# Human Genetics and Clinical Studies

> **NIH NIH P01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $424,240

## Abstract

Abstract
This core will facilitate the validation of mouse data in human cohorts through interactions with each project
and by pursuing the characterization of human BCG responses and susceptibility to TB disease. The primary
goal is to understand how human genetic variation regulates macrophage immune responses to Mtb infection,
in vivo T-cell responses to BCG vaccination, Mtb strain type associations with pulmonary TB, and overall
clinical susceptibility to TB. Over the past 10 years in Seattle, we used genetic studies to discover and
characterize common human Toll-like Receptor (TLR) pathway polymorphisms which regulate macrophage
and dendritic cell cytokine secretion and other host-defense pathways. Similar to gene deletion studies in
mice, these au naturel polymorphisms enable us to examine deficiencies of human innate immunity genes and
assess their role in ex vivo cellular function, in vivo vaccine T-cell responses, and clinical susceptibility to TB
disease. In Core B, we will examine candidate TB susceptibility genes identified in Projects 1 to 3. We will
determine whether candidate mouse TB susceptibility genes contain DNA variants which are functional and
control replication of MTb in infected macrophages. Using a candidate gene case-control study, determine
whether mouse TB susceptibility genes are associated with susceptibility to adult pulmonary TB disease in
Vietnam, BCG-induced T-cell responses in South Africa, and/or pediatric TB disease in South Africa. We
hypothesize that selected DNA variants in candidate TB susceptibility genes are associated with TB disease
and BCG vaccine responses, control gene expression and/or protein function and mediate an effective anti-
microbial macrophage response to Mtb infection. With a multidisciplinary team of epidemiologists, geneticists,
and immunologists with over 10 years of collaborative work together, we propose to couple genetic and cellular
analysis of Mtb-infected human macrophages and human clinical cohorts to discover the mechanisms of how
common human genetic variation regulates BCG-induced immune responses and susceptibility to TB.

## Key facts

- **NIH application ID:** 10219086
- **Project number:** 5P01AI132130-05
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** CHRISTOPHER M SASSETTI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $424,240
- **Award type:** 5
- **Project period:** 2017-08-05 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219086

## Citation

> US National Institutes of Health, RePORTER application 10219086, Human Genetics and Clinical Studies (5P01AI132130-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10219086. Licensed CC0.

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