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

Russell C Ault,Bridget J Carruthers,Asuncion Mejias,Alexander E Hare,Colwyn A Headley,Joanne Turner

doi:10.1038/s41598-020-73942-z

Russell C Ault, Bridget J Carruthers + Show 4 more

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https://doi.org/10.1038/s41598-020-73942-z

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Abstract

Tuberculosis (TB) is the leading cause of death due to a single infectious disease. Knowing when a person was infected with Mycobacteriumtuberculosis (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.

Highlights

Tuberculosis (TB) is the leading cause of death due to a single infectious disease
With time of exposure to an active TB case pinpointed within a two week period, and sometimes to a single day, Poulsen determined that these clinical features accompany and/or follow TST conversion, which occurs within 6 weeks of e xposure[14,39,40]
For TB disease risk prediction, we hypothesized that such a test could complement the recently developed RNA signatures of TB disease risk that are based on detecting incipient TB, which is the asymptomatic phase of early TB disease during which pathology progresses gradually before full-blown clinical TB21,22,44,45

Summary

Introduction

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. Genotyping M.tb isolates from active TB cases coupled with comparative genomic analysis has permitted population-level identification of hotspots of localized transmission, but these data are mostly available retrospectively and do not allow real-time monitoring of TB transmission in a community, in areas of high incidence[12] It remains unknown whether with current methods TB transmission can be appreciably disrupted in high incidence settings. While the positive predictive value of these RNA signatures of risk of active TB is higher than TST/IGRAs, they are still significantly less than ideal: to prevent one case of active TB, ~ 37-64 LTBI + people not at risk need to be treated (vs ~ 85 for TST/IGRA)[21,22,23,24] It is currently unknown whether these RNA signatures correlate with time since infection. Their positive predictive value for TB progression and the number needed to treat could be dramatically improved if combined with accurate knowledge of time since infection in the same individual

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