# Exploring an Incipient Tuberculosis Spectrum Through Highly-Sensitive MTB DNA Detection

> **NIH NIH K22** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $108,000

## Abstract

PROJECT SUMMARY
Tuberculosis (TB, Mtb) remains the leading infectious disease killer globally, despite the
availability of curative treatment for most individuals. Currently, individual care and TB
control efforts are dichotomized around “latent TB infection” and “active TB disease”
based on the absence or presence of clinical signs/symptoms and Mtb culture positivity.
However, none of the available methods for identifying latent tuberculosis infection
distinguishes the few individuals who will develop active, transmissible TB from the vast
majority of individuals who never will become ill from TB or transmit to others. The ability
to identify incipient TB – TB which has progressed beyond bacterial containment
associated with latency but not yet reached the burden of culture-positive, symptomatic
active disease – could have far-reaching impact in thwarting transmission and decreasing
individual morbidity and mortality. The global scale-up of ultra-sensitive Mtb DNA
detection assays, such as the recently WHO-recommended GeneXpert MTB/RIF Ultra
(Ultra), presents a critical opportunity to identify this incipient, pre-cultivatable disease
stage. In a recent diagnostic accuracy study, we found that Ultra diagnosed more patients
with TB, but also detected Mtb DNA in sputum among 5% of symptomatic, culture-
negative persons. We hypothesize that sputum Mtb DNA-positive/culture-negative
individuals are more likely to have incipient TB than Mtb DNA-negative/culture-negative
(TB-negative) individuals. To test this hypothesis, we propose a substudy to an R01-
funded Ultra diagnostic accuracy study of adults in Africa with signs/symptoms of TB to
evaluate the biology and natural history Ultra Mtb DNA-positive/culture-negative
individuals.
In the first two Aims, we will evaluate and compare biomarker correlates of TB disease
risk between MTB DNA positive/culture negative and TB-negative individuals. In Aim 1,
we will characterize host clinical and demographic factors associated with sputum Mtb
DNA-positive/culture-negative status and characterize these individuals on the spectrum
of Mtb infection using a pre-validated blood transcriptional signature predictive of
progression to active TB. In Aim 2, we will evaluate and compare microbiologic indicators
of TB disease between Mtb DNA positive/culture negative and TB-negative individuals.
Specifically, we propose to investigate the presence of Mtb mRNA from sputum as a
sentinel for transcriptionally-active Mtb populations among the symptomatic, untreated
study population, and evaluate for revivable Mtb populations through culture
supplementation of growth promoting factors from conditioned media. In addition to
evaluation of biomarkers at study entry, we will evaluate the natural history of Mtb DNA-
positive/culture-negative individuals with respect to TB-negative controls using
longitudinal clinical, microbiologic, and host transcriptional data collected over a 12-month
follow-up period in the parent study.
Toget...

## Key facts

- **NIH application ID:** 10007751
- **Project number:** 5K22AI137320-02
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Yingda Linda Xie
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $108,000
- **Award type:** 5
- **Project period:** 2019-09-04 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007751

## Citation

> US National Institutes of Health, RePORTER application 10007751, Exploring an Incipient Tuberculosis Spectrum Through Highly-Sensitive MTB DNA Detection (5K22AI137320-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10007751. Licensed CC0.

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