Project Grant R01AI169534

IMPACT OF SARS-COV-2 INFECTION ON REACTIVATION OF LATENT MTB INFECTIONS IN A KENYAN COHORT - SUMMARY CORONAVIRUS DISEASE OF 2019 (COVID-19) AND PULMONARY TUBERCULOSIS (PTB) HAVE BEEN REPORTED AS THE LEADING CAUSES OF MORTALITY FROM AN INFECTIOUS DISEASE PERSPECTIVE IN 2020. TB DISEASE IS CAUSED BY INFECTION WITH MYCOBACTERIUM TUBERCULOSIS (MTB), AND KENYA REMAINS ONE OF THE COUNTRIES WITH THE HIGHEST BURDEN OF TB INCIDENCE GLOBALLY. HOWEVER, THE MAJORITY OF INDIVIDUALS INFECTED WITH MTB NEVER DEVELOP ACTIVE TB, AND ARE CLASSIFIED AS LATENT INFECTIONS. VIRAL INFECTIONS CAN INCREASE THE RISK OF REACTIVATION OF TB DISEASE, HOWEVER, LITTLE INFORMATION IS KNOWN ABOUT THE IMPACT OF SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS-2 (SARS- COV-2) ON THE REACTIVATION OF LATENT MTB INFECTION. EXPOSURE TO SARS-COV-2 CAN INCREASE RISK OF PROGRESSION FROM LATENT TO ACTIVE TB THROUGH SEVERAL MECHANISMS. FIRST, SARS-COV-2 INFECTION CAN INCREASE EXPRESSION OF GENES THAT MEDIATE SYSTEMIC INFLAMMATION, WHICH ARE KNOWN TO BE ASSOCIATED WITH HEIGHTENED RISK OF PROGRESSION TO TB DISEASE. SECOND, SARS-COV-2 INFECTION CAN DRIVE DIFFERENTIATION AND EXHAUSTION OF T CELLS THAT TARGET MTB ANTIGENS AND CONFER PROTECTION AGAINST PROGRESSION TO DISEASE. IMPORTANTLY, DESPITE THE ROLLOUT OF COVID-19 VACCINES IN LOW- AND MIDDLE-INCOME COUNTRIES, THE RATE OF VACCINATION REMAINS SLOW, AND EMERGING SARS-COV-2 VARIANTS IN THE REGION ARE LIKELY TO CONTINUE TO COMPROMISE VACCINE EFFICACY IN THESE REGIONS. THIRD, CO-INFECTION WITH COVID-19 AND ACTIVE TB IS OF CONCERN, HYPER INFLAMMATORY RESPONSES MAY INDUCE COVID-19 INFECTION WHICH HAS THE POTENTIAL OF ACCELERATING TB DISEASE. THEREFORE, THE CO-EVOLUTION OF THE TB AND COVID-19 PANDEMICS WILL CONTINUE TO BE A PRESSING PUBLIC HEALTH CONCERN IN THE REGION. IN THIS STUDY, WE WILL RECRUIT A COHORT OF LATENTLY MTB INFECTED INDIVIDUALS FROM 3 MAJOR HEALTH FACILITIES IN TWO COUNTIES IN KENYA (NAIROBI AND KIAMBU), WITH AND WITHOUT HISTORY OF EXPOSURE TO SARS-COV-2 INFECTIONS. WE WILL STUDY THE IMPACT OF SARS-COV-2 INFECTIONS ON REACTIVATION OF LATENT TB TO TB DISEASE AND IMMUNITY TO MTB ANTIGENS USING A COMBINATION OF BIOMARKERS AND IMMUNOLOGICAL APPROACHES. THE QUANTIFERON-TB-GOLD IN TUBE INTERFERON-GAMMA RELEASE ASSAY AND A VALIDATED SEROLOGICAL LATERAL FLOW ASSAY SPECIFIC FOR IMMUNOGLOBULIN- G (IGG) ANTIBODIES WILL BE USED FOR SCREENING LATENTLY INFECTED TB AND SARS-COV-2 EXPOSED PARTICIPANTS, RESPECTIVELY. WE WILL USE FLOW CYTOMETRY APPROACH FOR IDENTIFICATION OF T CELL POPULATIONS IMPACTED BY CO- INFECTION. THE PRACTICAL IMPLICATION OF THIS WORK WILL INCLUDE IDENTIFICATION OF PATHO-IMMUNOLOGICAL MECHANISMS AT PLAY FOR TB LATENT DISEASE REACTIVATION IN SARS-COV-2 EXPOSED INDIVIDUAL'S POTENTIALLY UNVEILING SCREENING AND THERAPEUTIC TARGETS. THE WORK WILL ALSO BUILD A STRONG FOUNDATION IN RESEARCH NETWORK, INFRASTRUCTURE, SKILLS AND DATA FOR FOLLOW UP WORK ON COVID-19 AND TB STUDIES IN KENYA.