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

Abstract

ABSTRACT Fungal 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. IMPORTANCE Molds 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.