Journal Article

Neurovirulence of H5N1 Infection in Ferrets Is Mediated by Multifocal Replication in Distinct Permissive Neuronal Cell Regions

Plourde, Jennifer R., Vaughan, Sarah E., Tipper, Jennifer L., Layton, R. Colby, Pyles, John A., Harrod, Kevin S.

2012

Overview

Highly pathogenic avian influenza A (HPAI), subtype H5N1, remains an emergent threat to the human population. While respiratory disease is a hallmark of influenza infection, H5N1 has a high incidence of neurological sequelae in many animal species and sporadically in humans. We elucidate the temporal/spatial infection of H5N1 in the brain of ferrets following a low dose, intranasal infection of two HPAI strains of varying neurovirulence and lethality. A/Vietnam/1203/2004 (VN1203) induced mortality in 100% of infected ferrets while A/Hong Kong/483/1997 (HK483) induced lethality in only 20% of ferrets, with death occurring significantly later following infection. Neurological signs were prominent in VN1203 infection, but not HK483, with seizures observed three days post challenge and torticollis or paresis at later time points. VN1203 and HK483 replication kinetics were similar in primary differentiated ferret nasal turbinate cells, and similar viral titers were measured in the nasal turbinates of infected ferrets. Pulmonary viral titers were not different between strains and pathological findings in the lungs were similar in severity. VN1203 replicated to high titers in the olfactory bulb, cerebral cortex, and brain stem; whereas HK483 was not recovered in these tissues. VN1203 was identified adjacent to and within the olfactory nerve tract, and multifocal infection was observed throughout the frontal cortex and cerebrum. VN1203 was also detected throughout the cerebellum, specifically in Purkinje cells and regions that coordinate voluntary movements. These findings suggest the increased lethality of VN1203 in ferrets is due to increased replication in brain regions important in higher order function and explains the neurological signs observed during H5N1 neurovirulence.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animal species / Animals / Avian flu / Avian influenza / Avian influenza viruses / Biology / Bone / Brain / Brain research / Brain stem / Central Nervous System - virology / Cerebellum / Cerebral cortex / Cerebrum / Cortex / Cortex (frontal) / Cortex (olfactory) / Cortex (temporal) / Ferrets - virology / Fowl plague / Health aspects / Human populations / Immunohistochemistry / Infection / Infections / Infectious diseases / Influenza / Influenza A / Influenza A Virus, H5N1 Subtype - pathogenicity / Influenza A Virus, H5N1 Subtype - physiology / Kinetics / Laboratory animals / Lethality / Lung / Lung diseases / Lungs / Male / Medical laboratories / Medicine / Mortality / Mustela / Nervous system / Neurological complications / Neurons / Neurovirulence / Nose / Olfactory bulb / Olfactory nerve / Orthomyxoviridae Infections - virology / Paresis / Pathogenesis / Pathology / Purkinje cells / Real-Time Polymerase Chain Reaction / Replication / Respiratory diseases / Seizures / Studies / Swine flu / Temporal lobe / Tissues / Torticollis / Viral infections / Virology / Virulence / Virus Replication / Viruses