Host gene-encoded severe lung TB: from genes to the potential pathways

Area of Science:

• Immunogenetics
• Molecular Biology
• Infectious Diseases

Background:

• Tuberculosis (TB) is a major global health challenge.
• Host genetic factors influence TB disease severity and treatment response.
• Hyperinflammation contributes to severe TB pathology and extensive tissue damage.

Purpose of the Study:

• To identify genetic markers associated with severe pulmonary tuberculosis (TB) and delayed treatment response.
• To elucidate the molecular pathways driving hyperinflammation in TB.
• To provide a basis for developing host-targeted interventions for TB.

Main Methods:

• Genotyping of two-locus genotypes: -2518 MCP-1 and -1607 MMP-1.
• Analysis of human lung tissues, serum/plasma samples.
• In vitro experiments including THP-1 cell infections with Mycobacterium tuberculosis.
• Microarray analysis to study gene expression.

Main Results:

• The two-locus genotype -2518 MCP-1 GG and -1607 MMP-1 2G/2G is strongly associated with hyperinflammation, severe TB disease, and extensive tissue damage.
• Carriers of this genotype exhibit significantly higher risks for severe disease (13-fold), permanent lesions (6.5-fold), and delayed treatment response (3.864-fold).
• The MCP-1/MMP-1/PAR-1 pathway is identified as a potential driver of the hyperinflammation state.

Conclusions:

• The identified two-locus genotype serves as a potential marker for predicting severe TB and delayed treatment outcomes.
• Understanding the MCP-1/MMP-1/PAR-1 pathway offers a target for novel host-directed therapies to mitigate TB severity.
• This research enhances the identification of at-risk TB patients and supports personalized treatment strategies.