Characterizing the Impact of Gestational Diabetes on Immunity and Group B Streptococcal Virulence in the Maternal Reproductive Tract

表征妊娠期糖尿病对母体生殖道免疫和 B 族链球菌毒力的影响

• 批准号: 10590792
• 负责人: Vicki Mercado
• 金额: $ 0.25万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-03 至 2025-05-03
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590792
• 关键词: Address; Affect; Amniotic Fluid; Antibiotic Prophylaxis; Antibiotics; Bioinformatics; Candidate Disease Gene; Cell Line; Cells; Cervix Uteri; Cessation of life; Clinical; Coculture Techniques; Complex; Data; Diabetic mouse; Diet; Disease; Endometrial Stromal Cell; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Exhibits; Exposure to; Fatty acid glycerol esters; Fetal health; Fetus; Flow Cytometry; Functional disorder; Gene Expression; Genes; Genetic Transcription; Gestational Diabetes; Glucose; Goals; Growth; Health; Histology; Human; Hyperglycemia; Immune; Immune response; Immunity; Immunology; Impairment; In Vitro; Incidence; Infant; Infection; Insulin Resistance; Integration Host Factors; Knowledge; Life; Liver; Maternal Health; Maternal-Fetal Transmission; Measures; Mentorship; Metabolic; Microbiology; Modeling; Mucous Membrane; Mus; Neonatal; Neonatal Mortality; Nulliparity; Output; Pathogenesis; Patient Care; Pediatrics; Physicians; Physiology; Population; Predisposition; Pregnancy; Premature Birth; Process; Production; Published Comment; Quantitative Reverse Transcriptase PCR; Regulation; Research Proposals; Risk; Role; Scientist; Shapes; Source; Streptococcal Infections; Streptococcus Group B; Sucrose; Therapeutic; Tissues; Training; Uterus; Vagina; Virulence; Virulence Factors; Vulnerable Populations; Woman; Work; career; cytokine; design; diabetic; fetal; fetal infection; healthy pregnancy; improved; in utero; in vivo; in vivo Model; infant death; innovation; insight; intrapartum; knowledge base; macrophage; mast cell; microbial host; microbiome; microbiota; mouse model; mutant; neonatal morbidity; neonatal period; neonatal sepsis; neutrophil; new therapeutic target; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; pathobiont; pathogen; pregnant; prophylactic; recruit; reproductive; reproductive tract; response; standard of care; stillbirth; tool; transcriptome sequencing; transmission process; vaginal microbiota

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 of neonatal morbidity and mortality with conservative approximations attributing GBS to 147,000 stillbirths and infant deaths annually. The primary sources of neonatal GBS exposure are thought to be the maternal vaginal tract during labor and delivery or in utero GBS invasion of placental barriers resulting in fetal infection. Women with gestational diabetes mellitus (GDM) have a 20-50% increased risk for GBS neonatal sepsis and maternal invasive disease but mechanistic insight is lacking. While prophylactic antibiotics have decreased the risk of GBS disease in the first week of life, incidence of GBS-induced stillbirth and preterm birth remains unimproved and early exposure to antibiotics has long-term health consequences that are yet to be fully elucidated. Thus, alternative preventative and therapeutic options are urgently needed and can only be achieved by deepening our understanding of GBS pathogenesis. The aim of this proposal is to determine mechanistic factors that render gestational diabetic hosts uniquely susceptible to GBS. To do so, I have developed an in vivo model of GBS ascension in the reproductive tract of gestational diabetic mice. Preliminary data suggests that this model exhibits increased risk of fetal GBS infection in gestational diabetes as seen in humans. Using this novel model of in utero GBS dissemination in gestational diabetic mice, I will characterize how gestational diabetes alters GBS virulence and host immunity in the maternal reproductive tract. I hypothesize that gestational diabetic conditions perturb host immunity and increase GBS virulence. This hypothesis will be interrogated through specific aims designed to determine: 1) The impact of gestational diabetes on host immunity and 2) the GBS genes that are critical for uterine ascension in healthy and gestational diabetic pregnancy. These novel and advanced aims use multiple innovative tools including a recently established murine model of in utero GBS dissemination in GDM mice and utilization of mice that harbor a humanized microbiome to explore the role of reproductive tract microbiota in shaping local immunity against GBS. The breadth of work, mentorship and training plan outlined in this proposal will equip the candidate with the necessary expertise in mucosal immunology, bioinformatics and reproductive pathophysiology to achieve independence as a physician-scientist with an exciting career trajectory in the field of pediatrics. Together, this research proposal seeks to inform novel therapeutic strategies to better protect maternal-fetal health while advancing our current viewpoint on the complex interplay of gestational diabetes, immunity, local microbiota and GBS virulence in the maternal reproductive tract.

妊娠期或新生儿期感染每年造成全球200多万人死亡。