Thesis

How ∆9-Tetrahydrocannoabinol Affects Resistance to Systemic Candida Albicans Infection in Immunocompromised Mice

∆9-tetrahydrocannabinol (THC), marijuana’s principal psychoactive component, is known to suppress resistance to bacterial, viral and protozoan infections. However, the effect of THC on resistance to fungal infections is unclear. Recently, we found that chronic THC treatment decreased resistance to the yeast Candida albicans (C. albicans) in immune competent mice. However, nothing is known about how THC affects resistance to a fungal infection in an immunocompromised mouse. Our objective was to assess how chronic THC affects an immunocompromised mouse’s ability to ward off systemic candidiasis in an acute and secondary model of infection. 5-fluorouracil (5-F) is a commonly prescribed anti-cancer drug and is also a potent immunosuppressor, increasing susceptibility to C. albicans infection. We found that 5-F treatment severely decreased survival, white blood cell count, splenic IL-12p40 production and increased kidney fungal load. To investigate the effect of THC on resistance to C. albicans in immunosuppressed mice, c57BL/6 female mice were treated via an intraperitoneal (IP) injection with vehicle (ethanol, cremophor, saline (1:1:18)) or THC in vehicle (16mg/kg) 4 days a week, for three weeks (experimental days 1-18). For the secondary infection model, on day 2, the mice received a priming dose (0.75x105 cells) of C. albicans. On day 16, mice received an intravenous (IV) injection of 5-F (0.1ml of 50mg/ml). On day 19, mice were infected with an IV injection of 5x105 C. albicans cells. For the acute infection model, the mice only received an IV injection of C. albicans on day 19 without a priming dose. On day 22, tissues were harvested from some mice to assess tissue fungal load. In addition, splenocytes were cultured and treated with either Concanavalin A (Con A, 5µg/ml) or heat killed (HK) C. albicans (6.25x106 yeast cells/ml) to assess cytokine production responses. Remaining mice were observed for up to 2 weeks for survival and morbidity. We found that in both infection models, mice treated with 5-F and THC succumbed a day earlier to the yeast infection compared to 5-F and vehicle treated mice. In both infection models, 5-F decreased Con A stimulated splenocyte INF-γ secretion from vehicle and THC groups, with no significant difference between the groups. However, the decrease by 5-F was much more pronounced in the acute infection model compared to the secondary infection model. In both infection models, C. albicans-stimulated IFN-γ levels were significantly lower in the THC group compared to the vehicle group. These results strongly suggest that THC has an effect on splenic immune response, and they also suggest that although THC does make the 5-F treated mice slightly more susceptible to the infection, it is not significant enough to conclude that chronic THC treatment is detrimental to immunocompromised mice.

Relationships

Items