Olfactory receptor neurons prevent dissemination of neurovirulent influenza A virus into the brain by undergoing virus-induced apoptosis

Abstract

Olfactory receptor neurons (ORNs) were infected upon intranasal inoculation with the R404BP strain of neurovirulent influenza A virus. Virus-infected neurons and a small fraction of neighbouring uninfected neurons displayed apoptotic neurodegeneration substantiated by the immunohistochemistry for activated caspase-3 molecules and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling method. However, virus infection was restricted within the peripheral neuroepithelium and all mice survived the infection. Virus-infected ORNs revealed upregulated expression of the Fas ligand molecules, activating the c-Jun N-terminal kinase signal transduction pathway. In addition, Iba1-expressing activated microglia/macrophages appeared to partake in phagocytic activities, eventually clearing apoptotic bodies. These results raise the possibility that induction of apoptosis in olfactory receptor neurons at an early stage of infection may provide protective effects against invasion of the neurovirulent virus from the peripheral to the CNS.

Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus

“…Recently, we reported apoptosis of murine olfactory receptor neurons with activation of the JNK/c-Jun/Fas ligand pathway following intranasal infection with the R404BP strain of influenza A virus (Mori et al, 2002a). In the present study, however, we could not detect upregulated expression of Fas ligand molecules in the mouse brain following infection with the same virus.…”

Fas Ligand Interactions Contribute to CD8+T-Cell-Mediated Control of West Nile Virus Infection in the Central Nervous System

“…Basally, Fas is not expressed on neurons, but it can be upregulated by inflammatory stimuli (8,10,22,24) or viral infection (23,24,36). Indeed, the functional significance of this finding was suggested by prior studies with reovirus showing that apoptosis of cortical neurons was inhibited by soluble Fas molecules (4,33).…”

“…The engagement of Fas by FasL on effector cells activates the extrinsic pathway of apoptosis, culminating in caspase-3 activation and endonucleolytic cell death (3,19,28). Although Fas is normally expressed at low levels, if at all, on neurons, during physiologic stress its expression can be induced (20,23,24,27).…”

Olfactory ensheathing cells are attracted to, and can endocytose, bacteria

“…Olfactory ensheathing cells (OECs), a specialized glial cell type, accompany the olfactory axons along their entire length throughout the periphery and the CNS [3]. In healthy individuals mechanisms that prevent pathogenic infections include sneezing and mucociliary clearance, the presence of cells of the innate and adaptive immune system in the nasal mucosa, and apoptotic cell death of infected olfactory neurons [4,5]. In the unperturbed animal, small numbers of macrophages, assumed to be responsible for disposing of degenerating epithelial cells, are present in the olfactory epithelium of the nasal cavity.…”