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Cryptococcus gattii isolates induce less protective inflammation than Cryptococcus neoformans in a murine model of infection. Cheng, Po-Yan

Abstract

The fungal pathogen Cryptococcus neoformans variety grubii is an opportunistic pathogen of immunocompromised people while the related species, Cryptococcus gattii, appears to infect people regardless of their immune status. The objective of this study was to investigate the differences between C. neoformans and C. gattii infections in a mouse model of cryptococcosis in order to better understand why C. gattii is able to cause disease in immunocompetent hosts. Normally, protective inflammation mediated by neutrophils and an adaptive Th1-type immune response is required for clearance of C. neoformans infections, whereas a Th2-type immune response is inefficient. Furthermore, neutrophils act as important first-responders in innate immunity by initiating the adaptive Th1 immune response during the early stage of infection. We hypothesized that while C. neoformans infections are cleared because they elicit strong protective inflammatory immune responses, C. gattii infections persist because they do not, thus enabling this species to cause disease in immunocompetent hosts. The results support the hypothesis because we found that C. gattii infections induce less protective inflammation than C. neoformans infections with respect to leukocyte recruitment to the sites of infection and cytokine induction. Mice infected with the C. gattii strains tested had less neutrophil migration into their lungs and had a reduced protective cytokine profile, suggesting that C. gattii strains may be able to skew the immune response towards a less efficient response, but not necessarily a Th2 allergic immune response. However, we also observed that the C. gattii strains tested varied in virulence, indicating that their ability to limit protective inflammation is not the only factor involved in their pathogenicity. Overall, these results provide important new insights into the virulence of Cryptococcus species; this information may be useful in understanding the outbreak of C. gattii infections that is occurring in British Columbia.

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