# Type I IFN-dependent and independent contributions to the outcomes of early innate immune cell interactions during HIV/TB co-infection

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $899,894

## Abstract

PROJECT SUMMARY/ABSTRACT
Granuloma formation is a feature of tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb)
infection. Alveolar macrophages (alvMF) are central to this process as the first cells infected by Mtb and likely
as drivers of early granuloma development. The initial events when alvMFs encounter Mtb and the cell-cell
interactions occurring in mature granulomas are extensively investigated but less is known about what happens
between the initial infection event and later stages of disease. These early events have implications for the
trajectory of TB and some individuals restrict Mtb at this stage and never develop disease despite multiple
exposures whereas other individuals cannot restrict Mtb replication and progress to granuloma formation. Our
lack of knowledge of the molecular and cellular circuits underlying early granuloma formation and what
differentiates outcomes at this stage is a fundamental gap that limits the development of therapeutic interventions
for TB. This gap is especially acute for people infected with human immunodeficiency virus (HIV), which
significantly increases risks of poor outcomes from TB, and addressing it will have significant public health value.
Critical unanswered questions in the acute response to Mtb infection include (1) how do interactions between
immune cells immediately after alvMF infection contribute to granuloma formation, (2) which components of
these interactions can be perturbed to bias disease dynamics to improve control over Mtb replication, and (3)
what interactions are altered by HIV infection that increase susceptibility to active TB? We discovered that
infected MF secrete interferons (IFNs), cytokines, and chemokines within minutes to hours after infection that
drive the inflammatory responses that support granuloma formation. Moreover, we have shown that type I IFN
expression and neutrophil recruitment support Mtb replication and we are investigating how these responses
contribute to infection outcomes. Recently, we showed that type I IFN drives release of neutrophil extracellular
traps that promote Mtb replication instead of restricting it and are associated with the development of necrotic
granulomas. Based on these data, we hypothesize that early interactions between macrophages and neutrophils
are regulated by a self-propagating cycle of type I IFN and damage-associated molecular pattern (DAMP)
signaling that culminates in granuloma formation. Moreover, our work showing that I IFN-conditioned immune
cells are less able to control Mtb infection leads us to hypothesize that HIV-induced type I IFN signaling amplifies
this type I IFN–DAMP circuit and promotes an environment that supports Mtb replication, tissue damage, and
TB susceptibility. We predict that breaking the type I IFN–DAMP cycle therapeutically will push early responses
toward protective functions. To test our hypothesis, we propose to 1) Define type 1 IFN and DAMP signaling
effects in innate immune...

## Key facts

- **NIH application ID:** 10948788
- **Project number:** 1R01AI184666-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Bryan David Bryson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $899,894
- **Award type:** 1
- **Project period:** 2024-07-03 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948788

## Citation

> US National Institutes of Health, RePORTER application 10948788, Type I IFN-dependent and independent contributions to the outcomes of early innate immune cell interactions during HIV/TB co-infection (1R01AI184666-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10948788. Licensed CC0.

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