Canine Distemper Virus Uses both the Anterograde and the Hematogenous Pathway for Neuroinvasion

Abstract

Canine distemper virus (CDV), a member of the Morbillivirus genus that also includes measles virus, frequently causes neurologic complications, but the routes and timing of CDV invasion of the central nervous system (CNS) are poorly understood. To characterize these events, we cloned and sequenced the genome of a neurovirulent CDV (strain A75/17) and produced an infectious cDNA that expresses the green fluorescent protein. This virus fully retained its virulence in ferrets: the course and signs of disease were equivalent to those of the parental isolate. We observed CNS invasion through two distinct pathways: anterogradely via the olfactory nerve and hematogenously through the choroid plexus and cerebral blood vessels. CNS invasion only occurred after massive infection of the lymphatic system and spread to the epithelial cells throughout the body. While at early time points, mostly immune and endothelial cells were infected, the virus later spread to glial cells and neurons. Together, the results suggest similarities in the timing, target cells, and CNS invasion routes of CDV, members of the Morbillivirus genus, and even other neurovirulent paramyxoviruses like Nipah and mumps viruses.Canine distemper virus (CDV) and the closely related viruses that infect marine mammals have the highest incidence of central nervous system (CNS) complications among viruses of the genus Morbillivirus. Up to 30% of dogs exhibit signs of neurologic involvement during or after CDV infection, and most wild carnivores that succumb to CDV have some evidence of CNS infection (8,18,20,38,51). With 1 in 1,000 cases, the neurovirulent potential of measles virus (MV) is comparatively lower, but CNS complications remain one of the main problems associated with MV infections in countries with an established health care system (32). Because of its relatively high degree of neurovirulence and the availability of a sensitive small animal model, CDV is an ideal candidate to characterize the events involved in morbillivirus neuroinvasion.All morbilliviruses display a strong lymphotropism, which correlates with the presence of their principal receptor, the signaling lymphocytic activation molecule (SLAM, CD150), on a variety of immune cells (6,36,40). In ferrets infected with a virulent CDV strain, more than 50% of circulating peripheral blood mononuclear cells (PBMC) contain infectious virus, and up to 10% of PBMC in MV-infected monkeys are virus positive (46, 53). Because of these findings and the fact that morbilliviruses are highly cell associated, it is thought that the contact between virus and CNS occurs through infected PBMC. Previous studies of typical wild-type isolates like strain A75/17 in dogs further support this theory (38).At the onset of the symptomatic disease around 14 days after intranasal inoculation, infected cells are predominantly detected in the perivascular spaces of the CNS, the choroid plexus, and the ependyma (19,39). Around 3 weeks after infection, CDV-positive glial cells and neurons are found in the white matter, and...

Nipah Virus Entry and Egress from Polarized Epithelial Cells

“…Immune cells then likely play a crucial role in further virus dissemination (59,61). Similar to what has been shown for measles virus, canine distemper virus, or HIV (54,(62)(63)(64)(65), hijacking of immune cells might be primarily responsible for the initiation of systemic NiV infection. In the viremic phase, NiV reaches mucosal surfaces of the lower respiratory and urinary tracts by the hematogenous route and infects epithelial cells via basal membranes.…”

Recombinant Canine Distemper Virus Strain Snyder Hill Expressing Green or Red Fluorescent Proteins Causes Meningoencephalitis in the Ferret

“…Infection of olfactory neurons lining the nasal cavity and subsequent spread along axons through the cribriform plate enable direct infection of neurons in the olfactory bulb, thus enabling the virus to bypass the blood-brain barrier (34). However, the widespread distribution of foci of infection throughout the brain parenchyma of CDV-infected animals is indicative of a prominent role for hematogenous spread via infected lymphocytes following viremia (6).…”

“…A number of possible routes of virus spread from the periphery to the CNS have been suggested, such as hematogenous spread of virus-infected lymphocytes across the blood-brain barrier and virus spread along olfactory nerves within infected neurons from the nasal concha (5,34,40). Virus spread across the blood-cerebrospinal fluid (CSF) barrier is also suggested to play a role due to the observation of infected meningeal and ependymal cells early in the disease process (3).…”

Species-specific and individual differences in Nipah virus replication in porcine and human airway epithelial cells

“…Our finding of rather low expression levels of NiV entry receptors in porcine airway cells suggests that productive primary infection of these cells does not represent a very efficient entry pathway that would allow the virus to overcome the epithelial barrier and initiate systemic infection. It thus will be interesting to determine whether NiV can establish primary infection by hijacking immune cells in the respiratory tract, a highly efficient entry pathway known to be used by other paramyxoviruses causing systemic infections, such as measles virus or canine distemper virus (de Swart et al, 2007;Lemon et al, 2011;Rudd et al, 2006).…”