Pathogenesis of pulmonary Cryptococcus gattii infection: a rat model
Mark B Krockenberger1, Richard Malik, Popchai Ngamskulrungroj
1Faculty of Veterinary Science, Building B14, University of Sydney, Sydney, NSW, 2006, Australia.
Abstract:
A model of pulmonary cryptococcosis in immunocompetent rats was developed to better understand the virulence of Cryptococcus gattii. Six isolates were studied, representing four molecular genotypes (VGI-MATα, VGIIa-MATα, VGIIa-MAT a, VGIIb-MATα), obtained from Australia, Vancouver (Canada) and Colombia. These originated from human patients, a cat and the environment and were administered intratracheally (i.t.) or transthoracically into Fischer 344 or Wistar-Furth rats in doses varying from 10(4) to 10(7) colony-forming units (CFU) in 0.1 ml of saline. With the exception of animals given the VGIIa-MAT a isolate, rats consistently became ill or died of progressive cryptococcal pneumonia following i.t. doses exceeding 10(7) CFU. Affected lungs increased in weight up to tenfold and contained numerous circumscribed, gelatinous lesions. These became larger and more extensive, progressing from limited hilar and/or tracheal lesions, to virtually confluent gelatinous masses. Disease was localized to the lungs for at least 3-4 weeks, with dissemination to the brain occurring in some animals after day 29. The dose-response relationship was steep for two VGI isolates studied (human WM179, environmental WM276); doses up to 10(6) CFU i.t. did not produce lesions, while 10(7) or more yeast cells produced progressive pneumonia. Intratracheal inoculation of rats with C. gattii provides an excellent model of human pulmonary cryptococcosis in healthy hosts, mimicking natural infections. Disease produced by C. gattii in rats is distinct from that caused by C. neoformans in that infections are progressive and ultimately fatal.
Insights
A new rat model for pulmonary cryptococcosis using Cryptococcus gattii shows disease progression and fatality. This model mimics human infections in healthy hosts, aiding virulence studies.
Area of Science:
- Mycology
- Infectious Diseases
- Animal Models
Background:
- Cryptococcus gattii causes pulmonary cryptococcosis, a serious infection.
- Understanding C. gattii virulence is crucial for effective treatment.
- Existing models may not fully represent human infections in immunocompetent individuals.
Purpose of the Study:
- To develop and characterize a novel rat model for pulmonary cryptococcosis.
- To investigate the virulence of different Cryptococcus gattii genotypes.
- To establish a reproducible model for studying C. gattii pathogenesis.
Main Methods:
- Intratracheal inoculation of Fischer 344 or Wistar-Furth rats with C. gattii isolates.
- Use of six C. gattii isolates from diverse genotypes (VGI, VGII) and origins.
- Dose-ranging studies from 10(4) to 10(7) colony-forming units (CFU).
Main Results:
- Rats developed progressive pulmonary cryptococcosis and mortality with C. gattii doses >10(7) CFU.
- Lung lesions increased up to tenfold in weight, showing gelatinous masses.
- Disease remained localized to lungs for 3-4 weeks; brain dissemination occurred post-day 29.
Conclusions:
- Intratracheal inoculation of rats with C. gattii provides an excellent model for human pulmonary cryptococcosis in healthy hosts.
- The model effectively mimics natural C. gattii infections.
- C. gattii-induced disease in rats is progressive and fatal, distinct from C. neoformans infections.
