Women's Infectious Diseases

Scott J. Hultgren, PhD, is the Helen L. Stoever Professor of Molecular Microbiology and the director and principal investigator of the Center for Women’s Infectious Disease Research (cWIDR) at Washington University. cWIDR is part of the university’s BioMed 21 initiative, which is focusing efforts at Washington University on translation of laboratory discoveries into new approaches for diagnosis and treatment of disease. Hultgren’s research has long been focused on women’s health and infectious diseases, with studies funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Allergy and Infectious Diseases (NIAID). He has also been active in the Office of Research on Women’s Health, an agency that coordinates and advises on women’s health research throughout the National Institutes of Health. Hultgren’s lab uses a blend of disciplines to understand the molecular details of host-pathogen interactions in urinary tract infections (UTIs) caused by gram-negative Escherichia coli (UPEC) and gram-positive Enterococcus. Using genetics, biochemistry and X-ray crystallography, he has discovered a novel mechanism of donor-strand complementation and exchange by which the chaperone usher pathways of gram-negative bacteria assemble adhesive pili. He investigates the role of pili at the host-pathogen interface and the function of the Cpx two-component signal transduction system that monitors pilus biogenesis. In addition, diverse technologies are being used to study the export and assembly of an extracellular bacterial amyloid fiber called curli. Using time lapse, confocal and electron microscopy, his lab has shown that piliated UPEC invade bladder epithelial cells. UPEC then activates a complex genetic program that leads to the development of intracellular bacterial communities (IBCs) that have biofilm-like characteristics. During IBC maturation, bacteria go through several developmental switches as evidenced by changes in growth rate, motility, adhesin expression and cellular morphology. Dispersal of the IBC leads to the coordinated burst of thousands of UPEC into the bladder lumen, impacting transmission and leading to recurrent UTIs. The IBC maturation program facilitates subversion of early innate defenses including TLR4-signaling. The genome sequence of our model UPEC has been determined and functional genomics, mutational and promoter fusion analyses are being used to probe the role of specific genetic cascades throughout the infection cycle. This work is spawning new insights into infectious diseases in women, their relationship to cancer and better strategies for treatment and prevention of recurrent and primary UTIs.

Jeffrey I. Gordon, MD, is the Robert J. Glaser Distinguished University Professor of Pathology and Immunology and director of the Center for Genome Sciences. His laboratory is interested in the mutually beneficial relationships between microbes and animals, which are a pervasive feature of life on our microbe-dominated planet. Humans are no exception: the total number of microbes that colonize our body surfaces exceeds our total number of somatic and germ cells by tenfold. The majority of human symbionts reside in the intestines (10-100 trillion!), where they provide humans with traits not evolved by humans. In this sense, we should view ourselves as a composite of bacterial, archaeal and human cells, our genetic landscape as a summation of the genes embedded in our own human genome and the genes embedded in the genomes (“microbiome”) of our microbial partners, and our metabolic features as an amalgamation of human and microbial attributes. Gordon is interested in the following questions: What are the genomic and metabolic foundations of our mutually beneficial relationships with gut microbes? How do we acquire our microbiota and microbiome? How much diversity is there in our microbiomes: do all humans share an identifiable core microbiome? How is the human microbiome evolving as a function of our changing diets, lifestyle and biosphere? How does it contribute to health and our predispositions to various diseases? How can we intentionally manipulate our microbial communities to optimize their performance in the context of an individual or a population? To address these questions, Gordon’s lab is sequencing the genomes of 100 representative members of the human gut microbiota so that we can make predictions about what attributes they possess and what contributions they make to their microbial communities and hosts. He uses germ-free normal and genetically engineered mice, colonized with defined collections of sequenced wild-type (or mutant) bacteria and archaea that normally reside in the human gut, to simultaneously monitor host and microbial responses to colonization. He employs a variety of experimental and computational techniques, including metagenomics (sequencing whole microbial community DNA to define its gene content), functional genomics, and mass-spec-based metabolomics, so that he can compare and contrast the composition of the gut microbial community and its microbiome in normal mice and mice that serve as models for common human diseases. He is using the insights gained from mouse models and validating them in humans, including mono- and dizygotic twin pairs and their mothers and siblings. One key issue he is addressing is whether differences in gut microbial ecology in women affect their predisposition to obesity or malnutrition. These latter studies involve women living in developing countries.

Jeffrey F. Peipert, MD, PhD, is the Robert Terry Professor of Obstetrics and Gynecology and the vice chair for clinical research at Washington University School of Medicine. After completing his residency in obstetrics and gynecology, Peipert joined the Robert Wood Johnson Clinical Scholars Program at Yale University. This program prepares physicians for a career in academic medicine and health care and is a highly successful model for training physicians for academic medicine.

Peipert’s career has focused on clinical epidemiology and patient-oriented research with specific interests in the areas of infectious diseases (e.g., vaginitis, cervicitis, pelvic inflammatory disease/PID, sexually transmitted infections and post-operative morbidity) and contraception. He recently completed patient follow-up of an R01 funded by the National Institute of Child Health and Human Development (NICHD) to evaluate a behavioral change approach to encourage the use of dual methods of contraception to prevent sexually transmitted infections and unplanned pregnancy. Peipert received a K24 award from NICHD in March 2000 and was renewed for an additional five years beginning March 2005. As part of this K24 career development award, Peipert completed a doctorate in epidemiology at Brown University (May 2007).

Peipert has done considerable clinical research on vaginitis, cervicitis and PID. Peipert’s current research projects focus on prevention of STDs and unintended pregnancy. He is the principal investigator of a large prospective cohort study called the Contraceptive CHOICE project. This study is recruiting 10,000 women in the St. Louis Region and providing contraception for three years at no cost. The project provides all methods of contraception, but encourages the use of long-acting reversible contraception (LARC: intrauterine devices and implants). The objective of this study is to reduce the rates of teen pregnancies and unintended pregnancies in our region. The study will also assess continuation rates and satisfaction with all methods. Embedded in this cohort study is a randomized trial of home versus clinic-based screening for STDs.

SUMMARY
The field of infectious disease in women is an area of considerable interested at Washington University, and significant investment has been made in the cWIDR, the GSC and the DCR in the Department of Obstetrics and Gynecology. These three outstanding investigators are all highly suitable mentors for junior faculty interested in either a basic science or clinical science career. The perspective each of these mentors offers to young physician-scientists would be unique, and all would greatly add to our knowledge of infectious diseases in obstetrics and gynecology.