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.
Pediatric obese asthma is a severe disease that responds poorly to standard asthma medications and has higher rates of more severe viral asthma flares. Here, I have used a combination of advanced experimental methods and cutting-edge data analysis tools to uncover possible causes of immune system dysfunction in obese asthma that may play important roles in their poor anti-viral responses. Based on my data from patients, I will use mouse models of obese asthma to test whether changes in serum metabolites or immune exhaustion are important causes of the immune dysfunction observed in pediatric obese asthma.
