When the host is not healthy: Rethinking tuberculosis drug targets in comorbid conditions

Area of Science:

• Immunology
• Infectious Diseases
• Pharmacology

Background:

• Tuberculosis (TB) often co-occurs with chronic conditions (diabetes, HIV, etc.).
• Comorbidities significantly alter host environments, impacting Mycobacterium tuberculosis (Mtb) containment and treatment responses.
• Current TB drug discovery models often overlook this crucial host heterogeneity.

Purpose of the Study:

• To reframe TB as a spectrum of comorbidity-modulated disease mechanisms.
• To synthesize evidence on how comorbidities affect TB pathogenesis and treatment.
• To identify opportunities for host-directed therapies by repurposing existing drugs.

Main Methods:

• Review of mechanistic evidence linking comorbidities to TB.
• Analysis of how comorbidities rewire macrophage function, immune signaling, metabolism, autophagy, granuloma structure, and drug pharmacokinetics/pharmacodynamics.
• Exploration of novel experimental and computational strategies (organoids, systems biology) to model host complexity.

Main Results:

• Comorbidities profoundly alter host pathways essential for Mtb control.
• Drug distribution, accessibility, and efficacy are significantly impacted by comorbidities.
• Repurposing drugs for comorbid conditions offers potential cross-cutting host-directed TB interventions.

Conclusions:

• Embracing host heterogeneity is vital for developing resilient and effective TB therapeutics.
• Future TB research must embed host complexity into target discovery and validation.
• Therapeutic strategies need to be tailored for diverse, comorbidity-burdened TB patient populations.