Host-Directed Therapeutics in Tuberculosis Management

Host-directed therapeutics (HDTs) represent an innovative strategy in tuberculosis (TB) management that focuses on modulating the patient’s immune response rather than targeting the pathogen directly. By enhancing protective mechanisms such as autophagy, phagosome maturation and regulated inflammatory signalling, HDTs aim to improve bacterial clearance, reduce tissue damage and shorten treatment duration. This approach offers particular promise in the face of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains, as well as in patients with comorbidities that compromise immune competence. HDTs may be administered as small molecules, biologics or repurposed drugs and can act synergistically with conventional antibiotics. Beyond accelerating bacterial eradication, they have the potential to restore immune homeostasis, limit pathological inflammation in the lung and prevent long-term sequelae. The global significance of HDTs lies in their capacity to complement existing regimens, address treatment adherence challenges and contribute to integrated TB control programmes.

Research from Nature Portfolio

Recent studies have demonstrated that modulation of host immunometabolic circuits can substantially improve anti-tubercular responses. One investigation revealed that metformin treatment expanded a subset of memory-like CD8+ T cells with enhanced mitochondrial function and fatty acid oxidation. These metformin-educated T cells exhibited superior survival capacity and bactericidal activity against M. tuberculosis, and when combined with vaccination, augmented protection in animal models.

Another work employed a combined chemical genetics and bioinformatics approach to identify host receptor tyrosine kinase (RTK) inhibitors as potent adjunctive agents. By targeting RTK signalling pathways, these compounds restricted intracellular growth of drug-resistant M. tuberculosis in macrophages and were validated by complementary siRNA screening. This discovery highlights RTK inhibition as a druggable host pathway for enhancing the efficacy of existing anti-TB therapies.

Host-Directed Therapeutics in Tuberculosis Management publication trend

The graph below shows the total number of articles in host-directed therapeutics in tuberculosis management across all publications each year (not limited to Nature Index journals).

Technical terms

Host-directed therapy (HDT): An approach that enhances or modulates the host’s immune mechanisms to combat infection rather than directly attacking the pathogen.

Autophagy: A cellular degradation pathway in which intracellular components, including pathogens, are sequestered in autophagosomes and delivered to lysosomes for destruction.

Immunometabolism: The study of how metabolic processes within immune cells influence their function, activation and survival.

Receptor tyrosine kinase (RTK): A class of cell-surface receptors that, when activated, initiate signalling cascades regulating growth, differentiation and immune responses.

Phagocytosis: The process by which immune cells engulf and internalise pathogens or debris into membrane-bound vesicles for degradation.

References

1. Therapeutic host-directed strategies to improve outcome in tuberculosis. Mucosal Immunology (2019).
2. Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits. Nature Communications (2020).
3. Combined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials. Nature Communications (2018).
4. Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis. BMC Medicine (2016).
5. Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs. PLOS Pathogens (2011).
6. A Beneficial Effect of Low-Dose Aspirin in a Murine Model of Active Tuberculosis. Frontiers in Immunology (2018).