# CD8+ tissue-resident immunity to primary and heterotypic Influenza A controlled by commensal microbiota

> **NIH NIH F30** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $39,693

## Abstract

Project Summary/Abstract
Neonates have the highest infection-related mortality of any age group with viral pneumonia
causing the majority of these estimated 1 million deaths per year. A majority of neonates in the
neonatal intensive care unit (NICU) receive empiric antibiotic therapy. This antibiotic exposure
dysregulates the development of immunity, including influenza-specific CD8+ T cells, although
exactly how early-life antibiotic exposure affects the formation and function of tissue-resident
CD8+ T cells is unclear. With their canonical role as adaptive responders to viral infection, CD8+
T cells are key effector immune cells in both immediate and long-term host defense against
serious viral pneumonia. It is essential to better define how exactly early-life antibiotic exposure
disrupts tissue-resident CD8+ T cell formation and function in order to lessen the substantial
pneumonia-related mortality in neonates. Preliminary flow cytometry data in this proposal shows
that early-life antibiotic exposure reduces the formation of influenza-specific CD8+ T cells, which
leads to higher viral burden and morbidity. Preliminary single cell RNA (scRNA-) and single cell
Assay for Transposase-accessible Chromatin sequencing (scATACseq) data shows a similar
reduction in lung CD8+ T cells that is controlled by specific alterations in gene regulatory networks.
This data drives the overall hypothesis of this proposal that early-life antibiotic exposure
leads to a decrease in the formation and functions of tissue-resident CD8+ T cells following
both primary and heterotypic Influenza A infection. This proposal will test this hypothesis by
determining the effect of early-life antibiotic exposure on the formation and function of CD8+ T
cells in the lungs following challenge with Influenza A (Aim 1) and determining regulatory
mechanisms governing how this early-life antibiotic exposure affects the functions of CD8+ T cells
(Aim 2). Collectively, this work will provide novel, mechanistic insights into how early-life antibiotic
exposure is affecting the functions of influenza-specific tissue-resident CD8+ T cells. These Aims
expect to show an antibiotic-mediated reduction in CD8+ T cell cytotoxicity, cytokine production,
and proliferation, as well as changes in specific gene regulatory networks underlying the
functional dysregulation. The candidate driving this proposal is currently an MD/PhD student at
Cincinnati Children’s Hospital in the laboratory of Dr. Hitesh Deshmukh, who will use this proposal
to set a foundation for an independent career as a physician-scientist. The candidate will use this
proposal to support his future in the clinic as a pediatric intensivist, where findings from this
proposal will uncover new strategies leading to better outcomes for the most vulnerable neonates.

## Key facts

- **NIH application ID:** 10532029
- **Project number:** 1F30HL165594-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Joseph Jacob Stevens
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,693
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10532029

## Citation

> US National Institutes of Health, RePORTER application 10532029, CD8+ tissue-resident immunity to primary and heterotypic Influenza A controlled by commensal microbiota (1F30HL165594-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10532029. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*