Regulatory effects of macrophage inflammatory protein 1 alpha CCL3 on the development of immunity to Cryptococcus neoformans depend on expression of early inflammatory cytokines

Macrophage inflammatory protein 1 alpha (MIP-1 alpha)/CCL3 prevents the dev elopment of eosinophilic pneumonia (EP) driven by a nonprotective T2-type i mmunity during infection with a highly virulent strain of Cryptococcus neof ormans. The present study evaluated the interaction of MIP-1 alpha with oth er innate immune system cytokines by comparing the immune responses that fo llowed pulmonary infections with high- (C. neoformans 145A) and low (C neof ormans 52D)-virulence strains. In contrast to what was found for C neoforma ns 145A infection, lack of MIP-1 alpha in C. neoformans 52D infection did n ot cause the development of EP. C. neoformans 52D induced tumor necrosis fa ctor alpha (TNF-alpha), gamma interferon (IFN-gamma), and MCP-1 in the lung s of infected wild-type (WT) and MIP-1 alpha knockout (KO) mice by day 7 po stinfection. Both WT and MIP-1 alpha KO mice subsequently cleared this infe ction. Thus, the robust expression of early inflammatory cytokines in C. ne oformans 52D. infected mice promoted the development of protective immunity even in the absence of MIP-1 alpha. Alternatively, C. neoformans 145A-infe cted WT and MIP-1 alpha KO mice had diminished TNF-alpha, IFN-gamma, and ma crophage chemoattractant protein 1 (MCP-1) responses, indicating that virul ent C. neoformans 145A evaded early innate host defenses. However C. neofor mans 145A-infected WT mice had an early induction of MIP-1 alpha and subseq uently did not develop EP. In contrast, C. neoformans 145A-infected MIP-1 a lpha KO mice developed EP and had increased C. neoformans dissemination int o the brain by day 35. We conclude that, in the absence of other innate imm une response effector molecules, MIP-1 alpha is crucial to prevent the deve lopment of EP and to control C. neoformans dissemination to the brain.