Project Grant R21AI180914

DISSECTING A SENSORY SYSTEM FOR LEGIONELLA REPLICATION VACUOLE INTEGRITY - PROJECT SUMMARY INFECTIOUS DISEASE IS A MAJOR THREAT TO HUMAN HEALTH WORLDWIDE. THE EMERGENCE OF ANTIBIOTIC RESISTANCE PATHOGENS NECESSITATES THE DEVELOPMENT OF NEW DRUGS TO TREAT INFECTIONS. A FUNDAMENTAL CHALLENGE IN DEVELOPING ANTIBIOTICS IS THAT MANY PATHOGENS REPLICATE INSIDE HOST CELLS RENDERING THEM INACCESSIBLE TO ANTIMICROBIAL AGENTS. THE CRITICAL PROCESSES THAT GOVERN PATHOGEN GROWTH WITHIN HOST CELLS REPRESENT PROMISING NEW TARGETS FOR THERAPEUTIC INTERVENTION. PATHOGENS ENCOUNTER A BROAD ASSORTMENT OF CHALLENGES WITHIN THE HOST. THE ABILITY TO PERCEIVE AND ADAPT TO THESE CHALLENGES IS A CRITICAL DETERMINANT OF VIRULENCE. THESE ADAPTATIONS ARE MEDIATED BY SENSORY SYSTEMS THAT DETECT HOST-IMPOSED INSULT OR ALTERATIONS IN THEIR LOCAL ENVIRONMENT AND DRIVE AN APPROPRIATE RESPONSE. MANY BACTERIAL PATHOGENS THAT GROW INSIDE HOST CELLS DO SO IN SPECIALIZED COMPARTMENTS CALLED REPLICATION VACUOLES. MAINTAINING THE INTEGRITY OF THE REPLICATION VACUOLE IS PARAMOUNT TO BACTERIAL SURVIVAL AND GROWTH AS IT PROVIDES PROTECTION AGAINST HOST SURVEILLANCE SYSTEMS THAT DETECT AND ELIMINATE PATHOGENS. DISRUPTING THIS PROCESS WOULD THUS LIMIT BACTERIAL BURDEN AND ENABLE PATHOGEN KILLING BY THE HOST. DESPITE VACUOLE INTEGRITY BEING PARAMOUNT FOR PATHOGENESIS, THE MECHANISMS RESPONSIBLE AND HOW BACTERIA SENSE AND RESPOND TO DEFECTS IN THIS PROCESS ARE POORLY UNDERSTOOD. WE HAVE IDENTIFIED A CELL-SURFACE SIGNALING SYSTEM EMPLOYED BY THE BACTERIAL PATHOGEN LEGIONELLA THAT PLAYS A CENTRAL ROLE IN PROMOTING VACUOLE INTEGRITY. LEGIONELLA IS THE CAUSATIVE AGENT OF A LIFE-THREATENING PNEUMONIA CALLED LEGIONNAIRE'S DISEASE AND A WORLD-WIDE HEALTH PROBLEM. THE GOAL OF THIS RESEARCH IS TO CHARACTERIZE HOW SIGNALS ARE PROPAGATED AND THE RESPONSE PATHWAY THAT COMPENSATES ENSURES VACUOLE STABILITY. THIS WORK WILL DEFINE AN UNPRECEDENTED MOLECULAR SURVEILLANCE SYSTEM EMPLOYED BY A VACUOLAR PATHOGEN TO SUSTAIN ITS REPLICATION COMPARTMENT AND THUS, A NEW PARADIGM IN MICROBIAL PATHOGENESIS. AS VACUOLE INTEGRITY PLAYS IS A CENTRAL ROLE IN DEFINING THE VIRULENCE OF NUMEROUS INTRACELLULAR PATHOGENS, THIS WORK WILL HAVE BROAD IMPLICATIONS ACROSS THE FIELD OF MICROBIAL PATHOGENESIS. THIS WORK WILL PROVIDE UNPRECEDENTED INSIGHT INTO A CRITICAL EVENT THAT DETERMINES THE OUTCOME OF AN INFECTION AND A MEANS TO DEVELOP NEW STRATEGIES TO TREAT DISEASE.