Project Grant R21AI186346

POLYMICROBIAL INTERACTIONS THAT FACILITATE MUCOSAL COLONIZATION BY GROUP B STREPTOCOCCUS - PROJECT SUMMARY COMMENSAL PATHOGENIC GROUP B STREPTOCOCCUS (GBS) IS A GRAM-POSITIVE PATHOBIONT THAT ASYMPTOMATICALLY COLONIZES MUCOSAL SITES INCLUDING THE GASTROINTESTINAL TRACT AND THE FEMALE REPRODUCTIVE TRACT (FRT), HOWEVER MICROORGANISMS CONTRIBUTE SIGNIFICANTLY TO THE MUCOSAL ENVIRONMENT AND HOST DEFENSE AGAINST BACTERIA. (GI) THE INTERACTIONS WITH GBS AND NATIVE MICROBES IN THESE NICHES IS LARGELY UNSTUDIED. DURING PREGNANCY GBS VAGINAL COLONIZATION AND ASCENDING INFECTION IS ASSOCIATED WITH ADVERSE PREGNANCY OUTCOMES AND FETAL/NEONATAL INFECTION. THE TO ESTABLISHMENT OF GBS INTESTINAL COLONIZATION IN NEWBORNS I S ALSO BELIEVED TO BE A CRITICAL PRECURSOR LATE-ONSET DISEASE (LOD) WHICH TYPICALLY PRESENTS AS MENINGITIS AND RESULTS IN LONG-TERM NEUROLOGICAL SEQUALAE IN SURVIVORS. THE BACTERIAL AND HOST DETERMINANTS THAT PROMOTE GBS MUCOSAL COLONIZATION AND SYSTEMIC INFECTION, AS WELL AS THE ROLE OF NATIVE MICROBIOTA ARE ESSENTIALLY UNKNOWN AND REPRESENT SIGNIFICANT KNOWLEDGE GAPS IN THE FIELD. PREVIOUS MICROBIOME STUDIES HAVE DEMONSTRATED THAT GBS COLONIZATION IMPACTS VAGINAL MICROBIAL DIVERSITY. USING A MOUSE MODEL OF GBS VAGINAL COLONIZATION, WE FOUND THAT GBS VAGINAL PERSISTENCE IS ASSOCIATED WITH THE PRESENCE OF AKKERMANSIA MUCINIPHILA (AM), A GRAM-NEGATIVE INTESTINAL COMMENSAL THAT DEGRADES MUCIN; HOWEVER, THE SPECIFIC MECHANISM(S) FOR THIS SYNERGY IS UNKNOWN. OUR PRELIMINARY DATA SHOW THAT THE PRESENCE OF AM DRAMATICALLY INCREASES GBS ADHERENCE TO HUMAN VAGINAL EPITHELIAL CELLS (HVEC). USING TRIPLE RNA-SEQUENCING WE IDENTIFIED NUMEROUS GBS AND HVEC GENES THAT ARE SIGNIFICANTLY ALTERED IN THE PRESENCE OF AM, INCLUDING INCREASED BACTERIAL SURFACE ADHESINS, SUCH AS PILI, AND DECREASED TRANSCRIPTION OF HVEC GENES INVOLVED IN NEUTROPHIL SIGNALING AND CHEMOTAXIS. I HYPOTHESIZE THAT AM MAY PROMOTE THE OBSERVED INCREASE IN GBS VAGINAL PERSISTENCE BY INCREASING GBS ATTACHMENT AND MODULATING HOST IMMUNE RESPONSES THAT DAMPEN HOST DEFENSE AGAINST GBS. I FURTHER HYPOTHESIZE THAT AM WILL SIMILARLY PROMOTE GBS INTESTINAL COLONIZATION WHICH COULD IMPACT LOD. TO EXAMINE THESE HYPOTHESES, WE PROPOSE THE FOLLOWING AIMS: 1) DETERMINE THE MECHANISM BY WHICH AM PROMOTES GBS ATTACHMENT TO EPITHELIUM, 2) CHARACTERIZE THE IMPACT OF AM ON MUCOSAL IMMUNITY IN THE FRT, AND 3) EXAMINE THE EFFECT OF AM ON GBS INTESTINAL THESE MUCOSAL COLONIZATION AND LOD. STUDIES WILL GREATLY INCREASE OUR KNOWLEDGE OF GBS - COMMENSAL INTERACTIONS WHICH MAY IMPACT GBS COLONIZATION AND NEONATAL DISEASE.