Clemente Britto-Leon, MD

Dr. Britto is a Physician Scientist investigating pulmonary innate immunity with a focus on host-pathogen interactions in human airways. The overall goal of his research program is to investigate immune cell subset contributions to clinical variability and therapy response in CF or respiratory infections. Dr. Britto's laboratory established a multi-modality protocol to characterize the immune response profile of research subjects using high-throughput technologies including single-cell RNA sequencing (scRNAseq), mass cytometry (CyTOF), and multiplexed cytokine ELISA, for which he is nationally recognized. He currently focuses on two areas: 1) Mechanistic studies on the role of airway host defense proteins in regulating lung inflammation and injury during infection, and 2) Human translational studies of airway inflammation in CF. In addition to these two main areas of focus, in the past year he has collaborated in multiple mechanistic and clinical studies and scholarly activity related to my COVID-19 clinical work and he is a Co-Investigator on four R01-level studies investigating pathogenesis of CF, asthma, and COPD. Dr. Britto' mechanistic and translational work has been funded through multiple sources, including NIH, Cystic Fibrosis Foundation, and ATS Foundation.

His mechanistic studies focus on Short Palate Lung Nasal epithelium Clone-1 (SPLUNC1), an abundant airway protein with host protective functions that regulates inflammatory responses to bacteria and viruses through Interferon (IFN)-g and -l. He showed that SPLUNC1 modulates lung neutrophilic inflammation, revealing a novel target for future anti-inflammatory therapy development. In parallel human translational work, he showed that SPLUNC1 levels in sputum predict the likelihood of upcoming CF exacerbations, which could inform clinical management to minimize CF morbidity.

Dr. Britto's translational studies focus on single-cell immunophenotyping of cell populations in CF airways . In a recently published manuscript he performed the first single-cell transcriptomic characterization of CF airway immune cells (PMID:32603604). This work was editorialized by leading experts in the field (PMID:32721178) and expanded knowledge of subject-specific immune dysfunction and its contribution to CF clinical course. He is now expanding these studies to investigate sex- and treatment-related differences in CF, the foundation of an R01 proposal to be submitted in June 2024.

CF acute exacerbations (AE) are episodes of rapid clinical deterioration associated with worsening lung function. In work published in the European Respiratory Journal (PMID:33958427), he demonstrated that a combination of sputum inflammation markers including SPLUNC1 and inflammatory cytokines IL-1b and TNFa, robustly predicted upcoming AE. This work has important clinical implications as it could inform changes in clinical management to improve long-term disease control in CF. Our study was editorialized by Colin Bingle, the discoverer of SPLUNC1 (PMID: 34764214). He is now working to define more robust predictive models to anticipate AE and CFTR modulator responses based on integrated biomarker and genomic markers.

Dr. Britto collaborates extensively within and outside of Yale on numerous projects related to airway inflammation, host-pathogen interactions, and cell biology of lung diseases.