Abstract
Abstract Cryptococcus neoformans is an opportunistic fungal pathogen, and a leading cause of death among HIV-infected individuals. These encapsulated yeast fungi are believed to enter the body through the respiratory tract and initially cause pulmonary infection. If the host immune system fails to contain the fungal cells within the lung, the organism will disseminate to the brain via the bloodstream, consequently resulting in fatal meningoencephalitis. As such, the early interactions between immune cells and C. neoformans in the lung are critical for determining the progression of the disease. CX3CR1 is a chemokine receptor commonly expressed by most myeloid lineage cells. Despite its prevalence though, the role of CX3CR1 during cryptococcal infection has not been fully examined. Here we report that pulmonary infection with C. neoformans enhanced CX3CR1 expression in the lung. Following infection, mice lacking CX3CR1 had significantly higher pulmonary fungal burdens, as well as decreased survival times compared to wild type mice. These infected CX3CR1 knockout mice also displayed higher expression of pro-inflammatory cytokines including MIP-2, MCP-1 and CCL7, but lower expression of anti-inflammatory cytokines such as IL-10. In addition, CX3CR1 deficiency resulted in mice having dramatically enhanced neutrophil accumulation in the lungs following infection. Interestingly, depletion of neutrophils drastically improved lung CFU in infected knockout mice, indicating that excessive inflammation drove fungal growth. Taken together, these data indicate that CX3CR1 expression is essential for host resistance to pulmonary cryptococcal infection by inhibiting excessive lung inflammation.
Published Version
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