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The primary target organ of Cryptococcus gattii is different from that of Cryptococcus neoformans in a murine model.
mBio. 2012; 3(3)MBIO

Abstract

Cryptococcosis is caused by the opportunistic pathogen Cryptococcus neoformans or by the primary pathogen Cryptococcus gattii. Epidemiological studies suggest that patients infected with C. gattii mainly present with pulmonary disease, while those infected with C. neoformans commonly manifest meningoencephalitis. We compared the pathogenesis of the two species using the C. neoformans H99 and C. gattii R265 strains in a murine inhalation model. C. neoformans grew faster in the brain and caused death by meningoencephalitis, while C. gattii grew faster in the lungs and caused death without producing fulminating meningoencephalitis. Despite the consistent failure to recover R265 cells from blood, a fraction of the R265 population was detected in the extrapulmonary organs, including the brain. Upon intravenous (i.v.) inoculation of 10(4) cells via the tail vein, however, C. gattii produced severe meningoencephalitis, demonstrating that C. gattii cells can efficiently cross the blood-brain barrier. Interestingly, i.v. inoculation with five cells caused brain infection in only 10% of C. gattii-infected mice, compared to 60% of mice infected with C. neoformans. In mice that had been initially inoculated via the pulmonary route and subsequently challenged intravenously, a protective effect was observed only in mice infected with C. gattii. C. neoformans cells grew 10 to 100 times faster than C. gattii cells in blood or serum collected from naive mice. The paucity of meningoencephalitis upon inhalation of C. gattii, therefore, may be partly due to an unknown factor(s) in the host's blood coupled with immune protection that reduces dissemination to the brain and fosters lung infection.

IMPORTANCE

While Cryptococcus neoformans is the most common cause of fatal meningoencephalitis, especially in HIV patients, Cryptococcus gattii causes disease mainly in non-HIV patients. Clinical studies revealed that most patients infected with C. gattii VGII strains have lung infections with minimal brain involvement. Despite extensive clinicopathological studies on cryptococcosis in animal models, only a few have included C. gattii. We compared the pathogenesis of the two species in mice using an inhalation model. Similar to infection in humans, even though C. gattii can cross the blood-brain barrier, it failed to cause fatal meningoencephalitis but caused fatal lung infection. We show that growth of C. gattii in mouse blood is significantly slower than that of C. neoformans and that a secondary protective phenomenon, though weak, manifests itself only in C. gattii infection. Our study provides a model for understanding the clinicopathological differences between these two closely genetically related pathogens.

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Authors+Show Affiliations

Ngamskulrungroj P
Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
Chang Y
No affiliation info available
Sionov E
No affiliation info available
Kwon-Chung KJ
No affiliation info available

MeSH

AnimalsBlood-Brain BarrierBrainCryptococcosisCryptococcus gattiiCryptococcus neoformansDisease Models, AnimalLungMaleMiceMice, Inbred BALB CMice, Inbred C57BLOrgan Specificity

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

22570277

Citation

Ngamskulrungroj, Popchai, et al. "The Primary Target Organ of Cryptococcus Gattii Is Different From That of Cryptococcus Neoformans in a Murine Model." MBio, vol. 3, no. 3, 2012.
Ngamskulrungroj P, Chang Y, Sionov E, et al. The primary target organ of Cryptococcus gattii is different from that of Cryptococcus neoformans in a murine model. mBio. 2012;3(3).
Ngamskulrungroj, P., Chang, Y., Sionov, E., & Kwon-Chung, K. J. (2012). The primary target organ of Cryptococcus gattii is different from that of Cryptococcus neoformans in a murine model. MBio, 3(3). https://doi.org/10.1128/mBio.00103-12
Ngamskulrungroj P, et al. The Primary Target Organ of Cryptococcus Gattii Is Different From That of Cryptococcus Neoformans in a Murine Model. mBio. 2012;3(3) PubMed PMID: 22570277.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The primary target organ of Cryptococcus gattii is different from that of Cryptococcus neoformans in a murine model. AU - Ngamskulrungroj,Popchai, AU - Chang,Yun, AU - Sionov,Edward, AU - Kwon-Chung,Kyung J, Y1 - 2012/05/08/ PY - 2012/5/10/entrez PY - 2012/5/10/pubmed PY - 2012/8/21/medline JF - mBio JO - mBio VL - 3 IS - 3 N2 - UNLABELLED: Cryptococcosis is caused by the opportunistic pathogen Cryptococcus neoformans or by the primary pathogen Cryptococcus gattii. Epidemiological studies suggest that patients infected with C. gattii mainly present with pulmonary disease, while those infected with C. neoformans commonly manifest meningoencephalitis. We compared the pathogenesis of the two species using the C. neoformans H99 and C. gattii R265 strains in a murine inhalation model. C. neoformans grew faster in the brain and caused death by meningoencephalitis, while C. gattii grew faster in the lungs and caused death without producing fulminating meningoencephalitis. Despite the consistent failure to recover R265 cells from blood, a fraction of the R265 population was detected in the extrapulmonary organs, including the brain. Upon intravenous (i.v.) inoculation of 10(4) cells via the tail vein, however, C. gattii produced severe meningoencephalitis, demonstrating that C. gattii cells can efficiently cross the blood-brain barrier. Interestingly, i.v. inoculation with five cells caused brain infection in only 10% of C. gattii-infected mice, compared to 60% of mice infected with C. neoformans. In mice that had been initially inoculated via the pulmonary route and subsequently challenged intravenously, a protective effect was observed only in mice infected with C. gattii. C. neoformans cells grew 10 to 100 times faster than C. gattii cells in blood or serum collected from naive mice. The paucity of meningoencephalitis upon inhalation of C. gattii, therefore, may be partly due to an unknown factor(s) in the host's blood coupled with immune protection that reduces dissemination to the brain and fosters lung infection. IMPORTANCE: While Cryptococcus neoformans is the most common cause of fatal meningoencephalitis, especially in HIV patients, Cryptococcus gattii causes disease mainly in non-HIV patients. Clinical studies revealed that most patients infected with C. gattii VGII strains have lung infections with minimal brain involvement. Despite extensive clinicopathological studies on cryptococcosis in animal models, only a few have included C. gattii. We compared the pathogenesis of the two species in mice using an inhalation model. Similar to infection in humans, even though C. gattii can cross the blood-brain barrier, it failed to cause fatal meningoencephalitis but caused fatal lung infection. We show that growth of C. gattii in mouse blood is significantly slower than that of C. neoformans and that a secondary protective phenomenon, though weak, manifests itself only in C. gattii infection. Our study provides a model for understanding the clinicopathological differences between these two closely genetically related pathogens. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/22570277/The_primary_target_organ_of_Cryptococcus_gattii_is_different_from_that_of_Cryptococcus_neoformans_in_a_murine_model_ L2 - https://doi.org/10.1128/mBio.00103-12 DB - PRIME DP - Unbound Medicine ER -