Goldman D L, Casadevall A, Cho Y, Lee S C
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
Lab Invest. 1996 Dec;75(6):759-70.
The primary clinical manifestation of Cryptococcus neoformans infection in humans is meningoencephalitis. To study the defense mechanisms that participate in the host response against C. neoformans infection of the central nervous system (CNS), we have developed a new model of cryptococcal meningitis in rats. Intracisternal inoculation of C. neoformans produced a granulomatous meningitis with minimal brain parenchymal involvement, resembling cryptococcal meningitis in immunocompetent patients. The granulomas were composed of T cells (CD4+ and CD8+) and macrophages (CD11b/c+); a subpopulation of the macrophages expressed inducible nitric oxide synthase (NOS2). In this model, C. neoformans disseminated to systemic organs early in the course of infection and provoked granuloma formation and NOS2 expression. The temporal profile of inflammation indicated that the CNS inflammatory response is delayed relative to that in the lung and the spleen, which suggests that the effective inflammatory response within the CNS may follow activation of T cells in the periphery and their subsequent entry into the CNS. Inflammation in the meninges was associated with signs of subpial and subependymal glial activation, including enhanced expression of CD11b/c and CD4 in microglia and glial fibrillary acidic protein in astrocytes. Neither cells, however, expressed NOS2. Although C. neoformans invasion to the brain parenchyma was rare, soluble polysaccharide was commonly associated with reactive glial cells. Necrosis was not a feature of C. neoformans granulomas, but, instead, inflammatory cells underwent apoptosis in inflamed organs. The current rat intrathecal cryptococcosis model has several unique advantages for the study of human cryptococcal meningoencephalitis that include close resemblance of histopathologic changes to those in humans, easy accessibility to the cerebrospinal fluid compartment, and no requirement of immunosuppressive agents for establishment of infection.
新型隐球菌感染人类的主要临床表现是脑膜脑炎。为了研究参与宿主对抗中枢神经系统（CNS）新型隐球菌感染反应的防御机制，我们建立了一种新的大鼠隐球菌性脑膜炎模型。脑池内接种新型隐球菌可引起肉芽肿性脑膜炎，脑实质受累最小，类似于免疫功能正常患者的隐球菌性脑膜炎。肉芽肿由T细胞（CD4 +和CD8 +）和巨噬细胞（CD11b / c +）组成；巨噬细胞亚群表达诱导型一氧化氮合酶（NOS2）。在该模型中，新型隐球菌在感染过程早期扩散至全身器官，并引发肉芽肿形成和NOS2表达。炎症的时间特征表明，CNS炎症反应相对于肺和脾的炎症反应延迟，这表明CNS内有效的炎症反应可能在T细胞在外周激活并随后进入CNS之后发生。脑膜炎症与软脑膜和室管膜下神经胶质激活的迹象有关，包括小胶质细胞中CD11b / c和CD4表达增强以及星形胶质细胞中胶质纤维酸性蛋白表达增强。然而，这两种细胞均不表达NOS2。尽管新型隐球菌侵袭脑实质很少见，但可溶性多糖通常与反应性神经胶质细胞有关。坏死不是新型隐球菌肉芽肿的特征，相反，炎症细胞在发炎器官中发生凋亡。当前的大鼠鞘内隐球菌病模型对于研究人类隐球菌性脑膜脑炎具有几个独特的优势，包括组织病理学变化与人类相似、易于进入脑脊液腔室以及建立感染无需免疫抑制剂。
