Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans

ABSTRACT Cryptococcosis is a multifaceted fungal infection with variable clinical presentation and outcome. As in many infectious diseases, this variability is commonly assigned to host factors. To investigate whether the diversity of Cryptococcus neoformans clinical (ClinCn) isolates influences the...

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Autores principales:	Alexandre Alanio, Marie Desnos-Ollivier, Françoise Dromer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2011
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/edbd4b272ec4470bbd2412b219057ec4
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spelling	oai:doaj.org-article:edbd4b272ec4470bbd2412b219057ec42021-11-15T15:38:45ZDynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans10.1128/mBio.00158-112150-7511https://doaj.org/article/edbd4b272ec4470bbd2412b219057ec42011-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00158-11https://doaj.org/toc/2150-7511ABSTRACT Cryptococcosis is a multifaceted fungal infection with variable clinical presentation and outcome. As in many infectious diseases, this variability is commonly assigned to host factors. To investigate whether the diversity of Cryptococcus neoformans clinical (ClinCn) isolates influences the interaction with host cells and the clinical outcome, we developed and validated new quantitative assays using flow cytometry and J774 macrophages. The phenotype of ClinCn-macrophage interactions was determined for 54 ClinCn isolates recovered from cerebrospinal fluids (CSF) from 54 unrelated patients, based on phagocytic index (PI) and 2-h and 48-h intracellular proliferation indexes (IPH2 and IPH48, respectively). Their phenotypes were highly variable. Isolates harboring low PI/low IPH2 and high PI/high IPH2 values were associated with nonsterilization of CSF at week 2 and death at month 3, respectively. A subset of 9 ClinCn isolates with different phenotypes exhibited variable virulence in mice and displayed intramacrophagic expression levels of the LAC1, APP1, VAD1, IPC1, PLB1, and COX1 genes that were highly variable among the isolates and correlated with IPH48. Variation in the expression of virulence factors is thus shown here to depend on not only experimental conditions but also fungal background. These results suggest that, in addition to host factors, the patient’s outcome can be related to fungal determinants. Deciphering the molecular events involved in C. neoformans fate inside host cells is crucial for our understanding of cryptococcosis pathogenesis. IMPORTANCE Cryptococcus neoformans is a life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis/year, predominantly in HIV-infected patients. The diversity of infecting isolates is well established, as is the importance of the host factors. Interaction with macrophages is a major step in cryptococcosis pathogenesis. How the diversity of clinical isolates influences macrophages’ interactions and impacts cryptococcosis outcome in humans remains to be elucidated. Using new assays, we uncovered how yeast-macrophage interactions were highly variable among clinical isolates and found an association between specific behaviors and cryptococcosis outcome. In addition, gene expression of some virulence factors and intracellular proliferation were correlated. While many studies have established that virulence factors can be differentially expressed as a function of experimental conditions, our study demonstrates that, under the same experimental conditions, clinical isolates behaved differently, a diversity that could participate in the variable outcome of infection in humans.Alexandre AlanioMarie Desnos-OllivierFrançoise DromerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 2, Iss 4 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Alexandre Alanio Marie Desnos-Ollivier Françoise Dromer Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans
description	ABSTRACT Cryptococcosis is a multifaceted fungal infection with variable clinical presentation and outcome. As in many infectious diseases, this variability is commonly assigned to host factors. To investigate whether the diversity of Cryptococcus neoformans clinical (ClinCn) isolates influences the interaction with host cells and the clinical outcome, we developed and validated new quantitative assays using flow cytometry and J774 macrophages. The phenotype of ClinCn-macrophage interactions was determined for 54 ClinCn isolates recovered from cerebrospinal fluids (CSF) from 54 unrelated patients, based on phagocytic index (PI) and 2-h and 48-h intracellular proliferation indexes (IPH2 and IPH48, respectively). Their phenotypes were highly variable. Isolates harboring low PI/low IPH2 and high PI/high IPH2 values were associated with nonsterilization of CSF at week 2 and death at month 3, respectively. A subset of 9 ClinCn isolates with different phenotypes exhibited variable virulence in mice and displayed intramacrophagic expression levels of the LAC1, APP1, VAD1, IPC1, PLB1, and COX1 genes that were highly variable among the isolates and correlated with IPH48. Variation in the expression of virulence factors is thus shown here to depend on not only experimental conditions but also fungal background. These results suggest that, in addition to host factors, the patient’s outcome can be related to fungal determinants. Deciphering the molecular events involved in C. neoformans fate inside host cells is crucial for our understanding of cryptococcosis pathogenesis. IMPORTANCE Cryptococcus neoformans is a life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis/year, predominantly in HIV-infected patients. The diversity of infecting isolates is well established, as is the importance of the host factors. Interaction with macrophages is a major step in cryptococcosis pathogenesis. How the diversity of clinical isolates influences macrophages’ interactions and impacts cryptococcosis outcome in humans remains to be elucidated. Using new assays, we uncovered how yeast-macrophage interactions were highly variable among clinical isolates and found an association between specific behaviors and cryptococcosis outcome. In addition, gene expression of some virulence factors and intracellular proliferation were correlated. While many studies have established that virulence factors can be differentially expressed as a function of experimental conditions, our study demonstrates that, under the same experimental conditions, clinical isolates behaved differently, a diversity that could participate in the variable outcome of infection in humans.
format	article
author	Alexandre Alanio Marie Desnos-Ollivier Françoise Dromer
author_facet	Alexandre Alanio Marie Desnos-Ollivier Françoise Dromer
author_sort	Alexandre Alanio
title	Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans
title_short	Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans
title_full	Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans
title_fullStr	Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans
title_full_unstemmed	Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans
title_sort	dynamics of <named-content content-type="genus-species">cryptococcus neoformans</named-content>-macrophage interactions reveal that fungal background influences outcome during cryptococcal meningoencephalitis in humans
publisher	American Society for Microbiology
publishDate	2011
url	https://doaj.org/article/edbd4b272ec4470bbd2412b219057ec4
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Dynamics of <named-content content-type="genus-species">Cryptococcus neoformans</named-content>-Macrophage Interactions Reveal that Fungal Background Influences Outcome during Cryptococcal Meningoencephalitis in Humans

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