Immunopathogenic Overlap and Shared Therapeutic Targets for Covid-19 and Tuberculosis Predicted from Transcriptomic Meta-Analysis

Current and previous tuberculosis (TB) increase the risk for severe and fatal COVID-19. To identify mechanisms of immunopathogenic interaction which may increase severity of COVID-19 and determine the impact of co-infection on subsequent TB progression, we performed a systematic review and patient-level meta-analysis of COVID-19 transcriptomic signatures, spanning mild-critical disease, from whole blood, PBMCs and BALF. Thirty-five eligible signatures were profiled on 1181 RNA-seq samples from 853 individuals, across the spectrum of TB infection. Twenty COVID-19 gene-signatures had significantly higher “COVID-19 risk scores” in active and progressive TB compared with non-progressing latent infection and uninfected controls (p<0·005); thirteen validated in two independent TB-progressor cohorts. An integrative analysis between TB and COVID-19 scRNA-seq data identified FCN1- and SPP1-expressing macrophages enriched in BALF during severe COVID-19 in blood during active TB. Transcriptomic comparisons for shared gene ontologies and protein-protein interaction networks identified 12-gene disease exacerbation hot-spots between COVID-19 and TB which offer opportunity for therapeutic amelioration targeted at synergistic immunopathogenesis. Funding Information: D.S. is supported by the Walter and Eliza Hall Institute of Medical Research (WEHI). A. is supported by AXA research Fund (25776); National Research Foundation, South Africa (NRF; UID8829) and the Medical Research Council of South Africa (SAMRC; SHIP-02-013). X.W. is supported by the National Institutes of Health (NIH; R21AI154387). W.E.J. is funded by CRDF Global (DAA3-19-65672-1) and the NIH (U19AI111276, U01CA220413, R01GM127430, R21AI154387). A.C. is supported by WEHI, SAMRC (SHIP-02-2013), NIH (U19AI111276) and NRF (UID109040). Declaration of Interests: The authors declare no competing interests.