Project Grant F32AI191456

DEFINING MECHANISTIC DRIVERS OF IMPAIRED B CELL RESPONSE TO INFLUENZA A VIRUS VACCINE UNDER CONDITIONS OF OBESITY - PROJECT SUMMARY INFLUENZA A VIRUS (IAV) CAUSES MILLIONS OF INFECTIONS ANNUALLY IN THE UNITED STATES AND WORLDWIDE. ALTHOUGH MANY INFECTIONS RESULT IN MILD RESPIRATORY SYMPTOMS, SOME INDIVIDUALS ARE SUSCEPTIBLE TO SEVERE DISEASE. INDIVIDUALS WITH OBESITY (BMI > 30) INFECTED WITH IAV ARE AT INCREASED RISK FOR RESPIRATORY PATHOLOGY AND DEATH. DATA FROM THE CDC INDICATES APPROXIMATELY 40% OF US ADULTS AND 20% OF CHILDREN ARE OBESE. GIVEN THE HIGH PREVALENCE OF OBESITY AND HIGH CIRCULATION OF IAV, PROTECTING THIS GROUP REPRESENTS A CRITICAL PUBLIC HEALTH ISSUE. VACCINES THAT INDUCE LONG-LIVED PLASMA CELLS AND MEMORY B CELLS CAN DETER SEVERE OUTCOMES ASSOCIATED WITH RESPIRATORY INFECTION. PRIOR RESEARCH FROM OUR LAB AND OTHERS IN IAV VACCINE COHORTS HAS DISPLAYED OBESITY IS CORRELATED WITH IMPAIRED ABILITY TO SUSTAIN LONGITUDINAL B CELL RESPONSES. DESPITE THE OBSERVED IMPAIRMENT OF LONGEVITY OF THESE RESPONSES IN CONDITIONS OF OBESITY, LITTLE IS KNOWN REGARDING THE UNDERLYING MECHANISMS POST-VACCINATION IN THE B CELL LINEAGE THAT DRIVE THE DEFICIENCIES. MOST LONG-LIVED PLASMA CELLS AND MEMORY B CELLS FORMED POST-VACCINATION EMERGE FROM TIGHTLY ORGANIZED GERMINAL CENTER (GC) REACTIONS WHERE ACTIVATED B CELLS BATTLE FOR SURVIVAL AND DIFFERENTIATION SIGNALS FROM CD4+ T FOLLICULAR HELPER CELLS. AIM 1 PROPOSES TO UNCOVER DEFECTS IN THE CELLULAR AND GENETIC MACHINERY OF GC REACTIONS OCCURRING UNDER CONDITIONS OF OBESITY. THIS WILL BE ACHIEVED BY PHENOTYPICALLY PROFILING THE MAGNITUDE AND PERSISTENCE OF VACCINE-INDUCED GC B CELL AND CD4+ T FOLLICULAR HELPER CELL POPULATIONS. PHYSICAL ORGANIZATION OF THE GERMINAL CENTER INTO COMPARTMENTALIZED B AND T CELL REGIONS WILL BE ASSESSED BY MICROSCOPY. TRANSCRIPTOME PROFILES OF GC B CELLS AND CD4+ T FOLLICULAR HELPER CELLS WILL BE ESTABLISHED TO DETERMINE DISRUPTION IN PATHWAYS THAT PROMOTE ESSENTIAL GC PROCESSES AND SUPPORT DIFFERENTIATION INTO PLASMA CELLS AND MEMORY B CELLS. FOLLOWING GC REACTIONS, THE MAINTENANCE OF B CELL-MEDIATED IMMUNITY IS EXECUTED BY TWO DISTINCT CELL TYPES OF THE B CELL LINEAGE, LONG-LIVED PLASMA CELLS AND MEMORY B CELLS. AIM 2 PROPOSES TO DEFINE THE FUNCTIONAL SHORTCOMINGS OF THESE CELLS IN CONDITIONS OF OBESITY AND ESTABLISH ALTERNATIVE VACCINATION STRATEGIES. THE IMPACT OF OBESE CONDITIONS ON THE LONGEVITY OF VACCINE-INDUCED PLASMA CELLS WILL BE QUANTIFIED. THE ABILITY OF MEMORY B CELLS FORMED IN OBESE CONDITIONS TO PROPERLY REACTIVATE WILL BE TESTED EX VIVO, AND THE PROTECTIVE CAPACITY OF THESE CELLS AGAINST HETEROLOGOUS IAV STRAINS WILL BE ASSESSED BY IN VIVO CHALLENGE. THE UTILITY OF BOOSTER SHOTS, HIGH DOSE ANTIGEN, OR MOLECULAR ADJUVANTS WILL BE USED TO ASSESS RESTORATION OF PROPER PLASMA CELL AND MEMORY B CELL LONGEVITY IN OBESE CONDITIONS. IN SUMMARY, THIS PROPOSAL WILL DEFINE THE MECHANISTIC IMPACT OF OBESITY ON PRODUCTIVE B CELL RESPONSES TO IAV VACCINATION AND REVEAL STRATEGIES THAT CAN BOOST PROTECTION IN A VULNERABLE GROUP OF THE HUMAN POPULATION.