Differential Invasion by Sendai Virus of Abdominal Parenchymal Organs and Brain Tissues in Cortisone- and Cyclophosphamide-Based Immunosuppressed Mice

Miyamae, Takeo

doi:10.1292/jvms.67.369

Cited by 6 publications

(6 citation statements)

References 33 publications

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“…In addition, the dissemination pattern documented in the later infection stages in ferrets strongly resembles that of fatal measles in individuals that are unable to combat the infection (13,24). This link between the extent of spread and the ability of the host's immune response to control the infection is also apparent in studies in immunocompetent and immunosuppressed mice (26,42). In summary, our findings suggest that CDV neuroinvasion in ferrets reflects the events occurring in the context of other morbillivirus infections.…”

Section: Discussionsupporting

confidence: 61%

“…Consistent with this hematogenous route of CNS invasion, infected cells are usually first detected in the choroid plexus and in close association with cerebral blood vessels (34,39). Once inside the CSF, the viruses may invade the different membranes surrounding the CNS, the ependyma, and the superficial lining of the cerebral cortex (34,49), followed by infection of neurons and glia cells in close proximity and subsequent spread into deeper layers (19,26,29). Taken together, these observations suggest that paramyxoviruses use classical hematogenous CNS invasion pathways described for several other neurotropic viruses (17,33).…”

Section: Discussionmentioning

confidence: 90%

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

Rudd

Cattaneo

Messling

2006

J Virol

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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...

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 90%

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

Rudd

Cattaneo

Messling

2006

J Virol

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“…Respiratory tissues were promptly collected for ex vivo measurement of luminescence and viral titers. As in previous studies in immunocompetent mice [36], [37], viral titers and bioluminescence were limited to the respiratory tract. As shown in Figure S4, in vivo bioluminescence intensity levels in living animals were well correlated with ex vivo luminescence ( R 2 0.878) and with viral titers in the nasopharynx ( R 2 0.864), trachea ( R 2 0.915), and lungs ( R 2 0.961).…”

Section: Resultssupporting

confidence: 66%

Illumination of Parainfluenza Virus Infection and Transmission in Living Animals Reveals a Tissue-Specific Dichotomy

et al. 2011

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The parainfluenza viruses (PIVs) are highly contagious respiratory paramyxoviruses and a leading cause of lower respiratory tract (LRT) disease. Since no vaccines or antivirals exist, non-pharmaceutical interventions are the only means of control for these pathogens. Here we used bioluminescence imaging to visualize the spatial and temporal progression of murine PIV1 (Sendai virus) infection in living mice after intranasal inoculation or exposure by contact. A non-attenuated luciferase reporter virus (rSeV-luc(M-F*)) that expressed high levels of luciferase yet was phenotypically similar to wild-type Sendai virus in vitro and in vivo was generated to allow visualization. After direct intranasal inoculation, we unexpectedly observed that the upper respiratory tract (URT) and trachea supported robust infection under conditions that result in little infection or pathology in the lungs including a low inoculum of virus, an attenuated virus, and strains of mice genetically resistant to lung infection. The high permissivity of the URT and trachea to infection resulted in 100% transmission to naïve contact recipients, even after low-dose (70 PFU) inoculation of genetically resistant BALB/c donor mice. The timing of transmission was consistent with the timing of high viral titers in the URT and trachea of donor animals but was independent of the levels of infection in the lungs of donors. The data therefore reveals a disconnect between transmissibility, which is associated with infection in the URT, and pathogenesis, which arises from infection in the lungs and the immune response. Natural infection after transmission was universally robust in the URT and trachea yet limited in the lungs, inducing protective immunity without weight loss even in genetically susceptible 129/SvJ mice. Overall, these results reveal a dichotomy between PIV infection in the URT and trachea versus the lungs and define a new model for studies of pathogenesis, development of live virus vaccines, and testing of antiviral therapies.

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“…While wild-type Sendai virus infection is an acute infection restricted to the respiratory tract in immunocompetent mice, the virus can persist longer and disseminate to the spleen, pancreas, kidney, liver, brain, and blood in cortisone-and cyclophophasmide-based immunosuppressed mice (39). Persistent and systemic infection by HPIV3 has also been observed in immunosuppressed children (13,18,19).…”

Section: Discussionmentioning

confidence: 99%

Residues in the Heptad Repeat A Region of the Fusion Protein Modulate the Virulence of Sendai Virus in Mice

Luque¹,

Bridges²,

Mason³

et al. 2010

J Virol

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While the molecular basis of fusion (F) protein refolding during membrane fusion has been studied extensively in vitro, little is known about the biological significance of membrane fusion activity in parainfluenza virus replication and pathogenesis in vivo. Two recombinant Sendai viruses, F-L179V and F-K180Q, were generated that contain F protein mutations in the heptad repeat A region of the ectodomain, a region of the protein known to regulate F protein activation. In vitro, the F-L179V virus caused increased syncytium formation (cell-cell membrane fusion) yet had a rate of replication and levels of F protein expression and cleavage similar to wild-type virus. The F-K180Q virus had a reduced replication rate along with reduced levels of F protein expression, cleavage, and fusogenicity. In DBA/2 mice, the hyperfusogenic F-L179V virus induced greater morbidity and mortality than wild-type virus, while the attenuated F-K180Q virus was much less pathogenic. During the first week of infection, virus replication and inflammation in the lungs were similar for wild-type and F-L179V viruses. After approximately 1 week of infection, the clearance of F-L179V virus was delayed, and more extensive interstitial inflammation and necrosis were observed in the lungs, affecting entire lobes of the lungs and having significantly greater numbers of syncytial cell masses in alveolar spaces on day 10. On the other hand, the slower-growing F-K180Q virus caused much less extensive inflammation than wild-type virus, presumably due to its reduced replication rate, and did not cause observable syncytium formation in the lungs. Overall, the results show that residues in the heptad repeat A region of the F protein modulate the virulence of Sendai virus in mice by influencing both the spread and clearance of the virus and the extent and severity of inflammation. An understanding of how the F protein contributes to infection and inflammation in vivo may assist in the development of antiviral therapies against respiratory paramyxoviruses.

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Differential Invasion by Sendai Virus of Abdominal Parenchymal Organs and Brain Tissues in Cortisone- and Cyclophosphamide-Based Immunosuppressed Mice

Cited by 6 publications

References 33 publications

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

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

Illumination of Parainfluenza Virus Infection and Transmission in Living Animals Reveals a Tissue-Specific Dichotomy

Residues in the Heptad Repeat A Region of the Fusion Protein Modulate the Virulence of Sendai Virus in Mice

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