Autophagy restricts Mycobacterium tuberculosis during acute infection in mice

Golovkine, Guillaume; Roberts, Allison; Morrison, Huntly M.; Rivera‐Lugo, Rafael; McCall, Rita M.; Nilsson, Hannah; Garelis, Nicholas E; Repasy, Teresa; Cronce, Michael J.; Budzik, Jonathan M.; Dis, Erik Van; Popov, Lauren M.; Mitchell, Gabriel; Zalpuri, Reena; Jorgens, Danielle; Cox, Jeffery S.

doi:10.1038/s41564-023-01354-6

Cited by 29 publications

(29 citation statements)

References 65 publications

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“…However, trans -δ-viniferins have been reported as Wnt modulators, which in turn is hypothesized to be a target for pharmaceutical autophagy induction (Huber, Koval, et al, 2022). Interestingly, autophagy is also discussed as a central process of cell autonomous defence against Mtb and Mm (Aylan et al, 2023; Golovkine et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

Nitschke,

Huber,

Vossio

et al. 2024

Preprint

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This study evaluated the efficacy of a high-throughputDictyostelium discoideum–Mycobacterium marinumDd-Mm infection system by first benchmarking it against a set of antibiotics and second in screening a library of natural product (NP) derivatives for anti-infective activity against intracellularMycobacterium marinum(Mm). The study observed no activity of pyrazinamide against Mm, consistent with known resistance patterns, and confirmed other antibiotics, such as rifampicin and bedaquiline, with activity below defined antibacterial susceptibility breakpoints. From screening a small library of NP derivatives,trans-δ-viniferins emerged as promising anti-infective scaffolds, particularly two compounds which exhibited an anti-infective activity on Mm during infection but not on Mm in broth, with an IC50 of 18.1 µ with an IC50 of 9 µM). Subsequent exploration via halogenation and structure-activity relationship (SAR) studies led to the identification of derivatives with improved selectivity and potency. The observed anti-infective phenotype may involve mechanisms such as blocking mycobacterial virulence factors or boosting host defense. Furthermore, the study highlights the potential of natural product-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.

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Section: Discussionmentioning

confidence: 99%

Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

Nitschke,

Huber,

Vossio

et al. 2024

Preprint

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“…The impact of xenophagy seem to be more striking in primary murine macrophages with a severe delay in growth of Mtb in WT macrophages compared to Atg5, Atg7 or Atg16L1 KO cells). 72 The deletion of genes of proteins involved in canonical autophagy (such as ATG5) leads to increased susceptibility of the mice to the infection. 72 However, the mechanism underlying the susceptibility may not be linked to cell autonomous defense but possibly more related for example to a role of ATG5 in immune response modulation during the infection such as in the promotion of neutrophils recruitment.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Interplay of Autophagy and Membrane Repair DuringMycobacterium tuberculosisInfection

Augenstreich¹,

Phan²,

Allen³

et al. 2022

Preprint

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Autophagy can act as a defense mechanism for macrophages infected by intracellular pathogens. Mycobacterium tuberculosis (Mtb) is known to both induce and repress autophagic responses, such as xenophagy and LC3-associated phagocytosis (LAP) which both involve the recruitment of LC3 to the Mtb-containing vacuole (MCV). However, the dynamics of MCV interaction with xenophagy or LAP are unclear. Here, using time-lapse confocal microscopy, we present a comprehensive spatio-temporal analysis of the LC3 recruitment to the MCVs during the infection of macrophages. The results revealed frequent LC3 recruitment in the form of large tubule-vesicular structures to the MCV, characteristic of xenophagy, and demonstrated that Mtb could efficiently escape from this signal. We found that the main driver of the LC3 recruitment is the initial macrophage bacterial burden before a second phagocytosis event. We also assessed the potential bactericidal properties of the LC3 recruitment and observed that interferon-gamma treatments did not affect the LC3 recruitment frequency. Additionally, no sign of acidification in the formed autophagosome with or without interferon-gamma treatment was observed. Interestingly, the time-lapses using the acidification probe lysoview revealed that the LC3 recruitment happened shortly after a drop in acidity, a typical sign of membrane damage that is a well-known trigger for autophagy. However, LC3 subsequent loss of signal or escape could also be followed by a restoration of acidification in the vacuole, thus showing restoration of membrane integrity. In conclusion, we show that LC3 recruitment to the MCV correlates with subsequent membrane repair. However, the LC3 recruitment did not show bactericidal properties, questioning its cell intrinsic role in controlling the Mtb infection in macrophages.

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“…Studies using mouse models have demonstrated the protective role of ATG5 in host defense against infection. 74,75 Moreover, ATG7 and ATG14 have also been found to actively participate in phagosome-lysosome fusion. 76 Recently, receptor-interacting protein kinase-3 (RIP3), a crucial kinase in necroptotic cell death signaling, has been found to be involved in autophagy.…”

Section: Host-induced Autophagy In Response To Mtb Infectionmentioning

confidence: 99%

Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection

Ruan,

Lyu,

Lai

et al. 2024

Interdisciplinary Medicine

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Tuberculosis (TB) is a fatal infectious disease that continues to pose a serious public health threat. The emergence of drug‐resistant TB has further worsened the burden of the disease. The interaction between the host and the pathogen involves multiple modes of cell death, which play a role in determining immune outcomes. Several studies have established a strong correlation between cell death and TB progression. This review explores the molecular mechanisms of various cell death modes in Mycobacterium tuberculosis (Mtb) infection and how Mtb's virulence effectors regulate these pathways, including apoptosis, autophagy, pyroptosis, ferroptosis, and necrosis. Furthermore, therapeutic strategies targeting cell death pathways have shown promising results in TB treatment. Importantly, this review highlights the significant potential of mitochondria in mediating communication between different cell death modes and influencing the final outcomes. Overall, this work provides a comprehensive summary of the role of cell death in host immune responses and immune evasion by Mtb. It also offers valuable insights into the pathogenesis of TB and immune evasion strategies employed by Mtb and contributes to the development of more effective anti‐TB therapies.

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Autophagy restricts Mycobacterium tuberculosis during acute infection in mice

Cited by 29 publications

References 65 publications

Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

Dynamic Interplay of Autophagy and Membrane Repair DuringMycobacterium tuberculosisInfection

Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection

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