Bacterial vaginosis (BV) is an exceedingly common disorder of the vaginal microflora affecting >30% of all women, with higher rates in pregnancy and among African- American populations. Women with BV are at substantially increased risk of preterm birth, which is a major cause of neonatal morbidity and mortality, as well as acquisition of sexually transmitted diseases including human immunodeficiency virus. Despite its public health importance, the pathogenesis of BV is not well understood. We have recently characterized vaginolysin (VLY), a cholesterol-dependent cytolysin from Gardnerella vaginalis (a bacterial species present on the vaginal mucosa in the setting of BV and thought to contribute to the pathogenesis of disease) that exhibits exquisite human specificity. We hypothesize that this species-specific toxin may be an important virulence factor of G. vaginalis with relevance to the pathogenesis of BV. In our preliminary data, we have characterized the receptor for VLY (human CD59) on genital tract epithelial cells. Introduction of this receptor into non-susceptible cells renders them sensitive to VLY. We have engineered a transgenic mouse expressing the hCD59 receptor and also constructed a VLY chimera that is hCD59-independent. These represent candidate in vivo models for BV. In addition, we have developed techniques for genetic manipulation of G. vaginalis, including transposon mutagenesis.
In Aim 1, we will define genetic determinants of G. vaginalis virulence using new techniques for mutagenesis and assays of toxin production.
In Aim 2, we will determine the role of VLY at the host-pathogen interface both in vitro and in vivo with a focus on unique aspects of the VLY-hCD59 interaction. At the conclusion of these studies, we will have expanded our knowledge of G. vaginalis pathogenesis, evaluated new in vivo models of BV, identified candidate strategies to inhibit toxin-host interaction, and developed new tools for continued investigation into the pathogenesis of an important disorder.
Bacterial vaginosis (BV) is a very common but not well-understood disease affecting women. Women with this disorder are at substantially higher risk of preterm birth and acquisition of other serious diseases, including HIV. This project investigates the role of a newly described toxin made by Gardnerella vaginalis in causing inflammation and damage to vaginal cells during BV and focuses on the development of new models and treatments for this important disease.
|Randis, Tara M; Gelber, Shari E; Hooven, Thomas A et al. (2014) Group B Streptococcus ?-hemolysin/cytolysin breaches maternal-fetal barriers to cause preterm birth and intrauterine fetal demise in vivo. J Infect Dis 210:265-73|
|Ghartey, Jeny P; Smith, Benjamin C; Chen, Zigui et al. (2014) Lactobacillus crispatus dominant vaginal microbiome is associated with inhibitory activity of female genital tract secretions against Escherichia coli. PLoS One 9:e96659|
|LaRocca, Timothy J; Stivison, Elizabeth A; Hod, Eldad A et al. (2014) Human-specific bacterial pore-forming toxins induce programmed necrosis in erythrocytes. MBio 5:e01251-14|
|Sachdev, Darpun D; Yin, Michael T; Horowitz, Jason D et al. (2013) Klebsiella pneumoniae K1 liver abscess and septic endophthalmitis in a U.S. resident. J Clin Microbiol 51:1049-51|
|Randis, Tara M; Zaklama, Joanne; LaRocca, Timothy J et al. (2013) Vaginolysin drives epithelial ultrastructural responses to Gardnerella vaginalis. Infect Immun 81:4544-50|
|Planet, Paul J; Narechania, Apurva; Hymes, Saul R et al. (2013) Bordetella holmesii: initial genomic analysis of an emerging opportunist. Pathog Dis 67:132-5|
|Hymes, Saul R; Randis, Tara M; Sun, Thomas Yang et al. (2013) DNase inhibits Gardnerella vaginalis biofilms in vitro and in vivo. J Infect Dis 207:1491-7|
|Planet, Paul J; Rampersaud, Ryan; Hymes, Saul R et al. (2013) Genome Sequence of the Human Abscess Isolate Streptococcus intermedius BA1. Genome Announc 1:|
|Los, Ferdinand C O; Randis, Tara M; Aroian, Raffi V et al. (2013) Role of pore-forming toxins in bacterial infectious diseases. Microbiol Mol Biol Rev 77:173-207|
|Kulkarni, Ritwij; Randis, Tara M; Antala, Swati et al. (2013) *-Hemolysin/cytolysin of Group B Streptococcus enhances host inflammation but is dispensable for establishment of urinary tract infection. PLoS One 8:e59091|
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