IFN-γ-Mediated Innate Immunity in Females Is Less Efficient than That in Males in Restricting Cerebral Proliferation of Toxoplasma Tachyzoites During Reactivation of Chronic Infection with the Parasite

Female AIDS patients infected with Toxoplasma gondii have increased risks of developing toxoplasmic encephalitis caused by reactivation of chronic infection with this parasite when compared to males. In the present study, we compared the capability of innate immunity to limit proliferation of tachyzoites (the acute stage form) of T. gondii in the brain during reactivation of the infection between genders using SCID mice deficient in T and B cells. SCID mice were infected and treated with sulfadiazine to control tachyzoite proliferation during the acute stage of infection and establish chronic infection in their brains, and thereafter, sulfadiazine was discontinued to initiate reactivation of the infection. Notably, markedly higher levels of mRNA for tachyzoite-specific SAG1 and LDH1 as well as greater numbers of the areas associated with tachyzoite proliferation were detected in the brains of females than in the brains of male SCID mice during reactivation of the infection. Whereas IFN-γ-mediated protective immunity is required for preventing reactivation of cerebral T. gondii infection, expression levels of mRNA for IFN-γ, the IFN-γ receptor, the key mediator of the IFN-γ-mediated signaling pathway (STAT1), and effector molecules of IFN-γ-mediated protective immunity did not differ between the brains of male and female SCID mice. Cerebral mRNA levels for IL-1β and TNF-α also did not differ between the sexes of those mice even when tachyzoite proliferation became accelerated in the brain of the females. Notably, cerebral mRNA levels for immunosuppressive arginase 1 (Arg1) became significantly greater in female than in male SCID mice during reactivation of the infection, and increased Arg1 mRNA levels significantly correlated with increased levels of tachyzoite-specific SAG1 and LDH1 mRNA levels in the brains of only females of these mice. These results indicate that IFN-γ-mediated innate immunity to prevent cerebral tachyzoite proliferation is less efficient in female than in male SCID mice during reactivation of T. gondii infection, and that increased expression of Arg1 most likely contributes to the susceptibility of female SCID mice to reactivation of the infection.