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

Abstract

Macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3 prevents the development of eosinophilic pneumonia (EP) driven by a nonprotective T2-type immunity during infection with a highly virulent strain of Cryptococcus neoformans. The present study evaluated the interaction of MIP-1alpha with other innate immune system cytokines by comparing the immune responses that followed pulmonary infections with high- (C. neoformans 145A) and low (C. neoformans 52D)-virulence strains. In contrast to what was found for C. neoformans 145A infection, lack of MIP-1alpha in C. neoformans 52D infection did not cause the development of EP. C. neoformans 52D induced tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma), and MCP-1 in the lungs of infected wild-type (WT) and MIP-1alpha knockout (KO) mice by day 7 postinfection. Both WT and MIP-1alpha KO mice subsequently cleared this infection. Thus, the robust expression of early inflammatory cytokines in C. neoformans 52D-infected mice promoted the development of protective immunity even in the absence of MIP-1alpha. Alternatively, C. neoformans 145A-infected WT and MIP-1alpha KO mice had diminished TNF-alpha, IFN-gamma, and macrophage chemoattractant protein 1 (MCP-1) responses, indicating that virulent C. neoformans 145A evaded early innate host defenses. However C. neoformans 145A-infected WT mice had an early induction of MIP-1alpha and subsequently did not develop EP. In contrast, C. neoformans 145A-infected MIP-1alpha KO mice developed EP and had increased C. neoformans dissemination into the brain by day 35. We conclude that, in the absence of other innate immune response effector molecules, MIP-1alpha is crucial to prevent the development of EP and to control C. neoformans dissemination to the brain.

• Authors: M A Olszewski, G B Huffnagle, T R Traynor, R A McDonald, D N Cook, G B Toews
• Journal: Infection and immunity (Infect Immun) Vol. 69 Issue 10 Pg. 6256-63 (Oct 2001) ISSN: 0019-9567 [Print] United States
• PMID: 11553568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chemokine CCL2
• Chemokine CCL3
• Chemokine CCL4
• Macrophage Inflammatory Proteins
• Tumor Necrosis Factor-alpha
• Interferon-gamma

Topics

• Animals
• Brain (immunology, microbiology, pathology)
• Central Nervous System (immunology, microbiology, pathology)
• Chemokine CCL2 (genetics, immunology)
• Chemokine CCL3
• Chemokine CCL4
• Cryptococcosis (immunology, microbiology, pathology)
• Cryptococcus neoformans (growth & development, immunology, pathogenicity)
• Gene Expression
• Gene Expression Profiling
• Interferon-gamma (genetics, immunology)
• Leukocytes (classification, immunology)
• Lung (immunology, microbiology, pathology)
• Macrophage Inflammatory Proteins (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pulmonary Eosinophilia (immunology, microbiology, pathology)
• Tumor Necrosis Factor-alpha (genetics, immunology)
• Virulence