f Cryptococcal infections are primarily caused by two related fungal species: Cryptococcus neoformans and Cryptococcus gattii. It is well known that C. neoformans generally affects immunocompromised hosts; however, C. gattii infection can cause diseases in not only immunocompromised hosts but also immunocompetent individuals. While recent studies suggest that C. gattii infection could dampen pulmonary neutrophil recruitment and inflammatory cytokine production in immunocompetent hosts, the impact of C. gattii infection on the development of their adaptive T helper cell immune response has not been addressed. Here, we report that C. neoformans infection with highly virulent and less virulent strains preferentially induced pulmonary Th1 and Th17 immune responses in the host, respectively. However, fewer pulmonary Th1 and Th17 cells could be detected in mice infected with C. gattii strains. Notably, dendritic cells (DC) in mice infected with C. gattii expressed much lower levels of surface MHC-II and Il12 or Il23 transcripts and failed to induce effective Th1 and Th17 differentiation in vitro. Furthermore, the expression levels of Ip10 and Cxcl9 transcripts, encoding Th1-attracting chemokines, were significantly reduced in the lungs of mice infected with the highly virulent C. gattii strain. Thus, our data suggest that C. gattii infection dampens the DC-mediated effective Th1/Th17 immune responses and downregulates the pulmonary chemokine expression, thus resulting in the inability to mount protective immunity in immunocompetent hosts.
SummaryMatrix metalloproteinases (MMPs) are a family of extracellular proteases that play roles in regulating the immune response in inflammatory processes. Previous studies indicated that different MMPs were involved in the host defence and tissue damage in response to different pathogens. However, the contributions of MMPs during Cryptococcus infection have not been addressed clearly. Here, we examined the expression and activity of MMPs during Cryptococcus infection. Among MMP family members, we found significant increases of MMP-3 and MMP-12 mRNA levels and MMP12 zymographic activities in response to C. neoformans but not C. gattii infection. The expression of MMP12 was induced in RAW cells after C. neoformans treatment and in alveolar macrophages purified from C. neoformans-infected mice. Interestingly, administration of MMP inhibitor GM6001 into C. neoformans-infected mice resulted in a significantly increased pulmonary fungal burden with attenuated inflammatory cell infiltration. Corresponding to this finding, the expression of the macrophage-and neutrophil-attracting chemokines CCL2 and CXCL1 was inhibited in the GM6001-treated group and MMP12 levels were found to be correlated strongly with CCL2 mRNA expression. Thus, our data suggest that the induction of MMPs by C. neoformans infection potentiates inflammatory cell infiltration by modulating pulmonary chemokines, thereby promoting effective host immunity to pulmonary Cryptococcus infection.
Cryptococcal infections are caused mainly by two fungal species; Cryptococcus neoformans and C. gattii. While C. neoformans primarily affects the immunocompromised hosts, C. gattii causes disease in immunocompetent individuals. Recent studies suggest that C. gattii is capable of infecting immunocompetent hosts because of its ability in dampening inflammatory cell recruitments. We hypothesizes that C. gattii dampens pulmonary inflammation by attenuating chemokine expression. Mice were infected with the highly virulent strains C. neoformans and C. gattii and then analyzed for kinetics of inflammatory cell infiltration and chemokine expression. Inflammatory cells and chemokine transcripts were found to be up-regulated and reached the peak levels at day 7 post-infection. Mice infected with C. gattii recruited much fewer myeloid dendritic cells, neutrophils, and CD4+ T helper cells into the lungs than those in C. neoformans-infected mice. Interestingly, the expression levels of Cxcl1, Cxcl2, Mcp1, Cxcl9, and Ip10 transcripts known to be important for recruiting neutrophil and Th1 cells were significantly higher in C. neoformans-infected mice than in C. gattii-infected mice, whereas the expression levels of Ccl20, Ccl11 and Ccl17 were comparable. Our data suggest that C. gattii infection dampens pulmonary inflammation by down-regulating the pulmonary chemokine expression, thus resulting in the inability to mount protective immunity in immunocompetent hosts.
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