The monogenic basis of human tuberculosis

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• Tuberculosis (TB) pathogenesis is not fully understood, with only 5-10% of Mycobacterium tuberculosis-infected individuals developing disease.
• Human genetics plays a crucial role in TB susceptibility, as evidenced by classic genetic studies and research into Mendelian susceptibility to mycobacterial disease (MSMD).

Purpose of the Study:

• To investigate the genetic underpinnings of TB pathogenesis.
• To identify specific genetic factors contributing to the development of clinical TB disease.

Main Methods:

• Studied rare inborn errors of immunity, including autosomal recessive complete IL-12Rβ1 and TYK2 deficiencies.
• Investigated common genetic variants, specifically TYK2 (P1104A), in TB patient cohorts.

Main Results:

• Identified rare genetic deficiencies (IL-12Rβ1, TYK2) impairing IFN-γ induction in some TB patients.
• Discovered that homozygosity for the TYK2 (P1104A) variant, disrupting IL-23 responses, accounts for approximately 1% of TB cases in European populations.
• Both rare and common genetic factors affecting IFN-γ immunity contribute to TB development.

Conclusions:

• Genetic factors, both rare and common, significantly impact TB susceptibility by affecting IFN-γ immunity.
• Understanding these genetic etiologies offers potential for novel preventive and therapeutic strategies for TB control, including the use of recombinant IFN-γ.