Human upper airway immune memory kinetics and durability against respiratory pathogens

Project Summary Peripheral blood is the primary sample type collected to evaluate a vast range of medical conditions. However, peripheral blood testing may not reflect processes occurring in tissue, like the upper airway. The SARS- CoV-2 (SARS2) pandemic highlighted the importance of being able to sample the upper airway for purposes including evaluation of viral infection and clearance. Although the upper airway represents the primary site of infection for many human pathogens, critical questions remain regarding upper airway immunity and protection. Nasal cavity swab sampling can be used to bridge knowledge gaps regarding upper airway immunity to important respiratory pathogens like SARS2 and to address important immunologic questions where peripheral blood sampling is inherently insufficient. I established novel methods for reproducible, longitudinal sampling of upper airway immune cell populations using swabs and demonstrated that sufficient numbers of viable immune cells could be collected to allow for high resolution downstream analyses, including multiparametric flow cytometry and single cell RNA sequencing. Upper airway resident memory B and T cell populations, including SARS2- specific memory B and T cells were characterized using these methods. There is great interest in developing next generation vaccines, including vaccines that can elicit robust mucosal immune responses. This requires knowledge of the immunologic contexts in which mucosal immunity is generated and the requirements for maintenance of upper airway immune memory. I hypothesize that local antigen exposure is required to develop durable upper airway immune memory, and intramuscular immunization alone may fail to elicit upper airway immunity despite generating circulating immunity. I will test this hypothesis by studying upper airway memory B and T cell frequencies, diversity, kinetics and durability in distinct immunologic contexts including SARS2 breakthrough infection (BTI) and COVID-19 booster vaccination using this award. Other respiratory pathogens of public health importance will also be examined. If funded, this K08 will assist with my transition to becoming a successful independent physician scientist investigator in human immunology and infectious diseases. The La Jolla Institute for Immunology (LJI) is a superb training environment and located on the campus of another excellent academic research and medical institution, the University of California, San Diego (UCSD). I will receive ongoing mentorship from an established investigator with a track record for producing successful mentees, Professor Shane Crotty, PhD, a world- renowned expert in the field of immunology. LJI and UCSD are closely affiliated, and Dr. Crotty has an adjunct appointment at UCSD. I will have access to resources at both LJI and UCSD for this career development award. As an Associate Physician in UCSD's Division of Infectious Diseases I will receive additional mentorship in academic career development, and maintain my clinical acumen by providing part-time medical care and consultation services for medically complex patients.