Clonotyping Airway T-cells to Uncover Microbiome-Specific Inflammotypes in HIV-associated COPD - This is an application for the K43 Emerging Global Leader Award for Alex Kayongo, MD-PhD. Dr. Kayongo has shown great promise as a young investigator in low- and middle-income countries (LMICs) investigating the airway microbiome-host immune crosstalk in HIV-associated COPD. He proposes to gain advanced training in implementing high-quality multi-omics COPD studies in LMIC settings, which require additional training and mentorship. His career goal is to become an independent investigator and expert in the airway microbiome and mucosal immunology of COPD in HIV. This award will provide Dr. Kayongo with the support and training to accomplish this goal. He has assembled an experienced mentorship team, i.e., Dr. William Checkley (USA-based Primary Mentor, Professor of Medicine, Johns Hopkins University) and Dr. Moses Lutaakome Joloba (LMIC-based Primary Mentor, Professor of Molecular Biology, Makerere University). The team will have key collaborators: Dr. Sofia Forslund (Charite University, Professor of Applied Microbiology) and Dr. Miriam Moffatt (Imperial College London, Professor of Respiratory Genetics). Dr Kayongo proposes to accomplish advanced training in multi-omics analysis. COPD is an increasingly important comorbidity among people living with HIV (PLWH), including in the United States, where aging HIV populations face a rising burden of chronic lung disease despite effective antiretroviral therapy (ART). Despite viral suppression, it’s not fully known what drives chronic lung inflammation in this population. Lung dysbiosis, reported to persist following ART initiation, could be a potential driver of chronic inflammation. Despite reported links between COPD-specific bacterial taxa and immune dysregulation, there is limited understanding of the breadth of such cellular immune responses. The fundamental question of how airway CD4+T cells integrate microbiome stimuli remains unanswered. This proposal aims to characterise in vitro CD4+T-cell clonotypic library specific to airway microbiome signatures associated with COPD among HIV-infected individuals in a rural Ugandan cohort, a unique setting with a high prevalence of HIV-associated COPD, enabling access to patient populations, environmental exposures, and microbiome diversity not readily available in the United States. These conditions provide a scientifically necessary setting to capture a broader and more representative spectrum of microbiome-immune interactions, including chronic exposures and co-factors that shape airway immunity. Using this library as a reference, we will characterise ex vivo the microbiome-specific clonotypic landscape of broncho-alveolar lavage (BAL)-derived CD4+T cells obtained from a cross-sectional cohort of individuals stratified by HIV and COPD in rural Uganda. From a pool of these BAL-derived microbiome-specific clonotypes, we will uncover unique clonotypes driving inflammation, referred to as “T-cell inflammotypes”. To validate these identified inflammotypes, we will determine clonotypic variations in a sub-cohort of individuals from stable COPD disease to exacerbation. The knowledge generated from this work has direct relevance to American health. HIV-associated COPD is a growing clinical challenge in the United States, particularly among aging populations and underserved communities. By defining antigen-specific T cell responses to airway microbiota, this study will uncover conserved mechanisms of immune-mediated lung inflammation that are translatable across populations. These findings will inform development of targeted immunomodulatory and microbiome-based therapies to prevent or treat COPD in PLWH and the general population in the United States. This work advances NIH’s mission by integrating scientific opportunity with a clear pathway to improving understanding, prevention, and treatment of chronic lung disease in Americans.
