Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

Abstract

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.

Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

“…Heterogeneity among cases appears to be predominant in large scale genetic studies in TB and the existence of TB endotypes has been proposed ( 216 ). Recent advances in molecular and analytical techniques have allowed the identification of at least two TB endotypes through unbiased clustering of transcriptional changes in distinct molecular pathways ( 217 ). One endophenotype presented immune exhaustion resulting in poor prognosis compared to the second endophenotype.…”

Perspective for Precision Medicine for Tuberculosis

“…Therefore, implementation of host-directed therapies (HDT) should preferably not be indiscriminate, but needs to be guided by the tuberculosis immune endotype. Preliminary work supports the identification of divergent host endotypes with contradictory metabolic, epigenetic, and immune gene expression endotypes ( 7 ), but these transcriptional studies lack corresponding functional studies.…”

“…In the future, tuberculosis patient care may be individualized in at least 4 areas ( Figure 1 ): (I) next generation sequencing of microbial M. tuberculosis DNA can predict drug susceptibility in the first week of diagnosis ( 6 ); (II) host immunity can be detrimentally suppressed and need augmenting or it can be detrimentally exuberant and need to be suppressed ( 7 – 9 ); or other forms of host genetic variability that may be specifically addressed by immune-based interventions ( 10 ), (III) individualized drug concentrations that can guide antimicrobial dosing ( 11 ), and (IV) biomarkers that predict relapse-free cure and can guide duration of required therapeutics ( 12 ) ( Figure 1 ). Such stratified therapies are within reach and could soon become available for the clinical management of tuberculosis.…”

Host-directed therapies for tuberculosis: quantitative systems pharmacology approaches

“…For example, known differences in PK and immune-response components for HIV coinfected TB patients may be incorporated in the framework, enabling extrapolation of results from studies in TB patients to HIV-TB patients [61]. In addition, considering immune-response relevant endotypes is important [62,63]. Technological advances within the last century enabled generation of large-scale omics data.…”