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. 2005 Mar;79(5):3107-16.
doi: 10.1128/JVI.79.5.3107-3116.2005.

Estradiol regulates susceptibility following primary exposure to genital herpes simplex virus type 2, while progesterone induces inflammation

Amy E Gillgrass  1 , Sherie A Fernandez, Kenneth L Rosenthal, Charu Kaushic
Affiliations

Estradiol regulates susceptibility following primary exposure to genital herpes simplex virus type 2, while progesterone induces inflammation

Amy E Gillgrass et al. J Virol. 2005 Mar.

Abstract

We report here that sex hormones modulate susceptibility to a sexually transmitted viral agent, herpes simplex virus type 2 (HSV-2), in a mouse model. Ovariectomized mice were administered either saline (control), estradiol (E(2)), progesterone (P(4)), or a combination of both estradiol and progesterone (E+P) and infected intravaginally with HSV-2. With an inoculation dose of 10(5) PFU, the saline- and P(4)-treated mice were found to be highly susceptible to genital HSV-2 infection. Both groups had extensive pathology and high viral titers in vaginal secretions, and 100% of mice succumbed by day 4 postinfection. E(2)-treated mice were protected from HSV-2 infection at the same dose and did not display any vaginal pathology or viral shedding. There was a slow progression of genital pathology in the combination hormone-treated group, along with prolonged viral shedding; 80% of animals succumbed by day 13. With lower inoculation doses of 10(3) and 10(2) PFU, 50 and 100%, respectively, of the combination hormone-treated mice survived. Localization of HSV-2 infection showed extensive infection in the vaginal epithelium of P(4)- and saline-treated animals within 24 h of inoculation. E(2)-treated animals were clear of infection, while the E+P-treated group had focal infection at 24 h that had progressed extensively by day 3. Infection was accompanied by persistent inflammation and infiltration of neutrophils in the P(4)-treated group. An analysis of the genes in the vaginal tissue showed that inflammation in the P(4)-treated group correlated with local induction of chemokines and chemokine receptors that were absent in the E(2)-treated mice and in uninfected P(4)-treated mice. The results show that sex hormones regulate initiation of infection and immune responses to genital HSV-2 infection.

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Figures

FIG. 1.
FIG. 1.
Survival (A) and pathology (B) of OVX, hormone-treated mice inoculated with a high challenge dose (105 PFU) of HSV-2 strain 333. Mice were ovariectomized and given different combinations of hormones, as described in Materials and Methods. Following IVAG inoculation with HSV-2, vaginal pathology and survival were scored daily. Pathology scores of all of the mice in each group are shown as mean values. Each hormone group had six to eight mice per group. The experiment was repeated two times, with comparable results.
FIG. 2.
FIG. 2.
Virus titers from OVX, hormone-treated mice inoculated with 105 PFU of HSV-2 type 333. Mice were ovariectomized and given different hormone combinations, as described in Materials and Methods. Following IVAG inoculation with HSV-2, vaginal washes were collected daily, and viral plaque assays were done as described in the text. Plaques were counted, and viral titers were expressed in PFU per milliliter. Each symbol represents a single animal (n = 6 to 9 mice in each group). The dashed lines show the lower detection limit of the assay. Results are representative of two separate experiments.
FIG. 3.
FIG. 3.
Survival of OVX, hormone-treated mice inoculated with low challenge doses of 103 (A) and 102 (B) PFU of HSV-2 strain 333. Mice were ovariectomized and given different combination of hormones, as described in Materials and Methods. Following IVAG inoculation with HSV-2, vaginal pathology and survival were scored daily. Each hormone group had six to eight mice per group. The experiment was repeated two times, with comparable results.
FIG. 4.
FIG. 4.
Virus titers from OVX, hormone-treated mice inoculated with low challenge doses (103 and 102 PFU) of HSV-2 type 333. Mice were ovariectomized and given different hormone combinations, as described in Materials and Methods. Following IVAG inoculation with HSV-2, vaginal washes were collected daily, and viral plaque assays were done as described in the text. Plaques were counted, and viral titers were expressed in PFU per milliliter. Each symbol represents a single animal (n = 6 to 9 mice in each group). The dashed lines show the lower detection limit of the assay. Results are representative of two separate experiments.
FIG. 5.
FIG. 5.
Histopathology of vaginal tissue of OVX, hormone-treated mice inoculated IVAG with HSV-2. Mice were sacrificed either 24 h postinfection (A to D) or 3 days postinfection (E to H). Control noninfected mice that received hormones were also examined on the same day as the mice examined 3 days postinfection (I to L). Note the thin epithelium in saline-treated (A, E, and I) and progesterone-treated (C, G, and K) mice. Progesterone-treated mice also have acute inflammation and heavy leukocytic infiltration in the lumen. Also note the thickened epithelium in the estradiol-treated mice (B, F, and J), denoting the effect of the hormone, including keratinization of the superficial layer (B). Original magnification, ×100.
FIG. 6.
FIG. 6.
Localization of infection in the vaginal tissue of OVX, hormone-treated mice infected with HSV-2. A polyclonal rabbit serum was used to detect HSV-2-specific staining, as described in Materials and Methods. Representative tissue sections from each hormone group are shown for day 1 postinfection (A to D) and day 3 postinfection (E to H). Positive staining (pink) in the vaginal epithelium was seen in saline-treated mice (A and E) and progesterone-treated mice (C and G). The E+P group had focal infection at 24 h postinfection (D) and more extensive infection at day 3 (H). No HSV-2 staining was observed in estradiol-treated mice. Isotype controls for day 1 progesterone (I) and E+P (J) are also shown. Original magnification, ×100.
FIG. 7.
FIG. 7.
Localization of neutrophils in vaginal tissue of OVX, hormone-treated mice infected with HSV-2. A rat anti-mouse neutrophil antibody was used to detect specific staining, as described in Materials and Methods. Mice were sacrificed either 24 h postinfection (A to D) or 3 days postinfection (E to H). Control noninfected mice that received hormones were also examined on the same day as the mice examined 3 days postinfection (I to L). Positive staining (pink) is seen in the endothelium of saline-treated mice on day 1 (A) and mostly following infection of progesterone-treated mice (C and G). Significant numbers of neutrophils are also seen in the superficial layers of vaginal epithelium 3 days after E2 treatment was stopped in both infected and noninfected tissue (F and J). Original magnification, ×100.
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