Uniformed Services University of the Health Sciences
Department of Microbiology and Immunology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-9629
FAX: (301) 295-1545
The primary research focus of the Jerse lab is on how Neisseria gonorrhoeae adapts to host innate defenses during infection of the female genital tract. N. gonorrhoeae is a human-specific sexually transmitted pathogen that is very common in the U.S. and developing world. The majority of infections are uncomplicated infections of the lower urogenital tract; ascension to the upper reproductive tract occurs frequently in females and can have devastating consequences on reproductive health. The female genital tract is a dynamic ecosystem that is defended by hydrophobic agents, low pH, mucus shedding, complement, phagocytes, and commensal flora. Several of these host factors are influenced by cyclical fluctuations in reproductive hormones. We use a combination of in vitro assays and a mouse model of lower genital tract infection developed in our laboratory to explore how the gonococcus evades or capitalizes on host factors during genital tract infection in women.
One project in our laboratory is to study the expression of a set of outer membrane proteins called the opacity (Opa) proteins during infection. Gonococci can express no Opa proteins, one Opa protein or several antigenically distinct Opa proteins. Data from male volunteers suggest Opa protein expression is selected for or induced during urethral infection in men. The interplay between host factors in the endocervix and N. gonorrhoeae appears more complicated, based on a reported association between Opa protein expression in endocervical isolates and the menstrual cycle. Consistent with the hypothesis that hormonal state may influence Opa protein phenotype, we have shown that Opa protein expression is cyclical in the lower genital tract of female mice, with Opa-positive variants selected for during early in infection. This early selection is followed by reduced recovery of gonococci that express Opa proteins and then a re-emergence of Opa-positive variants. We are currently investigating the host factors responsible for the changes in Opa protein expression observed during murine infection, with a focus on hormonally-regulated components of the innate defense.
Complement and phagocytes are important participants in the host innate defense against gonorrhea. A second project in the lab is to identify genes that promote gonococcal evasion of complement- and phagocyte defenses. N. gonorrhoeae produces anti-oxidant factors (i.e. catalase, peroxidase) that may protect against toxic oxygen species by phagocytes; however, the importance of these factors during endocervical infection is questioned by the relatively low O2 tension of the female genital tract. To address these issues, we constructed a N. gonorrhoeae catalase mutant to test the role of catalase in surviving H2O2 produced by phagocytic cells. The catalase mutant was not essential for infection, but inactivation of the catalase gene caused increased sensitivity to neutrophil killing in vitro and reduced survival relative to the wild type strain in the lower genital tract of mice.
We also constructed a sialyltransferase mutant, and showed it was more susceptible to complement-mediated uptake and killing by phagocytes due to an inability to modify its lipooligosaccharide with host-derived sialic acid. The mutant was also attenuated for murine infection. The next phase of these studies will be to utilize complement-deficient mice and mice that are genetically deficient in the phagocytic oxidative burst to test the basis for the observed attenuation of the catalase and sialyltransferase mutants.
Lactobacilli are the predominant normal bacteria of the female lower genital tract. We showed H2O2-producing lactobacilli inhibit gonococci in vitro, and as expected, our catalase mutant was more susceptible to this inhibition. We are currently testing the hypothesis that lactobacilli reduce the risk of gonorrhea in women by pre-colonizing mice with lactobacilli and challenging them with N. gonorrhoeae. Studies thus far do not support this hypothesis. This result is consistent with the low O2 tension in the female genital tract, and in fact, in vitro data suggests lactobacilli may actually promote gonococcal growth or survival. An investigation of the interactions between N. gonorrhoeae and lactobacilli is underway.
The use of experimental murine infection in conjunction with one or more genetic screens for bacterial genes important in infection should lead to the identification of new genes important for survival in the lower genital tract. To this end we are utilizing signature tagged mutagenesis and DNA microarray to identify mutants that are important for persistence in the murine genital tract and for enes that are up-regulated under physiological conditions that are likely to be present in vivo, respectively.
Jerse, A.E. 1999. Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice. Infect. Immun. 179:911-920.
