# Elucidating the path to type I IFNs in TB infection

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $82,895

## Abstract

Tuberculosis (TB) is the leading cause of death from infection globally. Our knowledge of the cellular and
molecular events that link inhalation of the causative bacterium, Mycobacterium tuberculosis (Mtb), with either
clearance or productive infection remains limited. The type I interferon (IFN) response is among the first innate
immune responses triggered in Mtb-infected macrophages. Growing evidence suggests that type I IFNs, and
specifically cross-talk between the type I IFN response and the IL-1 axis, drive pathogenesis in TB. However,
our understanding of the cascade of events that initiate the type I IFN response in Mtb-infected host cells is
incomplete. The literature increasingly supports a model in which mitochondrial damage is a key driver of type I
IFN production in Mtb-infected macrophages. In preliminary work, we have uncovered a set of previously
unappreciated additional cellular pathways that contribute to Mtb-induced type I IFNs, including the ER stress
response (ESR), lipid droplet (LD) formation, and eicosanoid production. In the proposed work, we will build
upon our preliminary results to define molecular relationships between ER stress, LD formation, eicosanoid
production, and mitochondrial damage in type I IFN response to Mtb. We will then use a murine model of
infection to test the impact of modulating the ESR on infection outcomes. In Aim 1, we will use CRISPR
technology to build genetic tools to study the pathways of interest. Using these tools and small molecule
inhibitors, we will then test links between arms of the ESR, LD formation, eicosanoid production, and type I
IFNs. To more completely characterize the role of the ESR and individual response pathways in the
macrophage response to Mtb, we will additionally perform multiplexed cytokine analysis, transcriptional
profiling, and metabolomics using our genetic and small molecule tools that perturb the ESR. In Aim 2, we will
test which of the identified contributors to type I IFNs drive mitochondrial damage. In Aim 3, we will use small
molecule inhibitors in two murine models of TB infection to determine how modulating the ESR in the context
of TB infection changes bacterial burden, immune cell recruitment to the lung compartment, histopathology,
cytokine responses, and the transcriptional response. Upon achieving our aims, we anticipate having
developed a new, more complex model for induction of type I IFNs in Mtb-infected macrophages. Further, we
anticipate having determined how the ESR shapes the macrophage response to Mtb infection and contributes
to infection outcomes in vivo. We anticipate these results will ultimately inform the development of novel host
directed therapies for TB.

## Key facts

- **NIH application ID:** 11046071
- **Project number:** 3R01AI150762-04S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Amy K Barczak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $82,895
- **Award type:** 3
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11046071

## Citation

> US National Institutes of Health, RePORTER application 11046071, Elucidating the path to type I IFNs in TB infection (3R01AI150762-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11046071. Licensed CC0.

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