# Elucidation of the molecular mechanism(s) for the non-responsiveness of CD38- AMs to tuberculosis infection

> **NIH NIH R21** · CORNELL UNIVERSITY · 2024 · $49,305

## Abstract

The lung-resident alveolar macrophages (AMs) are the initial host cells infected by inhaled
Mycobacterium tuberculosis (Mtb). While traditionally perceived as a conducive environment for Mtb replication
and spread, our recent studies using fluorescent Mtb fitness reporter strains and single-cell RNA-sequencing
(scRNA-seq) have revealed a more intricate reality.
 We discovered two primary AM populations in the Mtb-infected lung: SiglecF+ CD38+ pro-inflammatory
AMs, which house stressed bacteria and express high levels of Nos2, and SiglecF+ CD38- AMs, which lack Nos2
expression and accommodate replicative bacteria.
 Intriguingly, our preliminary findings indicate that CD38- AMs, which exhibit limited Mtb containment
capabilities, are the predominant infected AM population during the early infection stages. Moreover, intranasal
BCG vaccination prior to Mtb exposure significantly reduces the number of Mtb-infected host cells and markedly
increases the proportion of CD38+ infected AMs. This suggests a critical role for the CD38+ AM phenotype in
triggering a protective immune response following vaccination.
 Although these AM subsets appear transcriptionally indistinguishable in naive mice, they demonstrate
distinct chromatin organization, suggesting that epigenetic factors dictate their response to infection.
Our hypothesis is that a higher prevalence of CD38+ AMs within the lung airways leads to improved early
inhibition of Mtb proliferation and spread, thereby unveiling a viable avenue for immune mediate control
of tuberculosis infection.
Specific Aim 1: Elucidate the host molecular mechanisms contributing to the limited response of CD38-
AMs to Mtb infection.
To decipher the host molecular mechanisms underlying the blunted response of CD38- AMs to Mtb infection, we
will employ an integrated multi-omics approach to analyze the changes in chromatin organization and
transcription factor activity post-Mtb infection. We will then manipulate the AM immune environment through
intranasal BCG vaccination to identify those epigenetic changes that are associated with long-term protection
against Mtb infection.
Specific Aim 2: Implement CRISPR-based genetic perturbation approaches in macrophages to evaluate
the role of selected host responses in Mtb infection.
Initially, we will use a CRISPR-based genetic perturbation approach to validate the role of candidate host genes,
identified in our existing datasets, in generating pro-inflammatory macrophage responses that control Mtb
infection. We will then extend this approach to functionally validate additional targets emerging from Specific
Aim 1.

## Key facts

- **NIH application ID:** 10888660
- **Project number:** 1R21AI178534-01A1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Davide Pisu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,305
- **Award type:** 1
- **Project period:** 2024-06-01 → 2024-10-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888660

## Citation

> US National Institutes of Health, RePORTER application 10888660, Elucidation of the molecular mechanism(s) for the non-responsiveness of CD38- AMs to tuberculosis infection (1R21AI178534-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10888660. Licensed CC0.

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