Genetics and evolution of tuberculosis pathogenesis: New perspectives and approaches

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• Tuberculosis (TB) remains a leading global infectious killer, yet most Mycobacterium tuberculosis (MTB) exposures do not result in active disease.
• A significant portion of exposed individuals harbor latent infections, highlighting host factors in disease progression.
• Existing genetic studies often lack clarity on which specific transition (exposure to infection vs. infection to active disease) is being investigated.

Purpose of the Study:

• To propose a framework for understanding transitions from MTB exposure to TB disease.
• To review genetic studies investigating host susceptibility to TB infection and active disease.
• To explore the role of host-pathogen co-evolution in TB severity.

Main Methods:

• Review of existing genetic studies on tuberculosis.
• Framework development for analyzing transitions in TB pathogenesis.
• Discussion of MTB lineage and human genetics interactions.

Main Results:

• Strong evidence supports a human genetic component for both TB infection and active disease.
• Specific genetic pathways associated with active TB include altered T and B cell signaling and T helper cell differentiation.
• Genetic factors influencing the transition from exposure to latent infection are less defined.
• TB severity offers a potential avenue for studying MTB-human co-evolution.

Conclusions:

• Human genetics plays a critical role in determining TB outcomes after MTB exposure.
• Further research is needed to clarify genetic influences on the initial infection phase.
• Investigating MTB-human co-evolution, particularly through TB severity, is crucial for a comprehensive understanding of TB's genetic basis.