Discerning divergent tuberculosis endotypes: A meta-analysis and systematic review of individual patient data

Rationale: Host response is a critical factor determining susceptibility to tuberculosis (TB). A delicate balance should be maintained between intracellular immunity against Mycobacterium tuberculosis (Mtb) and minimizing detrimental immunopathology. Studies have identified incongruous immune responses that can lead to a similar TB disease phenotype. Instead of envisioning that susceptibility to TB follows a singular path, we propose the hypothesis that varied host endotypes exist within the TB clinical phenotype. Methods and Results: Unbiased clustering analysis from 12 publicly available gene expression datasets consisting of data from 717 TB patients and 527 controls, identified 4 TB patient endotypes with distinct immune responses. The two largest endotypes exhibit divergent metabolic, epigenetic and immune pathways. TB patient endotype A, comprising 333 TB patients (46.4%), is characterized by increased expression of genes important for i) glycolysis, ii) IL-2-STAT5, IL-6-STAT3, Type I and II Interferon IFN-γ and TNF signaling and iii) epigenetic-modifying genes. In contrast, TB patient endotype B, comprising 313 TB patients (43.6%), is characterized by i) upregulated NFAT and hormone metabolism, and ii) decreased glycolysis, IFN-γ and TNF signaling. In silico evaluation suggests therapies beneficial for endotype A could be detrimental to endotype B, and vice versa. Multiplex ELISA completed from an external validation cohort confirmed a TB patient sub-group with decreased immune upregulation. Conclusions: Host immunity to TB is heterogenous. Unbiased clustering analysis identified distinct TB endotypes with divergent metabolic, epigenetic and immune gene expression profiles that may enable stratified or personalized treatment management in the future.