Clonotyping Airway T-cells to Uncover Microbiome-Specific Inflammotypes in HIV-associated COPD

About This Grant

Abstract 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, including Dr. William Checkley (USA- based Primary Mentor, Professor of Medicine in the Pulmonary and Critical Care Division at the Johns Hopkins School of Medicine and Dr. Moses Lutaakome Joloba (LMIC-based Primary Mentor, Professor of Molecular Biology, Makerere University). The team will include key collaborators: Dr. Sofia Forslund (Charite University, Professor of Applied Microbiology) and Dr. Miriam Moffatt (Imperial College London, Professor of Respiratory Genetics). Through close mentorship and practical experience, Dr Kayongo proposes to accomplish advanced training in multi-omics analysis. COPD is increasing in prevalence among people living with HIV (PLWH) primarily due to the widespread use of antiretroviral therapy (ART), which has increased longevity in this population. Sub-Saharan Africa, with the highest density of PLWH, has experienced dramatic increases in COPD-related morbidity and mortality. 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 diverse 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. 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 transitioning from stable COPD disease to exacerbation. This effort will guide therapeutics targeting microbiome-specific “inflammotypes” in COPD.