An experimental animal model of cerebral aspergillosis

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Sullivan, Brianne, Baggett, Mia A., Guillory, Christa, Jones, Mary Jane, Steele, Claude
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R3574

Invasive pulmonary aspergillosis (IPA), a leading cause of death in immunosuppressed patients, is an infection most often attributed to the opportunistic fungi Aspergillus fumigatus (AF). The most common site of primary infection with this invasive disease is the lung, and the most prevalent site of secondary infection following hematological dissemination is the central nervous system (CNS). Dissemination of AF to the CNS, termed cerebral aspergillosis (CA), occurs in up to 40% of immunocompromised patients with IPA and has a mortality rate approaching 90%. While the experimental murine model of IPA and the resulting immune response have been extensively characterized, the current models available for CA are inconsistent and physiologically irrelevant. The lack of relevant models results in a considerable gap in knowledge for the neurological pathogenicity of infection. To address this gap, we infected wild‐type male and female C57BL/6 immunocompetent, or immunosuppressed (via high‐dose corticosteroid) mice using a one‐ (intranasal) or two‐hit (intranasal plus intravenous) method of inoculation with AF. Following immunosuppression and infection, mice were monitored for severe weight loss (>20%), neurological symptoms (e.g., altered‐gate, severe head‐tilt, and/or spinning in cage), and mortality daily for 10 days. At day 4 post‐inoculation, both brain and lung were assessed for fungal burden, and the immunological response to AF was evaluated in the brain. We observed significant weight loss, worse disease severity, and increased fungal burden in the brain in immunosuppressed mice infected via the two‐hit method. Further, in these mice, we found a significant disruption in cytokine and chemokine response in the brain as well as immune cell trafficking to the brain. In conclusion, we have developed a well‐defined, physiologically relevant, model of disseminated CA in immunosuppressed mice with primary pulmonary infection. This model will serve to advance understanding of the disease mechanism, identify immunopathogenic processes, and aid in defining the neuroinflammatory response to CA.