Autophagy in Tuberculosis

Deretic, Vojo

doi:10.1101/cshperspect.a018481

Cited by 85 publications

(85 citation statements)

References 129 publications

(199 reference statements)

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“…In conclusion, DHEA in physiological conditions (that is in presence of cortisol) leads to autophagy induction and hence a better Mtb control. These results sound interesting since autophagy is not only important for bacterial clearance but also for the prevention of tissue damage [45]. Last but not least, present results add support to the use of DHEA as an adjuvant therapy for TB.…”

Section: Discusionsupporting

confidence: 54%

Effect of cortisol and/or DHEA on THP1-derived macrophages infected with Mycobacterium tuberculosis

et al. 2015

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Section: Discusionsupporting

confidence: 54%

Effect of cortisol and/or DHEA on THP1-derived macrophages infected with Mycobacterium tuberculosis

et al. 2015

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“…In cultured cells, Atg5 , p62/ SQSTM1, and Ulk1 have similar roles in controlling Mtb survival and replication 1,4,5,22 . We therefore explored the role of these and other genes involved in autophagy in vivo , by infecting mice with germline deletions of Ulk1 , Ulk2 (autophagy induction), Atg4B (isolation membrane elongation), or p62 /SQSTM1 (substrate targeting to autophagosome).…”

Section: Main Textmentioning

confidence: 99%

“…Alveolar MΦ are the first cells infected upon inhalation of Mtb and are required for the establishment of infection 30 . Furthermore, previous in vitro studies suggested that a predominant role for ATG5 during Mtb infection is to control bacterial replication in MΦ 1–4,6–8 . Therefore, we investigated whether ATG5 is required in alveolar MΦ to control Mtb by infecting Atg5 fl/fl -CD11c-Cre mice, which lack ATG5 in alveolar MΦ and DC 20 .…”

Section: Main Textmentioning

confidence: 99%

“…How IFN-γ elicits this effect is unknown, but many studies suggest a role for macroautophagy (autophagy herein), a cellular process by which cytoplasmic contents are sequestered into an autophagosome and targeted for lysosomal degradation 1 . The involvement of autophagy has been defined based on studies in cultured MΦ or dendritic cells (DC) where Mtb colocalizes with autophagy (ATG) factors ATG5, ATG12, ATG16L1, p62, NDP52, Beclin1 and LC3 2–6 , stimulation of autophagy increases bacterial killing 6–8 , and inhibition of autophagy allows for increased bacterial survival 1,2,4,6,7 . Notably, these studies reveal modest (e.g.…”

mentioning

confidence: 99%

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Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection

Kimmey

Huynh

Weiss

et al. 2015

Nature

322

339

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Summary Paragraph Mycobacterium tuberculosis (Mtb), a major global health threat, replicates in macrophages (MΦ) in part by inhibiting phagosome-lysosome fusion, until IFN-γ activates the MΦ to traffic Mtb to the lysosome. How IFN-γ elicits this effect is unknown, but many studies suggest a role for macroautophagy (autophagy herein), a cellular process by which cytoplasmic contents are sequestered into an autophagosome and targeted for lysosomal degradation1. The involvement of autophagy has been defined based on studies in cultured MΦ or dendritic cells (DC) where Mtb colocalizes with autophagy (ATG) factors ATG5, ATG12, ATG16L1, p62, NDP52, Beclin1 and LC32–6, stimulation of autophagy increases bacterial killing6–8, and inhibition of autophagy allows for increased bacterial survival1,2,4,6,7. Notably, these studies reveal modest (e.g. 1.5- to 3-fold change) effects on Mtb replication. In contrast, Atg5fl/fl-LysM-Cre mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorphic mononuclear cells, PMN) succumb to Mtb within 30 days4,9, an extremely severe phenotype similar to mice lacking IFN-γ signaling10,11. Importantly, ATG5 is the only ATG factor that has been studied during Mtb infection in vivo and autophagy-independent functions of ATG5 have been described12–18. For this reason, we used a genetic approach to elucidate the role for multiple ATG genes and the requirement for autophagy in resistance to Mtb infection in vivo. We have discovered that, contrary to expectation, autophagic capacity does not correlate with the outcome of Mtb infection. Instead, ATG5 plays a unique role in protection against Mtb by preventing PMN-mediated immunopathology. Furthermore, while ATG5 is dispensable in alveolar MΦ during Mtb infection, loss of Atg5 in PMN can sensitize mice to Mtb. These findings shift our understanding of the role of ATG5 during Mtb infection, reveal a new outcome of ATG5 activity, and shed light on early events in innate immunity that are required to regulate tuberculosis disease pathology and Mtb replication.

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“…This type of autophagy has been selectively termed as xenophagy. In case of Mycobacterium tuberculosis infection, when autophagy was induced in infected macrophages, there was restoration of phagosome maturation and mycobacterial killing [45]. The LC3 protein, a mammalian orthologue of Atg8 subfamily and an autophagosome membrane protein, can engage in xenophagy against Salmonella in the absence of upstream Atg proteins [46].…”

Section: Autophagy In Hostmentioning

confidence: 99%

Malaria: Autophagy as a Potential Therapeutic Target

Singh¹,

Chakraborty²

2016

JPP

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Malaria, where the causative agent Plasmodium is rapidly gaining resistance to practically all the antimalarial drugs in clinical use, requires the identification of new drug targets to enable the discovery of novel, more effective and safer drugs to treat the disease. Advancements in molecular techniques have provided the proof of existence of autophagy in Plasmodium; however, its role(s) in malaria is only becoming to be understood. Nevertheless, some of the recently explored dimensions of autophagy in Plasmodium have indicated its fairly larger role in parasite survival and growth. But then, autophagy is also essential for host cell survival and defence. There is thus need to explore chemotherapeutic strategies to specifically target autophagy in both the parasite and host. This review focuses on autophagy pathways in Plasmodium and in host with a view to identify autophagy-related new drug targets for the discovery of novel antimalarial drugs.

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Autophagy in Tuberculosis

Cited by 85 publications

References 129 publications

Effect of cortisol and/or DHEA on THP1-derived macrophages infected with Mycobacterium tuberculosis

Effect of cortisol and/or DHEA on THP1-derived macrophages infected with Mycobacterium tuberculosis

Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection

Malaria: Autophagy as a Potential Therapeutic Target

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