Dalal, S.J., J.S. Estep, I.E. Valentin-Bon, and A.E. Jerse. Standardization of the Whitten effect to induce susceptibility to Neisseria gonorrhoeae in female mice. 2001. Contemp. Topics in Lab. Anim. Sci. 40(2):12-16.
Jerse, A.E., E.T. Crow, A.N. Bordner, I. Rahman, C.N. Cornelissen, T.R. Moench, and K. Mehrazar. 2002. Growth of Neisseria gonorrhoeae in the female mouse genital tract does not require the gonococcal transferrin or hemoglobin receptors and may be enhanced by commensal lactobacilli. Infect. Immun. 70:2549-2558.
St. Amant, D.C., I.E. Valentin-Bon, and A.E. Jerse. 2002. Inhibition of Neisseria gonorrhoeae by Lactobacillus species that are commonly isolated from the female genital tract. Infect. Immun. 70:7169-7171.
Jerse, A.E., N. Sharma, A.N. Simms, E.T. Crow, L.A. Snyder, and W. Shafer. 2003. A gonococcal efflux pump system enhances bacterial survival in a mouse model of genital tract infection. Infect. Immun. 71:5576-5582.
Soler-Garcia, A.A., and A.E. Jerse. 2004. A Neisseria gonorrhoeae Catalase Mutant Is More Sensitive to Hydrogen Peroxide and Paraquat, an Inducer of Toxic Oxygen Radicals. Microbial Path. 37(2):55-63
Ngampasutadol J, Ram S, Blom AM, Jarva H, Jerse AE, Lien E, Goguen J, Gulati S, Rice PA. 2005. Human C4b-binding protein selectively interacts with Neisseria gonorrhoeae Proc Natl Acad Sci USA. 102 (47):17142-7.
Simms, A.N. and A.E. Jerse. 2006. In vivo selection for Neisseria gonorrhoeae opacity protein expression in the absence of human carcinoembryonic antigen cell adhesion molecules. Infect Immun. 74 (5):2965-74.
Wu, H. and A.E. Jerse. 2006. Alpha-2,3-sialyltransferase enhances Neisseria gonorrhoeae survival during experimental murine genital tract infection. Infect Immun. 74 (7):4094-103.
Exley RM, Wu H, Shaw J, Schneider MC, Smith H, Jerse AE, Tang CM. 2007. Lactate acquisition promotes successful colonization of the murine genital tract by Neisseria gonorrhoeae Infect Immun. 75 (3):1318-24.
Serino L, Nesta B, Leuzzi R, Fontana MR, Monaci E, Mocca BT, Cartocci E, Masignani V, Jerse AE, Rappuoli R, Pizza M.. 2007. Identification of a new OmpA-like protein in Neisseria gonorrhoeae involved in the binding to human epithelial cells and in vivo colonization. Mol Microbiol. 64(5):1391-403.
Warner DM, Folster JP, Shafer WM, Jerse AE.. 2007. Regulation of the MtrC-MtrD-MtrE efflux-pump system modulates the in vivo fitness of Neisseria gonorrhoeae. J Infect Dis. 196(12):1804-12.
Garvin LE, Bash MC, Keys C, Warner DM, Ram S, Shafer WM, Jerse AE.. 2008. Phenotypic and Genotypic Analyses of Neisseria gonorrhoeae Isolates that Express Frequently Recovered PorB PIA Variable Region (VR) Types Suggest Certain P1A Porin Sequences Confer a Selective Advantage for Urogenital Tract Infection. Infect Immun. Epub Jun 9.
Plante, M. , A.E. Jerse, J. Hamel, F. Coutre, C.R. Rioux, B.R. Brodeur, and D. Martin. 2000. Intranasal immunization with gonococcal outer membrane preparations reduces the duration of vaginal colonization of mice by Neisseria gonorrhoeae. J. Infect. Dis. 182:848-855.
Spencer, S.E., Valentin-Bon, I.E., Whaley, K., and A.E. Jerse. 2004. Inhibition of Neisseria gonorrhoeae genital tract infection by leading candidate topical microbicides in a mouse model. J. Infect. Dis. 189:410-419.