Mycobacterium avium MAV2054 protein induces macrophage apoptosis by targeting mitochondria and reduces intracellular bacterial growth

Lee, Kang-In; Whang, Jake; Choi, Heung Jai; Son, Young Soo; Jeon, Haet Sal; Back, Yong Woo; Park, Hye‐Soo; Paik, Seungwha; Park, Jeong‐Kyu; Choi, Chul Hee

doi:10.1038/srep37804

Cited by 33 publications

(33 citation statements)

References 59 publications

(72 reference statements)

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“…We observed, inhibiting caspase-12 significantly down-regulated the activation of caspase-9/3 axis, suggesting that caspase-9 can be activated by multiple pathways in M. fortuitum infected HKM. The involvement of caspase-9 is well documented in pathogenesis induced by several mycobacteria 12 , 43 – 45 our study extends this to M. fortuitum .…”

Section: Discussionsupporting

confidence: 80%

Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages

Datta

Khatri

Singh

et al. 2018

Cell Death Discovery

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Mycobacterium fortuitum is a natural fish pathogen. It induces apoptosis in headkidney macrophages (HKM) of catfish, Clarias sp though the mechanism remains largely unknown. We observed M. fortuitum triggers calcium (Ca2+) insult in the sub-cellular compartments which elicits pro-apototic ER-stress factor CHOP. Alleviating ER-stress inhibited CHOP and attenuated HKM apoptosis implicating ER-stress in the pathogenesis of M. fortuitum. ER-stress promoted calpain activation and silencing the protease inhibited caspase-12 activation. The study documents the primal role of calpain/caspase-12 axis on caspase-9 activation in M. fortuitum-pathogenesis. Mobilization of Ca2+ from ER to mitochondria led to increased mitochondrial Ca2+ (Ca2+)m load,, mitochondrial permeability transition (MPT) pore opening, altered mitochondrial membrane potential (ΔΨm) and cytochrome c release eventually activating the caspase-9/-3 cascade. Ultra-structural studies revealed close apposition of ER and mitochondria and pre-treatment with (Ca2+)m-uniporter (MUP) blocker ruthenium red, reduced Ca2+ overload suggesting (Ca2+)m fluxes are MUP-driven and the ER-mitochondria tethering orchestrates the process. This is the first report implicating role of sub-cellular Ca2+ in the pathogenesis of M. fortuitum. We summarize, the dynamics of Ca2+ in sub-cellular compartments incites ER-stress and mitochondrial dysfunction, leading to activation of pro-apoptotic calpain/caspase-12/caspase-9 axis in M. fortuitum-infected HKM.

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Section: Discussionsupporting

confidence: 80%

Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages

Datta

Khatri

Singh

et al. 2018

Cell Death Discovery

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“…Recent studies have focused on controlling mycobacteria by exploiting host innate immunity, principally apoptosis (Behar et al, ; Bhattacharyya et al, ; Parandhaman & Narayanan, ). In M. avium ‐infected macrophages, reactive oxygen species (ROS) induce caspase‐dependent apoptosis by disrupting the mitochondria membrane potential, precipitating release of cytochrome c (Lee et al, ). Previously, we reported that endoplasmic reticulum (ER) stress‐mediated apoptosis through ROS regulates the intracellular survival of mycobacteria in macrophages (J.…”

Section: Introductionmentioning

confidence: 99%

“…In M. avium-infected macrophages, reactive oxygen species (ROS) induce caspase-dependent apoptosis by disrupting the mitochondria membrane potential, precipitating release of cytochrome c (Lee et al, 2016). Previously, we reported that endoplasmic reticulum (ER) stress-mediated apoptosis through ROS regulates the intracellular survival of mycobacteria in macrophages (J.…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species‐mediated endoplasmic reticulum stress response induces apoptosis ofMycobacterium avium‐infected macrophages by activating regulated IRE1‐dependent decay pathway

