Gene Expression Signatures Identify Biologically and Clinically Distinct Tuberculosis Endotypes

In vitro, animal model and anecdotal clinical evidence suggests that tuberculosis (TB) is not a monomorphic disease, that host response to TB protean with multiple distinct molecular pathways pathologies (endotypes). We used unbiased clustering identify separate endotypes distinctive gene expression patterns different outcomes. A discovery cohort included 443 patients 527 asymptomatic controls identified two exhibiting in proliferation, metabolism, immune pathways. Specifically, TB patient endotype A was characterized by increased of genes related inflammation immunity decreased metabolism proliferation; contrast, B expressed proliferation.  The signatures were validated using an independent RNA-seq validation consisting studies 118 208 controls. second confirmed differential pathway activity between demonstrated had slower time culture conversion, risk death, poor outcomes. These observations suggest reflect functional immunity; this postulate further supported the observation hyperinflammatory showed hyporesponsive cytokine chemokine responses. Collectively, these findings provide metabolic profiling could inform optimize targeted endotype-specific therapies for TB.