Project Grant F31HD121285

IMPACT OF PERINATAL ANTIBIOTICS ON THE GENERATION OF PROTECTIVE MAMMARY IGA - PROJECT SUMMARY/ABSTRACT NEONATES ARE A PARTICULARLY VULNERABLE POPULATION DUE TO THE CHANGE IN THEIR ENVIRONMENT AT BIRTH, THE SUBSEQUENT MICROBIAL COLONIZATION THAT RESULTS, AND THE RELATIVE IMMATURITY OF THEIR IMMUNE SYSTEMS COMPARED TO ADULTS. OF IMPORTANCE IS THE FACT THAT NEONATES, ESPECIALLY THOSE OF VERY LOW BIRTH WEIGHT BORN TO PATIENTS EXPERIENCING PREMATURE BIRTH, ARE AT AN INCREASED RISK OF DEVELOPING SEPSIS RESULTING FROM A SYSTEMIC INFECTION. THOUGH PUBLISHED DATA HAS SHOWN THE BENEFIT OF MATERNAL ANTIBIOTICS WHICH REDUCE THE RISK OF EARLY-ONSET SEPSIS FROM VERTICAL BACTERIAL TRANSMISSION, THE RISK OF LATE-ONSET SEPSIS (LOS) IS INCREASED, HIGHLIGHTING THE NEED TO FURTHER UNDERSTAND HOW MATERNAL ANTIBIOTICS MIGHT IMPACT NEONATAL OUTCOMES. NEONATAL IMMUNOLOGICAL IMMATURITY AND ITS RAMIFICATIONS ARE MITIGATED THROUGH MATERNAL MEASURES INCLUDING TRANSPLACENTAL IGG TRANSFER DURING LATE PREGNANCY AND THROUGH IMMUNOGLOBULIN (IG) CONFERRED IN BREASTMILK. IN THE POST-BIRTH PERIOD BREASTMILK BECOMES THE ONLY SOURCE OF PROTECTIVE ANTIBODY WITH IGA, THE ANTIBODY FOUND MOST ABUNDANTLY AT MUCOSAL SURFACES, ACCOUNTING FOR THE HIGHEST CONCENTRATION OF IG. PRELIMINARY DATA FROM AN ONGOING COLLABORATION HAS SHOWN THAT IGA CONCENTRATIONS IN HUMAN BREASTMILK IS DECREASED FOLLOWING PERINATAL ANTIBIOTIC ADMINISTRATION IN PATIENTS. SIMILARLY, OUR LAB HAS SHOWN THAT IGA IS ALSO DECREASED IN THE BREASTMILK OF LACTATING MICE THAT WERE GIVEN ANTIBIOTICS FOR ONE WEEK PRIOR TO DELIVERY, UNDERSCORING THE POTENTIAL PERTURBATION OF PROCESSES CONTRIBUTING TO THE GENERATION OF IGA. MAMMARY IGA IS PREDOMINANTLY PRODUCED FROM PLASMA CELLS THAT TRAFFICKED TO THIS SITE AFTER GENERATION IN THE MATERNAL INTESTINE, SUGGESTING ANTIBIOTIC-MEDIATED PERTURBATION OF THE PERINATAL MATERNAL MICROBIOME DISRUPTS MAMMARY IGA. FURTHERMORE, WE HYPOTHESIZE THAT THE MATERNAL GUT MICROBIOTA DRIVES THE GENERATION OF PATHOGEN-SPECIFIC IGA IN LATE PREGNANCY THAT SERVES AS PROTECTION FROM INTESTINAL PATHOGENS IN NEONATES. TO TEST THIS HYPOTHESIS, WE HAVE DEVISED TWO AIMS TO FIRST, EVALUATE THE CONTRIBUTION OF THE MATERNAL MICROBIOTA IN LATE PREGNANCY IN THE GENERATION OF MAMMARY IGA AND SECOND, TO ASSESS THE ROLE OF MAMMARY IGA IN PROTECTING NEONATES FROM INTESTINAL PATHOGENS. WE WILL UTILIZE A MODEL OF PERINATAL ANTIBIOTIC ADMINISTRATION IN CONJUNCTION WITH OUR ESTABLISHED MODEL OF LOS IN BOTH WILDTYPE C57BL6 MICE AND IGA DEFICIENT MICE IN A C57BL6 BACKGROUND TO ADDRESS THESE AIMS. THIS WORK IS OF SIGNIFICANT CLINICAL IMPORTANCE DUE TO THE NEED TO BETTER UNDERSTAND MATERNAL PROTECTIONS CONFERRED TO NEONATES DURING PREGNANCY AND LACTATION. IN ADDITION, THIS WORK COULD CONTRIBUTE TO CLINICAL DECISIONS BY INFORMING THE IMPLEMENTATION OF ANTIBIOTIC REGIMENS DURING PREGNANCY WITH THE POTENTIAL FOR INFORMING REGIMEN ADJUSTMENTS TO BETTER ACCOUNT FOR LONG-TERM EFFECTS OF PERINATAL MATERNAL ANTIBIOTICS.