Lee

Choi

et al. 2019

Cellular Microbiology

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Mycobacterium avium, a slow‐growing nontuberculous mycobacterium, causes fever, diarrhoea, loss of appetite, and weight loss in immunocompromised people. We have proposed that endoplasmic reticulum (ER) stress‐mediated apoptosis plays a critical role in removing intracellular mycobacteria. In the present study, we investigated the role of the regulated IRE1‐dependent decay (RIDD) pathway in macrophages during M. avium infection based on its role in the regulation of gene expression. The inositol‐requiring enzyme 1 (IRE1)/apoptosis signal‐regulating kinase 1 (ASK1)/c‐Jun N‐terminal kinase (JNK) signalling pathway was activated in macrophages after infection with M. avium. The expression of RIDD‐associated genes, such as Bloc1s1 and St3gal5, was decreased in M. avium‐infected macrophages. Interestingly, M. avium‐induced apoptosis was significantly suppressed by pretreatment with irestatin (inhibitor of IRE1α) and 4μ8c (RIDD blocker). Macrophages pretreated with N‐acetyl cysteine (NAC) showed decreased levels of reactive oxygen species (ROS), IRE1α, and apoptosis after M. avium infection. The expression of Bloc1s1 and St3gal5 was increased in NAC‐pretreated macrophages following infection with M. avium. Growth of M. avium was significantly increased in irestatin‐, 4μ8c‐, and NAC‐treated macrophages compared with the control. The data indicate that the ROS‐mediated ER stress response induces apoptosis of M. avium‐infected macrophages by activating IRE1α‐RIDD. Thus, activation of IRE1α suppresses the intracellular survival of M. avium in macrophages.

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“…Using this strategy dependent on the RD1and other factors, the pathogen undoubtedly promotes bacterial cell-to-cell spread [25,26]. M. avium escapes macrophage killing by expressing MAV2054 virulence factor and promoting the intrinsic apoptotic pathway in cultured macrophages as well as in vivo via production of reactive oxygen species, damaging mitochondrial membrane [15]. Recent studies by our group have demonstrated that M. avium infection stimulates different modes of apoptotic escape in the primary-and secondary-infected cells [10,16].…”

Section: Discussionmentioning

confidence: 99%

“…Although macrophage apoptosis is an innate defense mechanism and is a strictly regulated process, M. avium escapes apoptotic killing [8,14]. It has been demonstrated that the pathogen targets intrinsic pathway to promote the apoptotic death in cultured macrophages and in vivo via production of reactive oxygen species, leading to mitochondrial membrane potential loss [15]. Moreover, M. avium uses apoptosis as one of mechanisms to spread from cell-to-cell and for dissemination [8,10].…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium avium subsp. hominissuis effector MAVA5_06970 promotes rapid apoptosis in secondary-infected macrophages during cell-to-cell spread

et al. 2018

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Mycobacterium avium subsp. hominissuis is an opportunistic intracellular pathogen associated with disease in patients either immunosuppression or chronic lung pathology. Once in the host, M. avium preferentially infects and replicates within the phagocytic cells. The host driven macrophage apoptosis appears to be an essential aspect of innate immunity during bacterial infection; however, the existing evidence suggests that M. avium has evolved adaptive approaches to trigger the phagocyte apoptosis, exit apoptotic cells or via ingestion of infected apoptotic bodies subsequently infect neighboring macrophages. By evaluating 4,000 transposon mutants of M. avium in THP-1 cells, we identified clones that can trigger a new form of early host cell apoptosis, which is only observed upon entry into the “secondary-infected” macrophages. Inactivation of MAVA5_06970 gene lead to significant attenuation in intracellular growth within macrophages and mice, and impaired M. avium to induce rapid apoptosis in the “secondary-infected” cells as measured by Annexin V-FITC detection assay. Complementation of MAVA5_06970 gene corrected the attenuation as well as apoptotic phenotypes. The MAVA5_06970 gene encodes for a secreted protein. Using the pull-down assay and then confirmed with the yeast two-hybrid screen, we found that MAVA5_06970 effector interacts with the Secreted Phosphoprotein 1, the cytokine also known as Osteopontin. This interaction enhances the THP-1 cell apoptosis and, consequently, restricts the production of interleukin-12 that likely may limit the activation of the type I immunity pathway in vivo. This work identified a key virulence effector of M. avium that contributes to the cell-to-cell spread of the pathogen.

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Mycobacterium avium MAV2054 protein induces macrophage apoptosis by targeting mitochondria and reduces intracellular bacterial growth

Cited by 33 publications

References 59 publications

Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages

Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages

Reactive oxygen species‐mediated endoplasmic reticulum stress response induces apoptosis ofMycobacterium avium‐infected macrophages by activating regulated IRE1‐dependent decay pathway

Mycobacterium avium subsp. hominissuis effector MAVA5_06970 promotes rapid apoptosis in secondary-infected macrophages during cell-to-cell spread

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