Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus

ABSTRACTFungal infections of the central nervous system are associated with high mortality and limited treatment options due to the poor permeability of the blood brain barrier to most antifungal drugs. The most common pathogenic mold is Aspergillus fumigatus, which typically causes invasive pulmona...

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Main Authors: Martin T. Kelty, Sarah R. Beattie
Format: Article
Language:English
Published: American Society for Microbiology 2023-12-01
Series:mSphere
Subjects:
Online Access:https://journals.asm.org/doi/10.1128/msphere.00468-23
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author Martin T. Kelty
Sarah R. Beattie
author_facet Martin T. Kelty
Sarah R. Beattie
author_sort Martin T. Kelty
collection DOAJ
description ABSTRACTFungal infections of the central nervous system are associated with high mortality and limited treatment options due to the poor permeability of the blood brain barrier to most antifungal drugs. The most common pathogenic mold is Aspergillus fumigatus, which typically causes invasive pulmonary disease that can disseminate to extrapulmonary organs, including the brain, resulting in cerebral aspergillosis (CA). Currently, the best treatment option for CA is antifungal therapy combined with resection of infected tissue; however, mortality rates of these infections still approach 100%. Despite these unacceptably high mortality rates, relatively little is known about the fungal determinants that allow Aspergillus to successfully establish infection and grow within the brain. Here, we present a murine model designed to study the fungal pathogenesis of CA using tail vein inoculation in C5-complement-deficient mice. In this model, mice develop a robust fungal burden in the brain and display hallmarks of invasive aspergillosis seen in both murine models of invasive aspergillosis and in human cases of CA. We highlight the role of one fungal transcription factor, PacC, in the hematogenous dissemination of A. fumigatus to extrapulmonary organs including the brain. This model will enable pathogenesis studies in a largely unexplored area of A. fumigatus infections with the goal of identifying novel targets and pathways for the development of more efficacious antifungal therapies to treat these infections.IMPORTANCEMolds are environmental fungi that can cause disease in immunocompromised individuals. The most common pathogenic mold is Aspergillus fumigatus, which is typically inhaled into the lungs and causes invasive pulmonary disease. In a subset of these patients, this infection can spread from the lungs to other organs including the brain, resulting in cerebral aspergillosis. How A. fumigatus causes brain disease is not well understood and these infections are associated with extremely high mortality rates. Thus, we developed an animal model to study the pathogenesis of cerebral aspergillosis to better understand this disease and develop better treatments for these life-threatening infections.
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spelling doaj.art-474ca213a0f741b0bd92fa779a37cfce2023-12-20T14:01:03ZengAmerican Society for MicrobiologymSphere2379-50422023-12-018610.1128/msphere.00468-23Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatusMartin T. Kelty0Sarah R. Beattie1Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USADepartment of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAABSTRACTFungal infections of the central nervous system are associated with high mortality and limited treatment options due to the poor permeability of the blood brain barrier to most antifungal drugs. The most common pathogenic mold is Aspergillus fumigatus, which typically causes invasive pulmonary disease that can disseminate to extrapulmonary organs, including the brain, resulting in cerebral aspergillosis (CA). Currently, the best treatment option for CA is antifungal therapy combined with resection of infected tissue; however, mortality rates of these infections still approach 100%. Despite these unacceptably high mortality rates, relatively little is known about the fungal determinants that allow Aspergillus to successfully establish infection and grow within the brain. Here, we present a murine model designed to study the fungal pathogenesis of CA using tail vein inoculation in C5-complement-deficient mice. In this model, mice develop a robust fungal burden in the brain and display hallmarks of invasive aspergillosis seen in both murine models of invasive aspergillosis and in human cases of CA. We highlight the role of one fungal transcription factor, PacC, in the hematogenous dissemination of A. fumigatus to extrapulmonary organs including the brain. This model will enable pathogenesis studies in a largely unexplored area of A. fumigatus infections with the goal of identifying novel targets and pathways for the development of more efficacious antifungal therapies to treat these infections.IMPORTANCEMolds are environmental fungi that can cause disease in immunocompromised individuals. The most common pathogenic mold is Aspergillus fumigatus, which is typically inhaled into the lungs and causes invasive pulmonary disease. In a subset of these patients, this infection can spread from the lungs to other organs including the brain, resulting in cerebral aspergillosis. How A. fumigatus causes brain disease is not well understood and these infections are associated with extremely high mortality rates. Thus, we developed an animal model to study the pathogenesis of cerebral aspergillosis to better understand this disease and develop better treatments for these life-threatening infections.https://journals.asm.org/doi/10.1128/msphere.00468-23fungal infectioncentral nervous system infectionsAspergillus
spellingShingle Martin T. Kelty
Sarah R. Beattie
Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus
mSphere
fungal infection
central nervous system infections
Aspergillus
title Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus
title_full Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus
title_fullStr Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus
title_full_unstemmed Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus
title_short Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus
title_sort development of a murine model to study the cerebral pathogenesis of aspergillus fumigatus
topic fungal infection
central nervous system infections
Aspergillus
url https://journals.asm.org/doi/10.1128/msphere.00468-23
work_keys_str_mv AT martintkelty developmentofamurinemodeltostudythecerebralpathogenesisofaspergillusfumigatus
AT sarahrbeattie developmentofamurinemodeltostudythecerebralpathogenesisofaspergillusfumigatus