Mycobacterium tuberculosis Type VII Secretion System Effectors Differentially Impact the ESCRT Endomembrane Damage Response

Mittal, Ekansh; Skowyra, Michael L.; Uwase, Grace; Tinaztepe, Emir; Mehra, Alka; Köster, Stefan; Hanson, Phyllis I.; Philips, Jennifer A.

doi:10.1128/mbio.01765-18

Cited by 92 publications

(66 citation statements)

References 73 publications

(124 reference statements)

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“…Since PM damage is actively repaired through many routes, including through Ca2+ - dependent ESCRT machinery 44, 69–71 , it is also interesting to note that this branch of ESCRT emerges as a negative regulator of NLRP3 activation and cell death during Mtb infection. The ESCRT machinery was also recently shown to be involved in repair of phagosomes damaged by mycobacteria 84, 85 and to regulate pyroptosis or necroptosis by repairing GSDMD pores 86 or MLKL pores 87 , respectively, further pointing to the importance of the ESCRT machinery in regulation of inflammation and securing cell viability.…”

Section: Discussionmentioning

confidence: 99%

Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

Beckwith

Ullmann

et al. 2019

Preprint

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AbstractMycobacterium tuberculosis (Mtb) is a major global health problem and causes extensive cytotoxicity in patient cells and tissues. Here we define an NLRP3, caspase-1 and gasdermin D-mediated pathway to pyroptosis in human monocytes following exposure to Mtb. We demonstrate an ESX-1 mediated, contact-induced plasma membrane (PM) damage response that occurs during phagocytosis or from the cytosolic side of the PM after phagosomal rupture in Mtb infected cells. This PM injury in turn causes K+ efflux and activation of NLRP3 dependent IL-1β release and pyroptosis, facilitating the spread of Mtb to neighbouring cells. Further we reveal a dynamic interplay of pyroptosis with ESCRT-mediated PM repair. Collectively, these findings reveal a novel mechanism for pyroptosis and spread of infection acting through dual PM disturbances both during and after phagocytosis. We also highlight dual PM damage as a common mechanism utilized by other NLRP3 activators that have previously been shown to act through lysosomal damage.Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

Beckwith

Ullmann

et al. 2019

Preprint

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“…Several mycobacterial proteins (e.g., Ag85, Mpt32/64, and HspX), including those secreted via the ESX-1 system (e.g., Esat-6 and Cfp-10), were detected in exosomes during M. tuberculosis infection (85). Furthermore, host ESCRT machinery (ESCRT III) that participates in exosome formation is recruited onto M. tuberculosis-containing phagosomes in an ESX-1-dependent manner (86). Likewise, ESX-1 modulates the presence of Hsp90 and Gal3 on M. tuberculosis phagosomes (86,87), suggesting the importance of the ESX-1 secretion system in exosome biogenesis and in the abundance/localization of Hsp90 and Gal3.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

Tyagi

Pal

Agrawal

et al. 2020

mBio

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The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1␣, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant-N-acetyl cysteine (NAC)-or with inhibitors of host factors-galectins and Hsp90 -attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies. IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.

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“…Accordingly, the authors hypothesised that membranes of the Coxiella ‐containing vacuole are prone to sporadic ruptures, which are repeatedly repaired by the ESCRT machinery. Various ESCRT‐III proteins are also recruited to phagosomes harbouring Mycobacterium tuberculosis (Mittal et al, ). Here, the authors speculate that the ESCRT‐III system is responding to phagosomal membrane damage inflicted by the ESX‐1 secretion system (T7SS) to maintain membrane integrity and allow phagosome expansion.…”

Section: Discussionmentioning

confidence: 99%

Role of the ESCRT‐III complex in controlling integrity of the Salmonella ‐containing vacuole

Göser

Kehl

Röder

et al. 2020

Cellular Microbiology

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Intracellular pathogens need to establish specialised niches for survival and proliferation in host cells. The enteropathogen Salmonella enterica accomplishes this by extensive reorganisation of the host endosomal system deploying the SPI2-encoded type III secretion system (SPI2-T3SS). Fusion events of endosomal compartments with the Salmonella-containing vacuole (SCV) form elaborate membrane networks within host cells enabling intracellular nutrition. However, which host compartments exactly are involved in this process and how the integrity of Salmonellamodified membranes is accomplished are not fully resolved. An RNA interference knockdown screen of host factors involved in cellular logistics identified the ESCRT (endosomal sorting complex required for transport) system as important for proper formation and integrity of the SCV in infected epithelial cells. We demonstrate that subunits of the ESCRT-III complex are specifically recruited to the SCV and membrane network. To investigate the role of ESCRT-III for the intracellular lifestyle of Salmonella, a CHMP3 knockout cell line was generated. Infected CHMP3 knockout cells formed amorphous, bulky SCV. Salmonella within these amorphous SCV were in contact with host cell cytosol, and the attenuation of an SPI2-T3SS-deficient mutant strain was partially abrogated. ESCRT-dependent endolysosomal repair mechanisms have recently been described for other intracellular pathogens, and we hypothesise that minor damages of the SCV during bacterial proliferation are repaired by the action of ESCRT-III recruitment in Salmonellainfected host cells.

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Mycobacterium tuberculosis Type VII Secretion System Effectors Differentially Impact the ESCRT Endomembrane Damage Response

Cited by 92 publications

References 73 publications

Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

Role of the ESCRT‐III complex in controlling integrity of the Salmonella ‐containing vacuole

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