Project Grant F32AI189066

INVESTIGATING THE ROLE OF INTRAHEPATIC PLASMA CELLS IN THE CLEARANCE OF HCV INFECTION: IMPLICATIONS FOR RATIONAL VACCINE DESIGN - PROJECT SUMMARY THE PROPOSED WORK ENTITLED "INVESTIGATING THE ROLE OF INTRAHEPATIC PLASMA CELLS IN THE CLEARANCE OF HCV INFECTION: IMPLICATIONS FOR RATIONAL VACCINE DESIGN" SEEKS TO DETERMINE THE MECHANISTIC ORIGINS OF LIVER-RESIDENT PLASMA CELLS ARISING DURING ACUTE HEPACIVIRAL INFECTION. UNDERSTANDING THESE CUES WOULD IDENTIFY SPECIFIC PREREQUISITES OF INTEREST TO INCORPORATE IN VACCINE REGIMENS AGAINST HEPATITIS C VIRUS (HCV). GIVEN THE ~2 MILLION NEW INFECTIONS OCCURRING ANNUALLY WORLDWIDE, A PROPHYLACTIC HCV VACCINE WOULD THUS PROVIDE SIGNIFICANT PUBLIC HEALTH BENEFIT. WE HAVE RECENTLY DEMONSTRATED THAT AN EARLY GENERATION OF VIRAL-SPECIFIC B CELLS AND ANTIBODIES IS CRITICAL FOR FACILITATING HEPACIVIRAL CLEARANCE IN BOTH HUMANS AND MICE INFECTED WITH HEPATITIS C VIRUS (HCV) AND AN HCV- RELATED RODENT HEPACIVIRUS (RHV), RESPECTIVELY. GIVEN THE ESSENTIAL NATURE OF PRODUCTIVE HUMORAL RESPONSES IN THIS SETTING, IT IS CRITICAL TO UNDERSTAND THE MECHANISTIC PREREQUISITES ENABLING INDIVIDUALS TO MOUNT SUCH A RESPONSE CAPABLE OF DERAILING PERSISTENT INFECTION AS OPPOSED TO SUCCUMBING TO CHRONICITY IN THE ABSENCE OF TIMELY ANTIBODY PRODUCTION. SEEKING TO DETERMINE THE SOURCE OF THIS IMMUNOGLOBULIN PRODUCTION, WE IDENTIFIED A MARKED ANATOMICAL SKEWING OF IGG+ ANTIBODY-SECRETING CELLS (ASCS) WITHIN THE LIVER DURING ACUTE RHV INFECTION, WHILE BEING VIRTUALLY ABSENT IN PERIPHERAL BLOOD, BONE MARROW, SPLEEN, AND LYMPH NODES. DISTINGUISHING WHETHER THIS PHENOMENON REPRESENTED A CONSERVED IMMUNOLOGICAL RESPONSE TO HEPACIVIRAL INFECTION, WE INDEED OBSERVED A ROBUST EXPANSION OF ANTIGEN-SPECIFIC ASCS WITHIN THE LIVER AS OPPOSED TO OTHER TISSUE COMPARTMENTS IN HUMAN HCV INFECTION AS WELL. SERVING TO FURTHER VALIDATE THE UTILITY AND BIOLOGICAL RELEVANCE OF THE RHV INFECTION MODEL FOR INTERROGATING IMMUNOLOGICAL FACETS OF HCV INFECTION, THESE PRELIMINARY FINDINGS NATURALLY ELICIT INVESTIGATION INTO HOW AND WHERE THESE PLASMA CELLS ORIGINATE. OUR IDENTIFICATION OF INTRAHEPATIC GERMINAL CENTER B CELLS AND IGG+ TERTIARY LYMPHOID STRUCTURES (TLSS) ALONGSIDE THE ABSENCE OF APPRECIABLE ASC FORMATION IN SLOS DURING ACUTE RHV INFECTION SUGGESTS THAT THE LIVER MAY BE CAPABLE OF ACTING AS A SURROGATE SECONDARY LYMPHOID ORGAN DURING HEPATOTROPIC INFECTION. FURTHER, AS WE HAVE PREVIOUSLY SHOWN THAT THE WINDOW OF ACUTE INFECTION WHERE B CELLS ARE ESSENTIAL FOR VIRAL RESOLUTION IS WITHIN THE FIRST TWO WEEKS OF INFECTION, THE COINCIDING KINETIC BURST OF PLASMA CELLS ARISING WITHIN THE LIVER AROUND THIS TIME FRAME SUGGESTS THAT THIS INTRAHEPATIC HUMORAL RESPONSE IS INTEGRAL FOR FACILITATING ULTIMATE VIRAL ELIMINATION. GIVEN THE CRITICAL NATURE OF THIS RESPONSE, THE PROPOSED STUDIES AIM TO CHARACTERIZE THE MECHANISTIC UNDERPINNINGS OF HOW AND WHERE PLASMA CELL RESPONSES ARE GENERATED DURING HEPATOTROPIC INFECTION. EITHER OUTCOME, DETERMINING WHETHER THEY FOLLOW TRADITIONAL SLO PRIMING AND INFLAMMATORY HOMING PATTERNS OR ARE PRIMED LOCALLY WITHIN THE LIVER PARENCHYMA, SHOULD PROVIDE VALUABLE INSIGHTS THAT ARE HIGHLY RELEVANT TO BASIC IMMUNOLOGICAL PARADIGMS. FURTHERMORE, THE PROPOSED WORK SHOULD INFORM STRATEGIES TO ENABLE FUNCTIONAL RECAPITULATION OF THESE PRODUCTIVE, ESSENTIAL RESPONSES IN THE RATIONAL DESIGN OF AN EFFICACIOUS VACCINE AGAINST HCV.