# Functions of TBK1 in neutrophils during bacterial pneumonia

> **NIH NIH R03** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $77,750

## Abstract

Project Summary
Bacterial pneumonia causes significant morbidity and mortality worldwide despite the availability of antibiotics.
The immune system must balance the competing requirements of clearing the pathogen while avoiding local
organ damage. There remains an unmet need for host-directed therapeutics that limit injury or promote
resolution without impairing pathogen control. Neutrophils constitute the initial response to bacterial pneumonia
and control infection through direct killing of bacteria and production of mediators including chemokines,
cytokines, proteases and reactive oxygen species (ROS). This R03 application aims to define novel functions
for the innate immune kinase TANK-binding kinase 1 (TBK1) in neutrophils during pneumonia. TBK1 promotes
the expression of type 1 interferons (IFN) by phosphorylating transcription factors from the interferon regulatory
family (IRF) during viral infection, but its functions in bacterial pneumonia and in neutrophils remain undefined.
My K08 Award investigates how TBK1 functions in monocytes and macrophages during influenza infection.
Data from that project and from our previous publication show that during S. pneumoniae pneumonia, lung
neutrophils upregulate genes coding for TBK1 and its accessory proteins, but fail to express the common
downstream product, type 1 IFN, suggesting that neutrophils use the TBK1 signaling module in a unique way.
We find that in S. pneumoniae pneumonia, TBK1 is required for multiple aspects of neutrophil function,
including elaboration of multiple cytokines, production of reactive oxygen species (ROS), and bacterial
clearance. We hypothesize that neutrophil TBK1 regulates both IRF-dependent and IRF-independent
transcriptional programs as well as other cellular programs such as metabolism. The proposed aims
focus on identifying cellular and molecular details of TBK1 signaling in neutrophils in response to infection by
S. pneumoniae. In Aim 1, we will determine the transcriptional programs driven by TBK1 in lung neutrophils,
characterizing in particular 1) the activation of transcription factors by assessing the expression of their target
genes and 2) the expression of genes that regulate metabolic processes. In Aim 2, we will determine how
TBK1 promotes neutrophil ROS production, with a focus on NADPH oxidase assembly and neutrophil
metabolism. We will assess glucose uptake, autophagy, and mitochondrial function in lung neutrophils from
WT and TBK1 KO mice in the setting of pneumonia. The proposed studies will explore new functions for the
kinase TBK1 with the ultimate goal of improving patient outcomes in this common form of lung injury. These
studies diverge from my K08 Award through their focus on neutrophils and bacterial pneumonia and their need
for technologies unfamiliar to me. They will increase the breadth and depth of my research program to engage
both myeloid cell lineages and both viral and bacterial pathogens.

## Key facts

- **NIH application ID:** 10102454
- **Project number:** 1R03HL155249-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Robert Stewart Hagan
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $77,750
- **Award type:** 1
- **Project period:** 2020-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102454

## Citation

> US National Institutes of Health, RePORTER application 10102454, Functions of TBK1 in neutrophils during bacterial pneumonia (1R03HL155249-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102454. Licensed CC0.

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