Abstract
Studies indicate that female mice are more susceptible to T. gondii infection, as defined by higher mortality rates in comparison to male mice. However, whether this is due to an inability to control initial parasite multiplication or due to detrimental effects of the immune system has not been determined. Therefore, the following studies were undertaken to determine the influence of sex on early parasite multiplication and the immune response during T. gondii infection and to correlate this with disease outcome. Early parasite replication was studied through applying an in vivo imaging system (IVIS) with luciferase expressing T. gondii. In parallel immunological events were studied by cytometric bead array to quantify key immunological mediators. The results confirmed the previous findings that female mice are more susceptible to acute infection, as determined by higher mortality rates and weight loss compared with males. However, conflicting with expectations, female mice had lower parasite burdens during the acute infection than male mice. Female mice also exhibited significantly increased production of Monocyte Chemoattractant Protein-1 (MCP-1), Interferon (IFN)-γ, and Tumour Necrosis Factor (TNF)-α than male mice. MCP-1 was found to be induced by T. gondii in a dose dependent manner suggesting that the observed increased levels detected in female mice was due to a host-mediated sex difference rather than due to parasite load. However, MCP-1 was not affected by physiological concentration of estrogen or testosterone, indicating that MCP-1 differences observed between the sexes in vivo are due to an as yet unidentified intermediary factor that in turn influences MCP-1 levels. These results suggest that a stronger immune response in female mice compared with male mice enhances their ability to control parasite replication but increases their morbidity and mortality.
Highlights
Toxoplasma gondii (T. gondii) is the most successful intracellular parasitic organism and its distribution is worldwide
Highly virulent strains of T. gondii can cause severe ocular disease even in immune-competent adults [1]. While immunocompromised individuals, such as AIDS patients, may experience toxoplasmic encephalitis associated with infection, T. gondii is medically important in other immunocompromised individuals such as patients undertaking cancer therapy or organ transplantation [2]
We use an in vivo imaging system (IVIS) and luciferase expressing T. gondii parasites to determine the role of sex in early parasite multiplication and a cytometric bead array to determine potential differences in multiple diverse immunological mediators in male and female BALB/c mice infected with T. gondii
Summary
Toxoplasma gondii (T. gondii) is the most successful intracellular parasitic organism and its distribution is worldwide. Subsequent studies found female severe combined immunodeficient (SCID) mice to have increased pathology in their brains and quantitatively different immune responses compared with male mice [13]. These studies indicate that early innate immune events are different between the sexes and are likely determinants of disease outcome. These early studies did not measure parasite multiplication during the acute stages of infection or look at levels of many circulating immune mediators These omissions, largely due to technological limitations at the time, are important since mortality in mice can be due to an inability to control parasite replication or through uncontrolled inflammation as exemplified in IL-4 and IL-10 deficient mice that succumb due to cytokine shock [14,15]. We use an in vivo imaging system (IVIS) and luciferase expressing T. gondii parasites to determine the role of sex in early parasite multiplication and a cytometric bead array to determine potential differences in multiple diverse immunological mediators in male and female BALB/c mice infected with T. gondii
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