CRYPTOCOCCUS-NEOFORMANS MENINGITIS IN THE RAT

The primary clinical manifestation of Cryptococcus neoformans infectio n in humans is meningoencephalitis. To study the defense mechanisms th at participate in the host response against C. neoformans infection of the central nervous system (CNS), we have developed a new model of cr yptococcal meningitis in rats. Intracisternal inoculation of C. neofor mans produced a granulomatous meningitis with minimal brain parenchyma l involvement, resembling cryptococcal meningitis in immunocompetent p atients. The granulomas were composed of T cells (CD4(+) and CD8(+)) a nd macrophages (CD11b/c(+)); a subpopulation of the macrophages expres sed inducible nitric oxide synthase (NOS2). In this model, C. neoforma ns disseminated to systemic organs early in the course of infection an d provoked granuloma formation and NOS2 expression. The temporal profi le of inflammation indicated that the CNS inflammatory response is del ayed relative to that in the lung and the spleen, which suggests that the effective inflammatory response within the CNS may follow activati on of T cells in the periphery and their subsequent entry into the CNS . Inflammation in the meninges was associated with signs of subpial an d subependymal glial activation, including enhanced expression of CD11 b/c and CD4 in microglia and glial fibrillary acidic protein in astroc ytes. Neither cells, however, expressed NOS2. Although C. neoformans i nvasion to the brain parenchyma was rare, soluble polysaccharide was c ommonly associated with reactive glial cells. Necrosis was not a featu re of C. neoformans granulomas, but, instead, inflammatory cells under went apoptosis in inflamed organs. The current rat intrathecal cryptoc occosis model has several unique advantages for the study of human cry ptococcal meningoencephalitis that include close resemblance of histop athologic changes to those in humans, easy accessibility to the cerebr ospinal fluid compartment, and no requirement of immunosuppressive age nts for establishment of infection.