Project Grant R21AI180695

UNCOVERING THE EVOLUTIONARY HISTORY OF BACTERIAL ENDOSYMBIOSIS IN OPPORTUNISTIC FUNGAL PATHOGENS OF HUMANS - PROJECT SUMMARY THE GOAL OF THIS EXPLORATORY WORK IS TO ELUCIDATE THE EVOLUTIONARY HISTORY OF SYMBIOTIC ASSOCIATIONS BETWEEN THE MUCOROMYCOTINA FUNGI AND THEIR ENDOSYMBIOTIC BACTERIA (EB), FOCUSING ON POPULATION-LEVEL PROCESSES, INCLUDING FUNGAL ADAPTATION TO HUMAN HOSTS AND CONTRIBUTIONS OF SHARED 6-METHYLADENINE (6MA) DNA EPIGENETIC MODIFICATIONS AS MEANS OF COMMUNICATION BETWEEN THE PARTNERS. WE EXPECT THAT THIS WORK WILL ESTABLISH FOUNDATIONS FOR FUTURE TREATMENT OF MUCORMYCOSES, WHICH ARE HUMAN INFECTIONS CAUSED BY MUCOROMYCOTINA. MUCORMYCOSES ARE INCREASINGLY FREQUENT, HIGHLY DESTRUCTIVE, AND OFTEN FATAL IN IMMUNE-COMPROMISED INDIVIDUALS. WHILE BACTERIA-FREE ASYMBIOTIC MUCOROMYCOTINA ARE RESPONSIBLE FOR MANY INFECTIONS, EB ARE OFTEN DETECTED IN CLINICAL ISOLATES AND KNOWN TO AFFECT MUCOROMYCOTINA VIRULENCE IN HUMANS. THEREFORE, ELUCIDATING POPULATION-LEVEL PROCESSES THAT GOVERN THESE MUCOROMYCOTINA-EB SYMBIOSES IS IMPORTANT FOR DEVELOPING NOVEL MUCOROMYCOSIS THERAPIES. ONE OF THE MECHANISMS CONTRIBUTING TO THE ESTABLISHMENT AND MAINTENANCE OF SUCH SYMBIOSES MAY BE SHARING OF 6MA DNA MODIFICATIONS BY MUCOROMYCOTINA AND BACTERIA. IMPORTANTLY, THESE MODIFICATIONS AND THE CONTRIBUTING ENZYMES ARE NEARLY ABSENT FROM MAMMALS AND POTENTIALLY COULD BE TARGETED BY PHARMACOLOGICAL INHIBITORS FOR MUCORMYCOSIS THERAPY. TO TEST THE HYPOTHESIS THAT EB MANIPULATE THEIR FUNGAL HOSTS THROUGH EPIGENOMIC REPROGRAMMING, WE PROPOSE FUNCTIONAL CHARACTERIZATION OF CANDIDATE BACTERIAL SYMBIOSIS FACTORS, INCLUDING ADENINE-SPECIFIC DNA METHYLTRANSFERASES. TO GAIN INSIGHTS INTO POPULATION-LEVEL PROCESSES SHAPING FUNGAL-BACTERIAL SYMBIOSES, WE PLAN TO CONDUCT A POPULATION GENOMIC STUDY OF A MODEL FUNGAL-BACTERIAL SYMBIOSIS COMPLEMENTED BY A POPULATION-LEVEL ANALYSIS OF GENOME-WIDE 6MA MODIFICATION AND TRANSCRIPTIONAL LANDSCAPES IN FUNGI DIFFERING IN THE SYMBIOTIC STATUS AND SOURCE OF ISOLATION (NATURAL VERSUS CLINICAL SETTINGS). EXPECTED OUTCOMES OF THE PROJECT INCLUDE INSIGHTS INTO POPULATION-LEVEL PROCESSES, INCLUDING FUNGAL ADAPTATION TO MAMMALIAN HOSTS AND THE ROLE OF EPIGENETIC REPROGRAMMING IN THE INITIATION AND FUNCTIONING OF FUNGAL- BACTERIAL SYMBIOSES IMPORTANT FOR HUMAN HEALTH AS WELL AS 6MA METHYLOME DATA FOR A LEADING CAUSAL AGENT OF MUCORMYCOSIS. THE FINDINGS ARE EXPECTED TO BE INSTRUMENTAL IN DEVELOPING FUTURE MUCORMYCOSIS THERAPIES RELYING ON 6MA DNA MODIFICATION INHIBITORS.