Host gene expression profiles in ferrets infected with genetically distinct henipavirus strains

Abstract

Henipavirus infection causes severe respiratory and neurological disease in humans that can be fatal. To characterize the pathogenic mechanisms of henipavirus infection in vivo, we performed experimental infections in ferrets followed by genome-wide gene expression analysis of lung and brain tissues. The Hendra, Nipah-Bangladesh, and Nipah-Malaysia strains caused severe respiratory and neurological disease with animals succumbing around 7 days post infection. Despite the presence of abundant viral shedding, animal-to-animal transmission did not occur. The host gene expression profiles of the lung tissue showed early activation of interferon responses and subsequent expression of inflammation-related genes that coincided with the clinical deterioration. Additionally, the lung tissue showed unchanged levels of lymphocyte markers and progressive downregulation of cell cycle genes and extracellular matrix components. Infection in the brain resulted in a limited breadth of the host responses, which is in accordance with the immunoprivileged status of this organ. Finally, we propose a model of the pathogenic mechanisms of henipavirus infection that integrates multiple components of the host responses.

Author summary

Henipavirus infection can cause severe and often lethal respiratory and neurological disease in humans. The mechanisms by which these viruses cause disease are unknown. To characterize the mechanisms of henipavirus disease in vivo, we performed experimental infections in ferrets followed by characterization of the host response in lung and brain tissues. Characterization of the host response showed early activation of antiviral responses in the lung, in the absence of lymphocyte activation. Infection in the brain resulted in a limited breadth of the host responses, in accordance with the immunoprivileged status of this organ. Overall, infection with distinct henipavirus strains differed in magnitude of the host responses rather than activation of different pathways. Finally, we propose a model of the pathogenic mechanisms of henipavirus infection that integrates multiple components of the host responses.