Sex-associated hormones and immunity to protozoan parasites

Abstract

Numerous epidemiological and clinical studies have noted differences in the incidence and severity of parasitic diseases between males and females. Although in some instances this may be due to gender-associated differences in behavior, there is overwhelming evidence that sex-associated hormones can also modulate immune responses and consequently directly influence the outcome of parasitic infection. Animal models of disease can often recreate the gender-dependent differences observed in humans, and the role of sex-associated hormones can be confirmed by experimentally altering their levels. Under normal circumstances, levels of sex hormones not only differ between males and females but vary according to age. Furthermore, not only are females of reproductive age subject to the regular hormonal cycles which control ovulation, they are also exposed to dramatically altered levels during pregnancy. It is thus not surprising that the severity of many diseases, including those caused by parasites, has been shown to be affected by one or more of these circumstances. In addition, infection with many pathogens has been shown to have an adverse influence on pregnancy. In this article we review the impact of sex-associated hormones on the immune system and the development and maintenance of immunity to the intracellular protozoan parasites Toxoplasma gondii, Plasmodium spp., and Leishmania spp.

FIG. 1

Influence of sex- and pregnancy-associated hormones on the development of an immune response against intracellular protozoan parasites such as T. gondii and L. mexicana. ROI, reactive oxygen intermediates; RNI, reactive nitrogen intermediates.

FIG. 2

Innate resistance to T. gondii is influenced by gender. (a) Determination of the area of brain lesions in T. gondii-infected male and female SCID mice. Chalkley counting (a microscpic method of determining area) of histological sections of brain tissue derived from animals at day 15 postinfection revealed that brains from female animals contained significantly greater lesion areas than those of their male counterparts. Female lesion area, 0.527%; male lesion area, 0.177%; P < 0.01. (b and c) Comparison of innate immunity-associated cytokines in male and female SCID mice infected with T. gondii. (b) Plasma samples from infected animals analyzed for IL-12 expression revealed significant differences between males and females. IL-12 plasma concentrations peaked at day 8 postinfection in males (122.3 ± 42.2 pg/ml) and day 10 in females (83.3 ± 40.8 pg/ml). The level of IL-12 in male samples was significantly higher at day 8 postinfection compared with females (P < 0.03). (c) Similar measurements of IFN-γ levels revealed that male SCID mice produced significantly higher amounts of this cytokine early after infection than females. At day 8, male IFN-γ plasma levels were 1,560 ± 140 pg/ml, compared with 104 ± 10.4 pg/ml in females (P < 0.001). This pattern of cytokine expression was consistently observed in two subsequent experiments. Statistical analyses were performed by the Mann-Whitney U test. For full details of experimental procedures, see reference . Reproduced with permission from reference .

FIG. 3

(a) Lesion growth in the shaven rumps of male (open squares) and female (solid squares) DBA/2 mice infected with L. mexicana. The values represent mean number of animals with lesions at week 10 postinfection/number in group. Similar results were obtained in three independent experiments. Error bars show standard error. (b) IFN-γ and (c) IL-5 production by inguinal lymph node cells from L. mexicana-infected male and female DBA/2 mice at week 10 postinfection following stimulation with Leishmania soluble antigen (20 μgml). ND, not detectable. Cytokine production from lymph node cells from individual mice was assayed separately, and four to five mice were used in each group. For full details of experimental procedures, see reference . Reproduced with permission from reference .