# Macrophage and monocyte TBK1 function in host defense against influenza

> **NIH NIH K08** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $178,217

## Abstract

Project Summary
The objective of this K08 Mentored Clinical Scientist Career Award Application is to facilitate development of
essential skills that will allow the candidate to become an academic physician-scientist. The candidate and his
mentor have designed a training plan that will include a rigorous research component along with didactic
instruction to establish the thought processes and principles necessary for successful career development.
Through coursework and practical experience, the candidate will develop a deeper understanding of the
complex immune mechanisms that underlie influenza pathogenesis and the host immune response to
infection. Through his continued clinical work in the medical intensive care unit, the candidate will have the
opportunity to inform his basic research program as well as guide the translation of that work to clinical studies
and practice. Influenza and other respiratory viruses cause thousands of cases of Acute Respiratory Distress
Syndrome (ARDS) yearly in the United States alone and are a substantial driver of morbidity and mortality
worldwide. Despite the availability of antiviral medications for influenza, there remains an urgent need for host-
directed therapeutics that limit organ damage and can be deployed in a variety of viral illnesses. The initial
response to viral infection centers on the innate immune system including type 1 interferon (IFN) expression
from infected cells and responding cells such as macrophages and monocytes. Multiple viral and inflammatory
inputs converge on signaling kinases such as TANK-binding kinase 1 (TBK1), and these proteins regulate
immunity and inflammation in a highly cell type-specific manner. The function of TBK1 in promoting immunity
apart from type 1 IFN expression remains highly undefined. The candidate's data demonstrate that TBK1
function in macrophages and monocytes promote accumulation of inflammatory macrophages in the lung, and
that deleting myeloid TBK1 lessens host morbidity while preserving viral control. This novel finding of TBK1
function in macrophages points to the TBK1 axis as a possible druggable target in inflammatory lung disease.
This proposal defines the contribution of TBK1 to monocyte- and macrophage-driven inflammation in lung
infections with the goal of identifying actionable mechanisms that can be manipulated for host-directed
therapeutics. The specific aims will utilize in vivo and in vitro techniques to study monocyte and macrophage
function and the molecular aspects of innate immune signaling. In Aim 1, we will determine which monocyte
subtype and macrophage subpopulation require TBK1 to enter the lung in influenza infection and examine the
transcriptomic consequences of TBK1 function. In Aim 2, we will use mouse models to determine the upstream
signals that activate macrophage TBK1 in influenza infection. Finally, in Aim 3 we will use biochemical and
proteomic tools to examine the signaling consequences of virus- and chemokine-driven TBK...

## Key facts

- **NIH application ID:** 10134414
- **Project number:** 5K08HL143271-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Robert Stewart Hagan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $178,217
- **Award type:** 5
- **Project period:** 2019-04-09 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134414

## Citation

> US National Institutes of Health, RePORTER application 10134414, Macrophage and monocyte TBK1 function in host defense against influenza (5K08HL143271-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10134414. Licensed CC0.

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