# Ontogeny and metabolism of lung alveolar macrophages in tuberculosis

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2024 · $769,925

## Abstract

Project Summary/Abstract
Our current vaccine development strategies against tuberculosis (TB) focus on the induction of adaptive immune
responses, but that may not be sufficient to mount effective immunity. Mycobacterium tuberculosis (Mtb) resides
in heterogenous lung macrophages with various levels of permissiveness in the presence of the same immune
pressure. Among them, lung alveolar macrophages (AMs) are highly permissive cells, which facilitate rapid
growth of Mtb and promote disease dissemination at the early stage of infection. However, the underlying
mechanism that determines this permissive nature of AMs during Mtb infection remains elusive. Identifying
determinants regulating the response of AMs to Mtb is thus essential for the development of new therapeutics
and novel vaccine platforms. While AMs are derived from embryonic precursors in naïve mice, they can be
replaced by bone marrow-derived monocytes during infection. It is unknown whether the origin of AMs change
and how the altered ontogeny impacts the permissiveness and functions of AMs during Mtb infection. In addition
to ontogeny, our previous work has demonstrated that lung macrophage metabolism plays a critical role in
promoting or controlling the progression of TB. AMs consume fatty acids and engage in fatty acid oxidation
(FAO), a pathway that has been associated with the optimal growth of Mtb. Given that both ontogeny and
metabolism play pivotal roles in modulating how macrophages respond to Mtb infection, we hypothesize that
ontogeny and metabolism are intrinsic features that regulate the permissiveness of AMs during Mtb infection.
We further propose that harnessing these two features will allow the reprogramming of AMs for better control of
Mtb at the early stage of infection. We will test this hypothesis with three aims: Aim 1. Determine how ontogeny
contributes to the response of AMs during Mtb infection. Aim 2. Delineate how glycolysis and FAO differentially
regulate the permissiveness of AMs during Mtb infection. Aim 3. Reprogramming AMs by leveraging their
ontogeny and metabolism against Mtb infection. To address these aims, we will exploit multi-disciplinary
approaches, including immunology, metabolism, genomics, microbiology, novel mouse models and human
primary AMs to directly probe how ontogeny and major metabolic pathways regulate the permissiveness of AMs
during Mtb infection. Knowledge gained from these studies is expected to provide a better understanding of the
mechanism regulating AM response to Mtb, which opens the gate for reprogramming AMs for enhanced control
of Mtb at the early stage of infection as well as aiding in development of host-directed therapies against TB.

## Key facts

- **NIH application ID:** 10942945
- **Project number:** 1R01AI184960-01
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Lu Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $769,925
- **Award type:** 1
- **Project period:** 2024-08-13 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942945

## Citation

> US National Institutes of Health, RePORTER application 10942945, Ontogeny and metabolism of lung alveolar macrophages in tuberculosis (1R01AI184960-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10942945. Licensed CC0.

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