Macrophage activation during experimental pulmonary cryptococcosis




Hardison, Sarah

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C. neoformans, the etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects immunocompromised individuals. Macrophages are the first line of defense during cryptococcal infection, and it has been demonstrated that different phenotypes of activated macrophages contribute to different outcomes of C. neoformans infections, classically activated (caMac) being associated with protection and alternatively activated (aaMac) being associated with pathology. Previous studies in our lab have demonstrated that immunization with a C. neoformans strain that expresses murine interferon-gamma, denoted H99gamma, induces complete protection against a challenge infection with the wild-type C. neoformans strain H99. The present studies seek to determine the activation phenotype of macrophages that respond to infection with H99gamma as well as during challenge infection in H99gamma-immunized mice. Furthermore, we seek to define the role of IL-17A in the induction of macrophage phenotype and protection against infection. We demonstrate caMac in lung tissue sections and purified macrophage populations during H99gamma infection as well as during infection in immune mice. Conversely, we observed robust expression of markers of aaMac during infection with H99. IL-17A was found not to play a role in caMac activation, as IL-17A neutralization did not alter the induction of the phenotype. Furthermore, a series of real-time PCR arrays demonstrated increased expression of genes in the STAT-1 signal transduction cascade in purified macrophage populations from H99gamma-immunized mice. Therefore, we conclude that caMac are elicited during the protective immune response to cryptococcosis in mice immunized with H99gamma, and that caMac are likely elicited via STAT-1 signaling.


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Integrative Biology