Exposure of immunosuppressed individuals to the opportunistic fungal pathogen Aspergillus (A.) fumigatus may result in invasive pulmonary aspergillosis (IPA), which could lead to the development of cerebral aspergillosis (CA), a highly lethal infection localized in the central nervous system. Disseminated CA following IPA contributes significantly to mortality amongst patients with hematologic malignancies (HMs). However, little is known about the risk factors for disease amongst HM patients. A systematic review using PRISMA guidelines was undertaken to define HM patient subgroups, preventative measures, therapeutic interventions, and outcomes of patients with disseminated CA. The systematic review identified the following patient populations as the highest risk for disseminated CA: patients with acute myeloid leukemia and patients receiving corticosteroids as a part of their HM therapeutic regimen. Currently, there are no experimental models of CA that effectively mimic human disease, resulting in a considerable knowledge gap regarding mechanisms of neurological pathogenicity and neuroimmune responses during infection. In the current report, the information derived from the systematic review was utilized to develop a novel, human-relevant model of disseminated CA. Specifically, mice were immunosuppressed via acute, high-dose corticosteroid administration, challenged with A. fumigatus resting conidia intranasally, followed by a 70-fold lower inoculum of pre-swollen conidia intravenously (IN+IV+steroid). Increased weight loss, clinical severity, fungal burden in the brain, and lethality compared to immunosuppressed mice challenged intranasally only (IN+steroid), or non-immunosuppressed mice challenged intranasally and intravenously (IN+IV) was observed. The IN+IV+steroid group demonstrated significant decreases in monocytes, eosinophils, dendritic cells, and invariant natural killer T-cells, but not neutrophils, macrophages, or γδT-cells, in the brain when compared to the IN+IV group. Likewise, the IN+IV+steroid group had significantly lower levels of IL-1β, IL-6, IL-17A, CCL3, CXCL10, and VEGF in the brain when compared to the IN+IV group. Notably, IN+IV+steroid was superior to both IN+IV+chemotherapy (cytarabine + daunorubicin) and IN+IV+neutropenia for the development of CA. In conclusion, we developed a well-defined, physiologically relevant model of disseminated CA in corticosteroid-induced immunosuppressed mice with a primary pulmonary infection and are the first to define the corresponding inflammatory and immune responses within the brain. This model will serve to advance understanding of disease mechanisms, identify immunopathogenic processes, and aid in defining the neuroinflammatory response to CA.
