# Obesity dysregulates immune and metabolic status in asthma and alters infection susceptibility.

> **NIH NIH K08** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $186,948

## Abstract

Project abstract
Asthma and obesity are two of the most common chronic diseases of childhood and are increasing in
prevalence in the US and worldwide. Obesity and asthma are linked: as body mass index increases, the risk of
asthma also increases. Asthma is not a single disease, but a group of overlapping phenotypes caused by
multiple distinct molecular mechanisms, many of which remain undefined. Obese asthmatics have a severe
phenotype of asthma that is poorly responsive to standard medication regimens and often characterized by
more severe exacerbations, most of which are due to viral infections. However, the underlying
immunometabolic mechanism leading to immune dysfunction in obese asthma remains unclear. To address
this and establish testable hypotheses, I conducted a pilot study of pediatric asthmatics (A), obese asthmatics
(OA), obese (O) and healthy control (HC) patients using multiple high dimensional assays, including mass
cytometry, metabolomics and serum cytokine measurements. This study showed that obese asthmatics have
two forms of immune dysregulation that may impair anti-viral responses: increased type 2 immunity and CD8 T
cell exhaustion. In addition, OA patients have alterations in serum metabolites, including increased levels of
glutamate, which may underlie some of these alterations in T cell state.
Here, I intend to tackle the fundamental and tractable question of the nature of immune dysregulation in obese
asthma by testing hypotheses derived from my human data using relevant mouse models of disease. First, I will
test whether elevated levels of serum glutamate, a serum metabolite increased in OA patients, directly increases
type 2 immunity (Aim 1). Second, I will confirm the presence of increased CD8 T cell exhaustion in a mouse
model of OA and assess the impact of T cell exhaustion on influenza infection by measuring the impact of
abrogating a core exhaustion pathway, the PD-1 pathway (Aim 2). Both aims will utilize novel techniques,
including mass cytometry and immunometabolic studies. I will receive training in bioinformatics and biostatistical
approaches to systems immunology, including machine learning, that will allow me to gain insight into these
comprehensive, multifaceted datasets to establish the core pathways and targets that should be pursued as
therapeutic targets in these complex patients.
My proposal outlines a 5-year training program for my development as a physician-scientist in Pediatric Allergy
Immunology. In particular, I will focus on gaining additional expertise in cutting-edge mass cytometry and
systems immunology data analysis techniques, as well as mouse models of asthma and obesity. This will allow
me to integrate complex human and mouse datasets, generating and testing mechanistic hypotheses with direct
clinical applicability. I believe my training plan, within the remarkable environments in Dr. Wherry’s lab, CHOP
and UPenn, will position me to become an independently funded physician scientist.

## Key facts

- **NIH application ID:** 9838149
- **Project number:** 5K08AI135091-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Sarah E Henrickson
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,948
- **Award type:** 5
- **Project period:** 2018-12-14 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838149

## Citation

> US National Institutes of Health, RePORTER application 9838149, Obesity dysregulates immune and metabolic status in asthma and alters infection susceptibility. (5K08AI135091-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838149. Licensed CC0.

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