Chlamydia trachomatis serovars D-K are the most common cause, in the USA and worldwide, of bacterially-acquired sexually transmitted diseases and their sequelae, including prostatitis, epididymitis, pelvic inflammatory disease, ectopic pregnancy and sterility. Chlamydial diseases are insidious and they constitute significant primary, secondary and tertiary health concerns in which women bear a special burden because of their increased risk of adverse reproductive consequences. The goal of this laboratory for 25 years has been to try to understand the basic biology of chlamydial growth in its host epithelial cell in order to understand the infectious process and to permit dissection of the cellular and molecular consequences of persistent infection, since the majority of chlamydial tubal disease appears to result from chronic subclinical, persistent infection. This proposal is a continuation of on-going efforts to understand the crucial attachment/entry steps, the signals in chlamydiae-infected epithelial cells which trigger neutrophil chemotaxis--since a prolonged inflammatory response to persistent chlamydial antigens is believed to be responsible for the damage and sequelae, and hormone modulation of entry and signaling of neutrophils.
In Aim 1, the chlamydial envelope-associated hsp70 and its co- chaperonins GrpE and DnaJ will be incorporated into liposomes, along with known and suspected adhesins, to define the role of hsp70 in entry and, in Aim 2, help identify the receptor which functions with newly identified, estrogen-responsive receptor accessory proteins. Also in Aim 2, the swine C. trachomatis S45 isolate- swine genital tissue model of infection will be developed to dissect hormone modulation of entry and neutrophil signaling (Aim 3).
In Aim 3, a comparison will be made of chlamydial and chemokine signals triggering neutrophil chemotaxis to polarized HeLa cells normally and persistently infected with non-invasive, asymptomatic serovar E versus invasive, symptomatic serovar L2. Finally, in Aim 4, cryo-electron microscopy and density gradients will be used to show that chlamydial antigen secretion and trafficking can occur via vesicles pinched off from the chlamydial inclusion.
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