Project Grant R01AI177991

SIGNAL TRANSDUCTION, METABOLIC SHIFTS, AND HOST INTERACTIONS DURING GROUP B STREPTOCOCCUS INFECTION - PROJECT SUMMARY GROUP B STREPTOCOCCUS (GBS) IS A PATHOBIONT THAT CAUSES DANGEROUS INFECTIONS DURING PREGNANCY AND IN THE NEONATAL PERIOD. THE GOAL OF OUR PROPOSED PROJECT IS TO DETERMINE MOLECULAR MECHANISMS THAT CAUSE FETAL INJURY, PRETERM LABOR, AND STILLBIRTH DURING GBS INTRAAMNIOTIC INFECTION. THE SCIENTIFIC PREMISE OF OUR WORK STEMS FROM THE FACT THAT GBS IS A COMMON AND ASYMPTOMATIC COMMENSAL MEMBER OF THE INTESTINAL MICROBIOTA IN UP TO 30% OF HEALTHY ADULTS, YET WHEN GBS TRANSITS TO THE INTRAAMNIOTIC SPACE IT DEMONSTRATES HOST CELL INVASIVENESS, CYTOTOXICITY, AND PRO-INFLAMMATORY CHARACTERISTICS THAT CAN BE CATASTROPHIC TO PREGNANCY VIABILITY. WE HYPOTHESIZE THAT SIGNIFICANT DROPS IN MICRONUTRIENT AVAILABILITY THAT OCCUR WHEN GBS MOVES FROM ITS COLONIZING NICHE IN THE INTESTINE AND VAGINA INTO THE NUTRITIONALLY AUSTERE ENVIRONMENT OF AMNIOTIC FLUID ACTIVATE CELLULAR STRESS RESPONSES THAT PROMOTE EXPRESSION OF VIRULENCE FACTORS AND DRIVE ADVERSE PREGNANCY OUTCOMES. THIS NUTRITIONAL VIRULENCE HYPOTHESIS IS SUPPORTED BY MULTIPLE STUDIES PUBLISHED BY OUR GROUP, WHICH POINT TO SMALL MOLECULE BYPRODUCTS OF NUCLEOTIDE SYNTHESIS PATHWAYS-UPREGULATED DURING HOST INVASION-AS MOLECULAR MEDIATORS OF THE GBS PHENOTYPIC SHIFT FROM COMMENSAL TO VIRULENT IN AMNIOTIC FLUID. OUR OWN PRELIMINARY DATA ARE FURTHER SUPPORTED BY EVIDENCE FROM OTHER, INDEPENDENT LABORATORIES, WHOSE FINDINGS CONFORM TO A MODEL OF SHIFTING BACTERIAL METABOLISM AS A SIGNALING EVENT THAT PROMOTES GBS VIRULENCE. OUR MULTI-INSTITUTIONAL, MULTI- DISCIPLINARY CONSORTIUM WILL DEPLOY A UNIQUE SET OF EXPERIMENTAL CAPABILITIES TO EXAMINE HOW ENVIRONMENTAL GROWTH CONDITIONS INTERACT WITH GENETICALLY ENCODED STRESS RESPONSES TO PRODUCE DISTINCT METABOLOMIC PROFILES IN GBS. THROUGH THREE SPECIFIC AIMS, WE WILL 1) DETERMINE THE IMPACT OF THE GBS METABOLOME ON EXPRESSION OF KNOWN VIRULENCE FACTOR PATHWAYS; 2) EVALUATE HOW ALTERING THE GBS METABOLOME AFFECTS ITS PROPENSITY TO INVADE AND INFLAME HUMAN FETAL MEMBRANES; 3) USE DIRECT INTRAAMNIOTIC INJECTION IN A MOUSE MODEL OF GESTATIONAL GBS INFECTION TO ASSESS IN VIVO THE IMPACT OF ALTERED GBS METABOLIC STATES AND SIGNALING MOLECULE PRODUCTION ON CLINICALLY RELEVANT PREGNANCY OUTCOMES OF FETAL DEMISE AND PRETERM DELIVERY. THESE STUDIES WILL ESTABLISH A NEW PARADIGM FOR UNDERSTANDING A CONSEQUENTIAL INFECTIOUS CAUSE OF PREGNANCY LOSS WORLDWIDE, GENERATING TRANSLATABLE INSIGHTS INTO MECHANISMS OF INTRAAMNIOTIC INFECTION BY GBS.