Cryptococci at the brain gate: break and enter or use a Trojan horse?

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Published in Volume 120, Issue 5 (May 3, 2010)

J Clin Invest. 2010;120(5):1389–1392. doi:10.1172/JCI42949.

American Society for Clinical Investigation

http://www.jci.org/articles/view/42949?key=6e99cf49f7699acede3e

Commentary

Cryptococci at the brain gate: break and enter or use a Trojan horse?

Arturo Casadevall

Department of Microbiology and Immunology and Medicine, Albert Einstein College

of Medicine, New York, New York, USA.

Address correspondence to: Arturo Casadevall, Department of Microbiology and

Immunology, 1300 Park Ave., Bronx, New York 10461, USA. Phone:

718.430.3665; Fax: 718.430.8711; E-mail: Arturo.casadevall@....

First published April 26, 2010

The mechanism by which Cryptococcus neoformans invades the central nervous

system is fundamental for understanding pathogenesis because cryptococcosis

commonly presents as meningoencephalitis. There is evidence for both direct

invasion of the endothelial cells lining the brain vasculature and a " Trojan

horse " mechanism whereby cryptococci enter the central nervous system after

macrophage ingestion. However, in this issue of the JCI, Shi et al. use

intravital microscopy to reveal that brain invasion by C. neoformans follows a

capillary microembolic event. They find that after suddenly stopping in brain

capillaries, cryptococci cross into the central nervous system in a process that

is urease dependent, requires viability, and involves cellular deformation. This

observation provides evidence for direct brain invasion by C. neoformans, but a

consideration of all the currently available evidence suggests a role for both

direct and phagocyte-associated invasion. Hence, the remarkable neurotropism of

C. neoformans may have more than one mechanism.

See the related article beginning on page 1683.

Cryptococcus neoformans is a soil-dwelling fungus that emerged in the late

twentieth century as a major human pathogen because of its propensity to cause

lethal meningoencephalitis. The burden of cryptococcosis is estimated to

approach one million cases per year, with a mortality that exceeds that from

tuberculosis (1). C. neoformans is acquired by inhalation of dehydrated cells or

spores (2). Serologic surveys indicate a high prevalence of human infection,

which is likely to be first acquired in childhood (3). Although infection is

common, disease is rare, and cryptococcosis occurs primarily in hosts with

impaired immunity, such as patients with AIDS, organ transplant recipients, and

those treated with immunosuppressive therapies (2). Hence, normal immune

responses are believed to control infection in the lung. Extrapulmonary

dissemination is therefore invariably associated with disease, with

meningoencephalitis being the most common clinical presentation of

cryptococcosis. To cause meningoencephalitis, C. neoformans must cross several

epithelial and/or endothelial cell layers, first to leave the lung and then to

reach the brain. How does a soil-dwelling organism that has no need for animal

pathogenesis for survival such as C. neoformans reach the brain to cause

meningoencephalitis? In this issue of the JCI, Shi et al. (4) shed new light on

this subject by applying the technique of intravital microscopy to visualize in

mice the process of brain invasion by C. neoformans.

Current views of brain invasion

Although the predisposition of C. neoformans to cause meningoencephalitis has

been known for more than a century, the mechanism by which fungal cells invade

the central nervous system has remained elusive. In recent years, two competing

hypotheses have been proposed for brain invasion (Figure 1). The first mechanism

posits a " Trojan horse " approach, whereby fungal cells gain access to the brain

by transport in phagocytic cells......