Estrogen and progesterone affect responses to malaria infection in female C57BL/6 mice

Previous data from our laboratory suggest that gonadally intact C57BL/6 male mice are more likely than their female counterparts to die from Plasmodium chabaudi infection, to recover more slowly from weight loss and hematocrit loss, and to have reduced interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) responses. Removal of the ovaries, and hence, the primary production of sex steroids in females, reverses these differences.

We hypothesized that sex differences in response to P chabaudi may be mediated by differential synthesis of IFN-gamma and IL-10 that is influenced by estrogen, progesterone, or both.

C57BL/6 female mice (n = 200; n = 10/time point/treatment/experiment) were ovariectomized and implanted with a 21-day controlled-release pellet containing either 0.1 mg of 17beta-estradiol (E(2)), 10 mg of progesterone (P(4)), 0.1 mg of E(2) plus 10 mg of P(4), or cholesterol (placebo). Females were inoculated with 10(6)P chabaudi-infected erythrocytes. Body mass, body temperature, hematocrit, parasitemia, cytokine production, and antibody responses were monitored 0, 3, 5, 7, 10, 14, and 21 days postinoculation.

Administration of E(2), either alone or in combination with P(4), mitigated infection-induced weight loss, hematocrit loss, and hypothermia, compared with females receiving placebo pellets (P < 0.05 in each case). Hormone treatment did not affect levels of parasitemia. Females administered E(2) alone or in combination with P(4) produced 4 to 7 times higher IFN-gamma and IL-10 during peak parasitemia than did females implanted with pellets containing either P(4) alone or placebo (P < 0.05 in each case). Exposure to E(2), either alone or in combination with P(4), increased anti-P chabaudi immunoglobulin G (IgG1) responses and the ratio of IgG1 to IgG2c (P < 0.05 in each case).

This animal study suggests that physiological levels of estrogen, rather than progesterone, enhance immunity and, possibly, protect females from disease symptoms during malaria infection.