Document text
Principal Investigator: Katy Patras
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $198,614
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Infections during pregnancy or the neonatal period account for more than two million deaths globally each year.
Frequently, the pathogens causing these infections begin as residents of the maternal vaginal microbiota and
ascend to the uterus during pregnancy. One such pathogen, group B Streptococcus (GBS), is a leading agent
neonatal morbidity and mortality, yet the factors driving GBS ascension into the uterus are poorly defined. The
current standard of care, antibiotic prophylaxis to GBS-positive mothers, is insufficient to prevent GBS-
associated preterm births of stillbirths and exposes ~1 million U.S. infants to antibiotics each year. Understanding
the biological principles controlling GBS-host dynamics is critical to developing defined, long-lasting preventions
for GBS infections in pregnancy and the early neonatal period. Clinical studies have identified gestational
diabetes mellitus (GDM) as a key risk factor for maternal colonization and neonatal disease. The objective of
this proposal is to interrogate the contribution of maternal immunity and GBS transcriptional adaptions in the
propagation of GDM-associated invasive GBS disease and adverse birth outcomes. Our preliminary murine
studies show enhanced susceptibility of diabetic mice to GBS fetal dissemination and adverse outcomes, altered
cytokine profiles, and differential GBS gene expression in a novel murine GDM model. We hypothesize that
GDM renders the host more susceptible to GBS by perturbing maternal immunity and altering GBS transcription
to enhance virulence and fitness. This hypothesis will be interrogated through specific aims designed to
determine: 1) the impact of GDM on the maternal and fetal immune responses at baseline and during GBS
ascending infection, and 2) the transcriptional adaptions required for GBS pathogenesis in the pregnant host in
the presence or absence of GDM. These aims are advanced using multiple innovative tools including recently
established murine models of GDM and GBS vaginal colonization, immune profiling across maternal and fetal
tissues, and comparative GBS transcriptional analyses from commensal and invasive niches. This research
takes place in the dynamic and interdisciplinary environment of Baylor College of Medicine and the Texas
Medical Center with diverse expertise in GBS-host interactions of the female reproductive tract, employment of
animal models to study gestational diabetes mellitus, and genetics of Streptococcal pathogenesis. This research
strategy seeks to more fully understand the complex processes governing host and pathogen dynamics in the
context of pregnancy and maternal metabolic disease. These studies will launch mechanistic studies into key
pathways dictating pregnancy outcomes, and will inform new therapeutic strategies for detecting and preventing
GBS infections in both healthy women and those with gestational diabetes.
Terms: <0-4 weeks old><Amniotic Fluid><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotic Premedication><Antibiotic Prophylaxis><Antibiotics><Antimicrobial Resistance><Aqua Amnii><Automobile Driving><Biological><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><Business-Friendly Atmosphere><Cell Body><Cells><Cells Placenta-Tissue><Cessation of life><Clinical><Clinical Data><Clinical Research><Clinical Study><Complex><Control Groups><D-Glucose><Death><Dextrose><Diabetic mouse><Diet><Disease><Disorder><Elderly><Employment><Environment><Exposure to><Fetal Tissues><Fetus><GBS beta-hemolysin><GBS colonization><Gene Expression><Gene Transcription><Genes><Genetic><Genetic Transcription><Gestation><Gestational Diabetes><Gestational Diabetes Mellitus><Glucose><Group B Streptococcus colonization><Hemalysins><Hemolysin><Host Defense><Host Factor><Host Factor Protein><Human><Hyperglycemia><Immune><Immune response><Immunes><Immunological response><Impairment><In Vitro><Incidence><Individual><Infant><Infant Mortality><Infant Mortality Total><Infection><Inflammatory><Insulin Resistance><Integration Host Factors><Invaded><Liquor Amnii><Macrophage><Marrow Neutrophil><Maternal Immunity><Maternally-Acquired Immunity><Measures><Medical center><Medicine><Membrane><Metabolic><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Mothers><Murine><Mus><Mφ><Neonatal><Neonatal Mortality><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Newborn Infant><Newborns><Normal Placentoma><Onset of illness><Outcome><Pathogenesis><Pathogenicity Factors><Pathway interactions><Physiology><Placenta><Placenta Embryonic Tissue><Placentome><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Predisposition><Pregnancy><Pregnancy Complications><Pregnancy Outcome><Pregnancy-Induced Diabetes><Pregnant Women><Premature Birth><Prematurely delivering><Preterm Birth><Prevention><Process><Production><Prognostic Marker><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Regulation><Research><Risk><Risk Factors><S agalactiae><S. agalactiae><Sampling><Self-Help Groups><Strept B hemolysin><Streptococcal Infections><Streptococcal group B beta-hemolysin><Streptococcus><Streptococcus Group B><Streptococcus agalactiae><Streptococcus infection><Support Groups><Susceptibility><Testing><Texas><Therapeutic><Thesaurismosis><Time><Tissues><Transcription><Uterus><Vagina><Virulence><Virulence Factors><Woman><Work><advanced age><adverse birth outcomes><adverse consequence><adverse outcome><amniotic cavity><anti-microbial resistant><biologic><business-friendly environment><collaborative atmosphere><collaborative environment><college><collegiate><comparative><complications during pregnancy><cytokine><death among infants><death among neonates><death among newborns><death in first year of life><death in infancy><death in infants><death in neonates><death in newborn><design><designing><diabetes control><diabetes mellitus control><diabetes mouse model><diabetic><diets><disease onset><disorder onset><driving><expectant mother><expecting mother><female genital tract><female reproductive tract><fetal><fetus tissue><fitness><genital tract><geriatric><global gene expression><global transcription profile><healthy pregnancy><host response><hyperglycemic><immune system response><immunoresponse><in vitro activity><in vivo><infant death><infant demise><infantile death><innovate><innovation><innovative><insight><insulin resistant><insulin tolerance><interactive atmosphere><interactive environment><interdisciplinary atmosphere><interdisciplinary environment><maternal risk><membrane structure><metabolism disorder><microbial><microbial consortia><microbial flora><microbiota><microflora><model of animal><mortality among neonates><mortality among newborns><mortality in infants><mortality in neonates><mortality in newborns><mouse model><multispecies consortia><murine model><neonatal death><neonatal demise><neonatal morbidity><neonatal period><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><newborn child><newborn children><newborn death><newborn morbidity><newborn mortality><next generation therapeutics><non-diabetic><nondiabetic><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><overexpress><overexpression><pathogen><pathogenicity gene><pathway><peer-group atmosphere><peer-group environment><permissiveness><pregnancy diabetes><pregnancy-related complications><pregnant><pregnant mothers><premature childbirth><premature delivery><preterm delivery><prevent><preventing><prognostic biomarker><pup><recruit><reproductive tract><resistance gene><resistance locus><resistance to anti-microbial><resistant gene><resistant to antimicrobial><response><self help organization><senior citizen><standard of care><stillbirth><stillborn><streptococcal group B hemolysin><therapeutic target><tool><transcriptome><transcriptome sequencing><transcriptomic sequencing><vagina microbiota><vaginal flora><vaginal microbial community><vaginal microbiota><vaginal microflora><virulence gene><virulent gene><womb><women's genital tract><women's reproductive tract>