Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

Area of Science:

• Immunology
• Genomics
• Infectious Diseases

Background:

• Tuberculosis (TB) is increasingly recognized as a disease with diverse host responses, not a single entity.
• Distinct molecular pathways and pathologies, termed endotypes, characterize individual TB patient responses.
• Understanding these endotypes is crucial for developing effective, personalized treatments.

Purpose of the Study:

• To identify and characterize distinct tuberculosis endotypes using unbiased gene expression profiling.
• To correlate identified endotypes with clinical outcomes and functional immune responses.
• To explore the potential for endotype-specific host-directed therapies.

Main Methods:

• Unbiased clustering of microarray gene expression data from a large cohort of TB patients and controls.
• Validation of identified endotypes using independent RNA-sequencing cohorts with longitudinal clinical data.
• Assessment of functional immune responses in relation to identified endotypes.

Main Results:

• Two distinct TB endotypes (A and B) were identified based on gene expression patterns.
• Endotype A exhibits increased inflammation and immunity gene expression, while Endotype B shows increased metabolism and proliferation.
• Endotype A was associated with treatment failure, slower culture conversion, and reduced cure rates, indicating poorer prognosis.
• Endotype A patients displayed less responsive cytokine production upon stimulation, suggesting a hyperinflammatory state.

Conclusions:

• The study provides robust evidence for distinct tuberculosis endotypes with differing clinical trajectories.
• Gene expression profiling and immune response assessment can classify TB endotypes.
• Findings support the development of endotype-specific host-directed therapies for improved tuberculosis treatment outcomes.