# Immune Determinants of the Course of Mycobacterium tuberculosis infection and                                                 Disease

> **NIH NIH U19** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $507,661

## Abstract

ABSTRACT - PROJECT 2 Between the initial encounter of Mycobacterium tuberculosis (Mtb) with
alveolar macrophages (AM) and the development of active disease lies a continuum in which asymptomatic
infection may progress to tuberculosis (TB) disease over an extended timeframe. The host response that
must evolve as the infection progresses toward disease has not been defined. Equally unclear is the role of
Mtb-intrinsic factors in modulating the host response and consequently, the kinetics of the progression of
infection to disease. We have characterized a biomarker signature (PREDICT29) that can predict the
risks for progression from infection. Clinical epidemiological study identified 2 classes of Mtb based
on the capacity of the bacilli from index cases to be transmitted to cause infection in household contacts
(HHC): Mtb-HT (high transmission) and Mtb-LT (low transmission). Chest x-ray of Mtb-HT IC displayed
increased frequency of cavitary disease. Analysis of Mtb-HT and Mtb-LT in C3HeB/FeJ mice revealed
remarkable differences among the 2 strains in i) the responses elicited in AM; ii) the immunopathological
patterns, with lung necrotic lesions only apparent in Mtb-HT infected mice; iii) the T cell response during
the chronic phase of infection; and iv) the expression of phthiocerol dimycocerosate (PDIM), an Mtb cell
envelope lipid. These characteristics of Mtb-HT and Mtb-LT may thus link Mtb-intrinsic factors to differential
regulation of the early innate immune response (the Mtb-AM interaction) that leads to the development of
distinct adaptive immunity that in turn, governs the kinetics and frequency with which asymptomatic
infection progresses to disease. PREDICT29 (segregates progressors vs nonprogressors), in
conjunction with the ACS-COR signature (identifies individuals at a later phase of infection),
enables the placement of subjects in our cohorts infected with Mtb-HT and Mtb-LT at the early phase
of infection that are progressors or nonprogressors or late phase of infection. A combination of ex vivo
cellular systems, singe-cell RNA-seq analysis, hi-dimensional mass cytometry, and Nanostring technology
will be employed to characterize the immune response exhibited by these various subgroups. We propose
to test the following hypothesis: i) Mtb-HT and Mtb-LT elicit differential AM response; ii) Disparate T cell and
antibody response in HHC infected with Mtb-HT and Mtb-LT differentially regulate the
immunopathology and progression to disease; iii) memory T cells play a role in regulating infection
progression. Immunological analysis of these subgroups comprising Mtb-HT and Mtb-LT infected
subjects in specific phase of infection, with a focus on the early Mtb-AM interaction, adaptive T cell and
antibody response, will provide a large body of information that will shed light on the mechanisms that
regulate infection and disease outcomes in the context of progressors and nonprogressors and Mtb-
intrinsic factors.

## Key facts

- **NIH application ID:** 10271649
- **Project number:** 1U19AI162598-01
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Padmini Salgame
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,661
- **Award type:** 1
- **Project period:** 2021-09-23 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271649

## Citation

> US National Institutes of Health, RePORTER application 10271649, Immune Determinants of the Course of Mycobacterium tuberculosis infection and                                                 Disease (1U19AI162598-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271649. Licensed CC0.

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