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Abstract

Cryptococcocal meningoencephalitis is always considered secondary to initial lung infection. Because of the unquestionable evidence of haematogenious spread from the lungs, few publications have reported about other possible primary sites of infection or other routes to the central nervous system. This study was designed to investigate the infiltrative pattern of C. neoformans in immunocompromised mice by treatment with dexamethasone. The infection was performed by nasal instillation (30 mice) or injection into the retro-orbital space (12 mice). From the group infected intranasally, 3 mice presented diffuse invasive fungal colonisation of the mucosa and submucosa. The histologic findings showed infiltrative growth along the periosteum, sometimes surrounded nervous endings of submucosa, invasion along the olfactory nerve and simultaneous meningeal involvement in 2 mice on the 6th and 8th day of infection. All mice infected into the retro-ocular space developed lesions containing numerous cryptococci in the local of the inoculum. Out of the main lesion we observed preferential growth along the perineural spaces with adherence to the perineurium, perivascular spaces and sometimes along aponeurosis. Simultaneous invasion of trigeminal ganglio and trigeminal branches was observed in 4 mice. These morphologic patterns suggest the hypothesis of direct infiltrative invasion of the central nervous system.

Cryptococcus neoforman s rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia

“…We also note that veterinary observations in naturally exposed animals ( 45 , 46 ) show fungal cells posterior (deep) into the upper airways, consistent with our observations in intranasally instilled animals. Similarly, penetration of nasal mucosa after intranasal instillation was reported before ( 44 ), demonstrating cryptococci have the capacity to overcome the first defensive layers in respiratory and olfactory mucosa and posits a tropism for the olfactory mucosa due to an unknown factor in this tissue. There are some anatomical differences between turbinates of animals and humans, a topic which was expertly reviewed by reference 51 ; immunological and/or tissue differences are the poorly characterized ( 52 , 53 ).…”

“…While we and others had previously detected cryptococci in upper airways of mice ( 42 – 44 ), we report for the first time that titan cells are abundant in airway turbinates of mice. Titan cells had been previously observed in nasal cavities of mammals with advanced symptomatic disease: from the necropsied fungal nasal mass of a dog with central nervous system (CNS) disease ( 45 ) and biopsy of nasal granuloma in a cat with localized disease ( 46 ).…”

Intranasal Inoculation of Cryptococcus neoformans in Mice Produces Nasal Infection with Rapid Brain Dissemination

“…In the case of C. neoformans, the possibility of brain dissemination through the nose was investigated previously (35). In mice, yeast cells were observed along the olfactory nerve and the meninges starting at day 3 after intranasal instillation (35).…”

“…neoformans, the possibility of brain dissemination through the nose was investigated previously (35). In mice, yeast cells were observed along the olfactory nerve and the meninges starting at day 3 after intranasal instillation (35). Our study differed from that previous study in that we focused on the earliest stages of infection and found no evidence of an upward movement that would result in invasion of the brain.…”

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…These findings prompted investigations into the possibility of an alternative direct route of CNS entry from the nose. Gomes et al followed the progression of intranasal C. neoformans infection in immunodeficient mice and demonstrated colonization of the olfactory mucosa, invasion along the olfactory nerve, and meningeal involvement (401). In a study of the pathological features of three patients with AIDS and cryptococcal meningitis, C. neoformans was observed in the subarachnoid space around the olfactory tracts and bulbs and in the olfactory nerve fascicles (402).…”