Impaired interferon-γ responses, increased interleukin-17 expression, and a tumor necrosis factor–α transcriptional program in invasive aspergillosis

Abstract

Background - Invasive aspergillosis (IA) is the most common cause of death associated with fungal infection in the developed world. Historically, susceptibility to IA has been associated with prolonged neutropenia; however, IA has now become a major problem in patients on calcineurin inhibitors and allogenic hematopoetic stem cell transplant patients following engraftment. These observations suggest complex cellular mechanisms govern immunity to IA. Methods - To characterize the key early events that govern outcome from infection with Aspergillus fumigatus we performed a comparative immunochip microarray analysis of the pulmonary transcriptional response to IA between cyclophosphamide-treated mice and immunocompetent mice at 24 h after infection. Results - We demonstrate that death due to infection is associated with a failure to generate an incremental interferon-γ response, increased levels of interleukin-5 and interleukin-17a transcript, coordinated expression of a network of tumor necrosis factor–α-related genes, and increased levels of tumor necrosis factor–α. In contrast, clearance of infection is associated with increased expression of a number genes encoding proteins involved in innate pathogen clearance, as well as apoptosis and control of inflammation. Conclusion - This first organ-level immune response transcriptional analysis for IA has enabled us to gain new insights into the mechanisms that govern fungal immunity in the lung.