Abstract
In order to understand the mechanism of neuroinvasion of a highly pathogenic avian influenza virus (HPAIV) into the central nervous system (CNS) of chickens, specific pathogen free chickens were inoculated with a H7N1 HPAIV. Blood, cerebrospinal fluid (CSF), nasal cavity and brain tissue samples were obtained from 1 to 4 days post-inoculation (dpi) of infected and control chickens. Viral antigen topographical distribution, presence of influenza A virus receptors in the brain, as well as, the role of the olfactory route in virus CNS invasion were studied using different immunohistochemistry techniques. Besides, viral RNA load in CSF and blood was quantified by means of a quantitative real-time reverse transcription-polymerase chain reaction. Viral antigen was observed widely distributed in the CNS, showing bilateral and symmetrical distribution in the nuclei of the diencephalon, mesencephalon and rhombencephalon. Viral RNA was detected in blood and CSF at one dpi, indicating that the virus crosses the blood-CSF-barrier early during infection. This early dissemination is possibly favoured by the presence of Siaα2,3 Gal and Siaα2,6 Gal receptors in brain vascular endothelial cells, and Siaα2,3 Gal receptors in ependymal and choroid plexus cells. No viral antigen was observed in olfactory sensory neurons, while the olfactory bulb showed only weak staining, suggesting that the virus did not use this pathway to enter into the brain. The sequence of virus appearance and the topographical distribution of this H7N1 HPAIV indicate that the viral entry occurs via the haematogenous route, with early and generalized spreading through the CSF.
Highlights
Influenza A viruses (IAV) are important pathogens that infect a wide range of avian and mammal species around the world [1]
highly pathogenic avian influenza viruses (HPAIV) neuroinvasiveness and neurovirulence are considered to be one of the main factors leading to the fatal course of infection in birds [22], few detailed studies on viral neuropathogenesis have been conducted in chickens
Previous experimental studies carried out on different species have suggested that IAV could enter into the central nervous system (CNS) through one or more of these three pathways: haematogenous [5,23], olfactory [24,25] and neural routes [7,26]
Summary
Influenza A viruses (IAV) are important pathogens that infect a wide range of avian and mammal species around the world [1]. They are able to infect humans causing upper respiratory disease and sporadically more severe health complications, such as pneumonia and central nervous system (CNS) dysfunction [2]. Previous studies in natural and experimental HPAIV infections have demonstrated the association between the severity of the lesions and the affinity of the virus for endothelial cells in specific tissues, indicating that the endothelial tropism has a central role in the pathogenesis [4,5,13,14]
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