Pathogenesis of CerebralCryptococcus neoformansInfection after Fungemia

Abstract

The pathogenesis of cerebral infection after Cryptococcus neoformans fungemia in outbred mice was investigated. Confocal microscopy and cultures on ficoll-hypaque gradient-separated blood cells were used to detect yeasts in the cytoplasms of monocytes. In semithin brain sections, poorly capsulated yeasts were seen in macrophages in the leptomeningeal space, in monocytes circulating in leptomeningeal capillaries, or in the endothelial cells themselves, strengthening the hypothesis that monocytes and endothelial cells play key roles in the pathogenesis of cryptococcal meningitis. Similar fungal loads and cellular reactions were seen in mice and in 1 patient with acquired immune deficiency syndrome (AIDS), all with acute cryptococcal meningoencephalitis, and in mice and in 1 patient with AIDS, all with cured cryptococcal infection. Immunostaining revealed both the presence of cryptococcal polysaccharide in various brain cells and antigenic variability both from yeast cell to yeast cell and over time. Thus, our data established the relevance and interest that this experimental model has for investigation of the pathogenesis of human cryptococcal meningitis.

Capsule Structure Changes Associated with Cryptococcus neoformans Crossing of the Blood-Brain Barrier

“…This strain of mice was selected for its individual susceptibility to C. neoformans infection in previous studies showing the clinical relevance of this murine model. 10,18 Mice were housed 7 to 8 per cage in our animal facilities and received food and water ad libitum. This study was conducted in accordance with the EC guidelines for animal care [Journal Officiel des Communuté s Europé ennes, L358, December 18, 1986].…”

“…Fungemia is a bad prognosis factor during cryptococcosis in both HIV-infected and -non-infected patients 8,9 and is almost certainly a requirement for fungal dissemination and crossing of the blood-brain barrier (BBB). 10,11 Very little is known about the sequential events leading to disseminated meningoencephalitis, the major clinical presentation and cause of death during cryptococcosis. For a long time it was generally believed that invasion of the central nervous system (CNS) followed seeding of the leptomeninges and growth of "microcysts" along the perivascular Virchow-Robin spaces.…”

“…In particular, we were interested in knowing whether phenotypic changes would be associated with tissue invasion in a relevant model of murine disseminated cryptococcal meningoencephalitis. 10,18 …”

The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation

“…Moreover, many pathogens use the host cell as a nutrient source to support rapid replication, thus acting as genuine intracellular parasites (1,2). The human fungal pathogen Cryptococcus is an intracellular parasite of macrophages (3,4) and is believed to exploit these host cells to traffic from the lung, the primary site of infection, into the central nervous system (5,6).…”

Host Cell Invasion by Medically Important Fungi

“…The capacity of C. neoformans to directly invade the endothelial cell lining of cerebral blood vessels in vivo has been shown by experiments in which live organisms were injected intravenously into mice. Studies in which the infected brains were examined by histopathology showed the presence of C. neoformans cells either within or between the cerebral endothelial cells, indicating that the organism was crossing the blood -brain barrier by either a transcellular or paracellular route (Chretien et al 2002;Chang et al 2004). Using intravital imaging of live mice that had been injected with fluorescently labeled C. neoformans, it was observed that, although both live and killed organisms lodged in the cerebral capillaries, only live organisms were able to traverse endothelial cells and invade the brain ).…”