[Research Interests] [Representative Publications] [Lab Members] RESEARCH INTERESTSOur
“Mucosal Protection Laboratory” is developing barrier methods for
protecting against sexually transmitted diseases (STDs) and unwanted
pregnancy, methods more appealing to use than condoms. Microbicides for
this purpose must not only block the infectious entry of STD pathogens
they must also be safe to use repeatedly on mucosal surfaces, and they
must not disturb healthy microflora of the vagina (lactobacilli).
Research
in the Mucosal Protection Laboratory helped create “BufferGel”, a
spermicidal microbicide now in major clinical efficacy trials (funded by
NIH) for preventing HIV infections and for contraception. BufferGel’s
basic mechanism of protection is quite simple: The vagina is mildly
acidic (~pH 4), sufficiently acidic to protect against many types of
pathogens. But sperm are
acid-sensitive, so semen is alkaline and the ejaculate abolishes the
protective acidity of the vagina for many hours after intercourse.
Otherwise sperm would be killed within seconds by vaginal acidity.
Unfortunately the alkalinizing action of semen helps
acid-sensitive STD pathogens, not just sperm, to survive in the vagina.
Acid sensitive STD pathogens include HIV, HSV, syphilis, and chlamydia. Since
BufferGel can rapidly acidify semen it is expected to protect against
both sperm and these acid-sensitive pathogens while not disturbing
acid-tolerant vaginal lactobacilli. Research on BufferGel and other
microbicides is being performed in part through an ongoing Research
Agreement with ReProtect, Inc, the JHU-associated company that is
pursuing commercial development of BufferGel.
What is the most common
vaginal infection? (It is more common than yeast infections.) The answer:
Bacterial Vaginosis (“BV”). Most
people have never heard of it, and it is asymptomatic in most women.
Worldwide, it is estimated that 1 out of 4 women have BV. Even though
most people don’t know about it, recent epidemiological studies have
revealed that BV is a major health problem: Women with BV are at greatly
increased risk of HIV and other STD infections, and BV greatly increases
the risk of stillbirths, premature births, and pelvic and perinatal
infections.
During a BV infection, the lactobacilli die off, the pH of the
vagina rises, and a marked polymicrobial overgrowth occurs, coating
every epithelial cell with a carpet of bacteria.
Our research suggests that BufferGel will help prevent BV, and
the ongoing clinical trials will determine whether or not it does. In
the meantime our lab is investigating what causes BV and the mechanisms
by which BV might increase the risk of HIV and other STD infections.
Little is known about what causes BV, and no one knows how it is
transmitted, so we are embarking on several foundation-building research
projects that use simple microbiology techniques. The first graduate
student to pursue research on BV in the Mucosal Protection Lab was
Elizabeth Boskey. She chose to investigate the question: “What makes
the vagina acidic?” For over 100 years many clinicians have thought
that the vagina is probably acidified by the lactic acid produced by
lactobacilli, but no one actually tested whether or not this hypothesis
was correct. More recently, some clinicians suggested another reasonable
hypothesis is that since the vagina is anaerobic, anaerobic metabolism
by the epithelial cells produces most of the lactic acid. Boskey’s
thesis research provided the first definitive evidence that vaginal
acidity is in fact produced primarily by lactobacilli, not by the
vaginal epithelium (see Boskey et al, 2001). We are now investigating
how the lactic acid produced by vaginal lactobacilli inhibits the growth
of BV-associated microbes. REPRESENTATIVE PUBLICATIONSCone, R.A, Hoen, T., Wong, X., Abusuwwa, R., Anderson, D.J., and Moench, T.R. 2006. Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect Dis. 6:90. Lai, S. K., O'Hanlon, D.E., Harrold, S., Man, S.T., Wang, Y.Y., Cone, R., Hanes J. 2007. Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc Natl Acad Sci U S A. 104:1482-7. Boskey ER, Moench TR, Hees PS, Cone RA. 2003. A self-sampling method to obtain large volumes of undiluted cervicovaginal secretions. Sex Transm Dis.Feb;30:107-9. Hildreth JE, Hoen TE, Shultz L, Markham RB. 2002. Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent. J Clin Invest. Jan;109:205-11. Achilles SL, Shete PB, Whaley KJ, Moench TR, Cone RA. 2002. Microbicide efficacy and toxicity tests in a mouse model for vaginal transmission of Chlamydia trachomatis. Sex Transm Dis. 29:655-64. Castle PE, Karp DA, Zeitlin L, Garcia-Moreno E B, Moench TR, Whaley KJ, Cone RA. 2002. Human monoclonal antibody stability and activity at vaginal pH. J Reprod Immunol. 56:61-76. Boskey E.R., R.A. Cone, K.J. Whaley, and T.R. Moench. 2001. Origin of vaginal acidity: High D/L lactate ratio is consistent with bacteria being the primary source. Hum. Reprod., 16:1809-1813. Olmsted, S.S., J.L. Padgett, A.I. Yudin, K.J. Whaley, T.R. Moench, and R.A. Cone. 2001. Diffusion of macromolecules and virus-sized-particles in human cervical mucus. Biophys. J. 81:1930-1937. Cone, R.A. 1999. Mucus. In Handbook of mucosal immunology, Second Edition, ed. by Ogra, Mestecky, Lamm, McGhee, and Bienenstock. 43-64. San Diego: Academic Press. Castle, P.E., K.J. Whaley, T.E. Hoen, T.R. Moench, and R.A. Cone. 1997. Contraceptive effect of sperm-agglutinating monoclonal antibodies in rabbits. Biol. of Reprod. 56:153-159. Cone, R.A., and K.J. Whaley. 1994. Monoclonal antibodies for reproductive health: Preventing sexual transmission of disease and pregnancy with topically applied antibodies. Am. J. Reprod. Immunol. 32:114-131. Lab MembersResearch Associates:
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