Host-Directed Therapies and Autophagy in Mycobacterial Infections

Tuberculosis remains a leading cause of infectious mortality worldwide, driven by the ability of Mycobacterium tuberculosis to survive within host macrophages. Autophagy, a conserved cellular degradation pathway, has been recognised as a critical defence mechanism that captures intracellular pathogens and delivers them to lysosomes for destruction. Host-directed therapies aim to enhance or restore autophagic flux, overcome bacterial evasion strategies and reduce treatment duration or the emergence of drug resistance. Recent advances have elucidated how M. tuberculosis subverts autophagosome maturation, manipulates ubiquitin-mediated signalling and exploits host death pathways. By targeting key regulators—such as E3 ubiquitin ligases, SNARE proteins and metabolic checkpoints—novel adjunctive strategies seek to boost host immunity, attenuate inflammation and improve clinical outcomes across diverse patient populations.

Research from Nature Portfolio

Studies have revealed that neurotransmitter signalling can modulate antibacterial autophagy. Activation of GABAergic receptors in macrophages triggers intracellular calcium release and recruitment of autophagy-related proteins, enhancing phagosomal maturation and restricting mycobacterial growth in vitro and in vivo. Another discovery identified a mycobacterial surface protein binding directly to host ubiquitin, recruiting the autophagy receptor p62 and delivering bacteria into LC3-positive autophagosomes. Disruption of this interaction compromises pathogen clearance and amplifies inflammation. Together, these findings define novel host–pathogen interfaces and propose targets for small-molecule or biologic interventions that safely amplify xenophagic responses without eliciting excessive tissue damage.

Host-Directed Therapies and Autophagy in Mycobacterial Infections publication trend

The graph below shows the total number of articles in host-directed therapies and autophagy in mycobacterial infections across all publications each year (not limited to Nature Index journals).

Technical terms

Autophagy: A cellular degradation process that delivers cytoplasmic material, including pathogens, to lysosomes for recycling or elimination.

Xenophagy: A selective form of autophagy that targets invading microorganisms for lysosomal degradation.

Ubiquitination: The covalent attachment of ubiquitin molecules to substrate proteins, marking them for degradation or signalling trafficking events.

Autophagosome: A double-membrane vesicle that encloses cellular cargo for delivery to lysosomes during autophagy.

Host-directed therapy (HDT): A treatment approach that modulates host immune or metabolic pathways to enhance pathogen clearance and improve disease outcomes.

References

1. Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection. Interdisciplinary Medicine (2024).
2. The ubiquitin ligase TRIM32 promotes the autophagic response to Mycobacterium tuberculosis infection in macrophages. Cell Death & Disease (2023).
3. TRAF6 triggers Mycobacterium-infected host autophagy through Rab7 ubiquitination. Cell Death Discovery (2023).
4. Autophagy: A new strategy for host-directed therapy of tuberculosis. Virulence (2018).
5. GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. Nature Communications (2018).
6. A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy. Nature Communications (2019).