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A dissemination-prone morphotype enhances extrapulmonary organ entry by Cryptococcus neoformans.

ABSTRACT: Environmental pathogens move from ecological niches to mammalian hosts, requiring adaptation to dramatically different environments. Microbes that disseminate farther, including the fungal meningitis pathogen Cryptococcus neoformans, require additional adaptation to diverse tissues. We demonstrate that the formation of a small C. neoformans morphotype-called "seed" cells due to their colonizing ability-is critical for extrapulmonary organ entry. Seed cells exhibit changes in fungal cell size and surface expression that result in an enhanced macrophage update. Seed cell formation is triggered by environmental factors, including C. neoformans' environmental niche, and pigeon guano with phosphate plays a central role. Seed cells show the enhanced expression of phosphate acquisition genes, and mutants unable to acquire phosphate fail to adopt the seed cell morphotype. Additionally, phosphate can be released by tissue damage, potentially establishing a feed-forward loop of seed cell formation and dissemination. Thus, C. neoformans' size variation represent inducible morphotypes that change host interactions to facilitate microbe spread.

SUBMITTER: Denham ST

PROVIDER: S-EPMC9588642 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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A dissemination-prone morphotype enhances extrapulmonary organ entry by Cryptococcus neoformans.

Denham Steven T ST Brammer Brianna B Chung Krystal Y KY Wambaugh Morgan A MA Bednarek Joseph M JM Guo Li L Moreau Christian T CT Brown Jessica C S JCS

Cell host & microbe 20220912 10

Environmental pathogens move from ecological niches to mammalian hosts, requiring adaptation to dramatically different environments. Microbes that disseminate farther, including the fungal meningitis pathogen Cryptococcus neoformans, require additional adaptation to diverse tissues. We demonstrate that the formation of a small C. neoformans morphotype-called "seed" cells due to their colonizing ability-is critical for extrapulmonary organ entry. Seed cells exhibit changes in fungal cell size and ...[more]

PMID: 36099922

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Project description: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. 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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A dissemination-prone morphotype enhances extrapulmonary organ entry by Cryptococcus neoformans.

Publications

A dissemination-prone morphotype enhances extrapulmonary organ entry by Cryptococcus neoformans.

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