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Obesity dysregulates immunometabolic status in pediatric asthma and impacts vaccine responses
Sarah E. Henrickson1,2, Peyton Conrey2, Sasikanth Manne1,3, , Samir Sayed2, Kaitlin C. O’Boyle3 Bertram Bengsch1,† , Ting Qian4, Ramin S. Herati1,5†††, Laura A. Vella1,6, Allison R. Greenplate1,3, Sam J. McCright1,7, Cécile Alanio1,3, 12, Frank Mentch11, Kenneth E. Schmader8, Christopher F. Pastore9, Li-Yin Hun9, Scott E. Hensley1,10, De’Broski Herbert9, Aaron J. Masino4, Jorge Henao-Mejia1,7, Hakon Hakonarson11, Joshua D. Rabinowitz12, Susan E. Coffin6 and E. John Wherry1,3,12
1Institute for Immunology, University of Pennsylvania, Philadelphia, PA.
2Division of Allergy-Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA.
3Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA.
4Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA.
5Department of Medicine, University of Pennsylvania Perelman School of Medicine
6Division of Infectious Disease, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA.
7Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA.
8Division of Geriatrics, Department of Medicine, Duke University Medical Center and Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, NC.
9School of Veterinary Medicine, Department of Pathobiology, University of Pennsylvania, Philadelphia. PA
10Department of Microbiology, University of Pennsylvania, Philadelphia, PA.
11Center for Applied Genomics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA.
12Parker Institute for Cancer Immunotherapy at University of Pennsylvania
13Department of Chemistry, Princeton University, Princeton, NJ.
†1Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, Freiburg, Germany, and Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
††Department of Medicine, New York University, Grossman School of Medicine, New York City, NY.
Asthma and obesity are two of the most common chronic childhood diseases worldwide, with dramatically increasing prevalence over the last few decades. These diseases impact morbidity and mortality and strain health care systems financially. Asthma risk increases as body mass index (BMI) increases, suggesting a pathophysiological link. Both asthma and obesity are independently linked to altered immune status, however, it remains unclear how these diseases converge to affect pediatric immune function. To address this question, we investigated the immunometabolic profile in obese asthmatic (OA), non-obese asthmatic (A), obese non-asthmatic (O), and healthy control (HC) children using mass cytometry, serum metabolomics, cytokine analysis and clinical history. This multi-modal approach revealed two major forms of immune dysfunction in pediatric allergic OA: altered baseline T cell activation state (exhaustion-like) and increased type 2 immunity. OA had increased Th2 differentiation and decreased Th17 differentiation and these changes were associated with altered blood metabolites, including increased glutamate and decreased acetate. A mouse model of OA confirmed increased exhausted-like CD8 T cells compared to A and HC mice. Finally, immunometabolic dysregulation and altered T cell activation status in O and OA patients was linked to prolonged retention of humoral vaccine responses. These insights into the mechanistic links between metabolic alterations and immune dysfunction in OA may improve understanding of the severe asthma exacerbations secondary to viral upper respiratory tract infections seen in OA and provide opportunities for novel therapeutic approaches.