Sexually Transmitted Disease
Interactions Between Chlamydiae and The Mammalian Host.
The chlamydiae are obligate intracellular bacteria that cause disease in a wide variety of animal species. In humans, chlamydial disease affects millions of people worldwide and lead to billions of dollars in medical expenses yearly in the U.S. alone. Much is still unknown regarding the basic biology of chlamydial development, their interaction with host cells, and the means by which they cause serious disease.
Our laboratory focuses on three main areas of chlamydial research. First, we investigate the mechanisms used by chlamydiae to develop and maintain their intracellular environment (the inclusion) within infected cells. We (and others) have identified a collection of proteins- termed Inc proteins- that localize to the inclusion membrane. These proteins contact the cytosol in the infected cell and are positioned to directly interact with host cell proteins. Continued studies in this area will further our understanding of the cellular processes parasitized by chlamydiae, and may identify ways to interfere with this parasitism.
Second, we conduct genomics analyses of clinical C. trachomatis isolates. A transformation system has just been developed for the chlamydiae, and the analysis of individual genes within this system remains challenging. We approach this problem through the study of a large library of clinical isolates assembled by collaborators at the University of Washington. We have identified strains within this library that have unique properties in vitro and in vivo, and we are currently using a genomics approach to investigate these unusual strains. Our approach has thus far been successful in associating IncA with a nonfusogenic phenotype, and in the identification of a unique property of secondary inclusion formation by some strains.
We also investigate antibiotic resistance and antibiotic design in this system. Our group participated in the first identification of an antibiotic resistant chlamydial species, Chlamydia suis, in which resistance is mediated via a TetC efflux pump. We have also shown in the laboratory that the resistance gene can be transferred to the human pathogen Chlamydia trachomatis via a poorly characterized horizontal transfer system. This is significant because tetracycline is a frontline drug of choice in treatment of both human and veterinary chlamydial infections, and the spread of this resistance in clinical settings would be a serious problem. This is also the first example of any horizontally acquired antibiotic resistance gene in any chlamydial species.
We continue our study of antibiotics in chlamydial biology by using chlamydiae as model organisms for antibiotic design, through collaborative efforts with a local biotechnology company. Novel antimicrobials are a critical need in the world today, as more and more clinical conditions are being met with significant resistance problems. Our efforts in this area have led to the identification of several lead compounds that may have utility against a variety of important bacterial species.