Jamwal et al, ). These findings made us test different DIM‐deficient mutants in recently developed phagosomal rupture screens, and we demonstrate that DIM are required for the induction of phagosomal membrane rupture in infected human macrophages, a yet unknown function for these lipids.…”

Section: Discussionmentioning

confidence: 99%

ESX-1 and phthiocerol dimycocerosates ofMycobacterium tuberculosisact in concert to cause phagosomal rupture and host cell apoptosis

Augenstreich

Arbués

Siméone

et al. 2017

Cellular Microbiology

186

226

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Although phthiocerol dimycocerosates (DIM) are major virulence factors of Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, little is known about their mechanism of action. Localized in the outer membrane of mycobacterial pathogens, DIM are predicted to interact with host cell membranes. Interaction with eukaryotic membranes is a property shared with another virulence factor of Mtb, the early secretory antigenic target EsxA (also known as ESAT-6). This small protein, which is secreted by the type VII secretion system ESX-1 (T7SS/ESX-1), is involved in phagosomal rupture and cell death induced by virulent mycobacteria inside host phagocytes. In this work, by the use of several knock-out or knock-in mutants of Mtb or Mycobacterium bovis BCG strains and different cell biological assays, we present conclusive evidence that ESX-1 and DIM act in concert to induce phagosomal membrane damage and rupture in infected macrophages, ultimately leading to host cell apoptosis. These results identify an as yet unknown function for DIM in the infection process and open up a new research field for the study of the interaction of lipid and protein virulence factors of Mtb.

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“…Several mycobacterial proteins are known to escape into the cytosol from the arrested phagolysosome2930. Another possibility is that mycobacteria themselves can escape directly into the cytosol from phagolysosomes to release virulent proteins for modulating host functions313233. Interestingly, PE_PGRS6234, PE5 and PE1535 can also inhibit inos gene transcription in macrophages.…”

Section: Discussionmentioning

confidence: 99%

The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production

Bhat

Srivastava

Kotturu

et al. 2017

Sci Rep

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Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is one of the most successful pathogens of humans. It has evolved several adaptive skills and evasion mechanisms to hijack the immunologically educated host to suit its intracellular lifestyle. Here, we show that one of the unique PPE family member proteins of M. tuberculosis, PPE2, can limit nitric oxide (NO) production by inhibiting inos gene transcription. PPE2 protein has a leucine zipper DNA-binding motif and a functional nuclear localization signal. PPE2 was translocated into the macrophage nucleus via the classical importin α/β pathway where it interacted with a GATA-binding site overlapping with the TATA box of inos promoter and inhibited NO production. PPE2 prolonged intracellular survival of a surrogate bacterium M. smegmatis in vitro as well as in vivo. This information are likely to improve our knowledge of host-pathogen interactions during M. tuberculosis infection which is crucial for designing effective anti-TB therapeutics.

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Mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism

Cited by 100 publications

References 45 publications

Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions

Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions

ESX-1 and phthiocerol dimycocerosates ofMycobacterium tuberculosisact in concert to cause phagosomal rupture and host cell apoptosis

The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production

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