Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

Abstract

Tuberculosis (TB) is the leading cause of death due to a single infectious disease.Knowing when a person was infected with Mycobacterium tuberculosis (M.tb) is critical as recent infection is the strongest clinical risk factor for progression to TB disease in immunocompetent individuals. However, time since M.tb infection is challenging to determine in routine clinical practice. To define a biomarker for recent TB exposure, we determined whether gene expression patterns in blood RNA correlated with time since M.tb infection or exposure.First, we found RNA signatures that accurately discriminated early and late time periods after experimental infection in mice and cynomolgus macaques. Next, we found a 6-gene blood RNA signature that identified recently exposed individuals in two independent human cohorts, including adult household contacts of TB cases and adolescents who recently acquired M.tb infection. Our work supports the need for future longitudinal studies of recent TB contacts to determine whether biomarkers of recent infection can provide prognostic information of TB disease risk in individuals and help map recent transmission in communities.

Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

“…This would be an extraordinarily large study to conduct, since on a population level only a minority of individuals who acquire M.tb infection progress to disease [44]. Further, limited sample availability prevented us from testing other recently described biomarkers, such as those based on T cell proliferation [32] or gene expression [33].…”

“…Other functional assays that measure M.tbspecific T cell properties such as Th1 cytokine co-expression profiles [27,28], T cell differentiation (CD27, [29,30]) and T cell activation [17][18][19][20][21][22] have been proposed as new potential immunodiagnostic concepts that can distinguish between M.tb infection and disease. In line with this principle, potential biomarkers of recent M.tb infection based on proportions of TNF-only (IFN--IL-2-) TE (CD45RA-CCR7-CD127-) CD4 T cells or T cell proliferation, as well as a blood transcriptomic signature, have been described [31][32][33]. Halliday and colleagues demonstrated that the proportion of PPD-reactive TNF-only TE CD4 T cells was highest in tuberculosis patients and lowest in individuals with remote M.tb infection, and distinguished between recent and remote M.tb infection with a sensitivity and specificity of 89% and 65%, respectively [31].…”

Blood RNA signatures predict recent tuberculosis exposure in mice, macaques and humans

“…We thank L. Schlesinger and L. Barreiro for critical review of the manuscript. This manuscript has been released as a Pre-Print at bioRxiv 73 .…”