Transcriptional Changes in Canine Distemper Virus-Induced Demyelinating Leukoencephalitis Favor a Biphasic Mode of Demyelination

Ulrich, Reiner; Puff, Christina; Wewetzer, Konstantin; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang

doi:10.1371/journal.pone.0095917

Cited by 27 publications

(77 citation statements)

References 54 publications

(84 reference statements)

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“…If the virus is not cleared, focal infection of neurons and glial cells in the grey and white matter ensues four to five weeks after infection, with a concomitant onset of demyelination in these areas [52]. There is increasing evidence that this demyelination primarily results from an antiviral response in the CNS [53,54,55], even though virus-induced death of infected cells may also be a contributing factor [56]. While the presence of a virus in the CNS seen in CDV-infected animals clearly differs from the findings in ADEM patients, where little to no CNS infection is seen, the characterization of the immune mediated demyelination in this model may still provide valuable insights into the mechanisms involved in ADEM.…”

Section: Neurologic Complicationsmentioning

confidence: 99%

Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus

Budaszewski

Messling

2016

Viruses

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Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying pathogenesis and the clinical signs are comparable. Thus, insights gained with one morbillivirus often apply to the other members of the genus. Since the Canine distemper virus (CDV) causes severe and often lethal disease in dogs and ferrets, it is an attractive model to characterize morbillivirus pathogenesis mechanisms and to evaluate the efficacy of new prophylactic and therapeutic approaches. This review compares the cellular tropism, pathogenesis, mechanisms of persistence and immunosuppression of the Measles virus (MeV) and CDV. It then summarizes the contributions made by studies on the CDV in dogs and ferrets to our understanding of MeV pathogenesis and to vaccine and drugs development.

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Section: Neurologic Complicationsmentioning

confidence: 99%

Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus

Budaszewski

Messling

2016

Viruses

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“…Demyelination in advanced disease phases is believed to be no longer directly virus-induced, but rather represents an immunopathological bystander phenomenon in a biphasic disease process [9,51]. Numerous studies have consequently focused on the immunopathological basis of CDV-DL in order to elucidate the molecular mechanisms that contribute to lesion initiation and progression, respectively.…”

Section: Canine Distemper Leukoencephalitis — Novel Aspects Of Itsmentioning

confidence: 99%

New Aspects of the Pathogenesis of Canine Distemper Leukoencephalitis

Lempp

Spitzbarth

Puff

et al. 2014

Viruses

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Canine distemper virus (CDV) is a member of the genus morbillivirus, which is known to cause a variety of disorders in dogs including demyelinating leukoencephalitis (CDV-DL). In recent years, substantial progress in understanding the pathogenetic mechanisms of CDV-DL has been made. In vivo and in vitro investigations provided new insights into its pathogenesis with special emphasis on axon-myelin-glia interaction, potential endogenous mechanisms of regeneration, and astroglial plasticity. CDV-DL is characterized by lesions with a variable degree of demyelination and mononuclear inflammation accompanied by a dysregulated orchestration of cytokines as well as matrix metalloproteinases and their inhibitors. Despite decades of research, several new aspects of the neuropathogenesis of CDV-DL have been described only recently. Early axonal damage seems to represent an initial and progressive lesion in CDV-DL, which interestingly precedes demyelination. Axonopathy may, thus, function as a potential trigger for subsequent disturbed axon-myelin-glia interactions. In particular, the detection of early axonal damage suggests that demyelination is at least in part a secondary event in CDV-DL, thus challenging the dogma of CDV as a purely primary demyelinating disease. Another unexpected finding refers to the appearance of p75 neurotrophin (NTR)-positive bipolar cells during CDV-DL. As p75NTR is a prototype marker for immature Schwann cells, this finding suggests that Schwann cell remyelination might represent a so far underestimated endogenous mechanism of regeneration, though this hypothesis still remains to be proven. Although it is well known that astrocytes represent the major target of CDV infection in CDV-DL, the detection of infected vimentin-positive astrocytes in chronic lesions indicates a crucial role of this cell population in nervous distemper. While glial fibrillary acidic protein represents the characteristic intermediate filament of mature astrocytes, expression of vimentin is generally restricted to immature or reactive astrocytes. Thus, vimentin-positive astrocytes might constitute an important cell population for CDV persistence and spread, as well as lesion progression. In vitro models, such as dissociated glial cell cultures, as well as organotypic brain slice cultures have contributed to a better insight into mechanisms of infection and certain morphological and molecular aspects of CDV-DL. Summarized, recent in vivo and in vitro studies revealed remarkable new aspects of nervous distemper. These new perceptions substantially improved our understanding of the pathogenesis of CDV-DL and might represent new starting points to develop novel treatment strategies.

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“…This disease possesses a multifactorial etiology, wherein multiple pathogens act sequentially or synergistically to cause the disease, which is common within large dog populations (Mitchell and Brownlie 2015). Currently, a number of viruses such as canine influenza virus (Crawford et al 2005;Song et al 2008), canine parainfluenza virus (Chen et al 2012;Weese and Stull 2013), canine pneumovirus (Decaro et al 2014;Mitchell et al 2013), canine distemper virus (Carvalho et al 2012;Ulrich et al 2014); bacteria such as Streptococcus (Jaeger et al 2013) and Bordetella bronchiseptica (Ellis et al 2014); and other pathogenic microorganisms, such as cardiopulmonary parasitic nematodes (Traversa et al 2010), are thought to lead to canine respiratory diseases. However, compared with pathogens in humans, avian species or other mammals such as swine and mice, pathophysiological studies of canine pathogens have been largely performed in separate organs or tissues (Kang et al 2013;Zeng et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Establishment and characterization of a telomerase-immortalized canine bronchiolar epithelial cell line

Xie

Pang

Shan

et al. 2015

Appl Microbiol Biotechnol

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Dogs are susceptible to infectious diseases that occur primarily in the respiratory tract. The airway epithelium acts as a first line of defense and is constantly exposed to microorganisms present in the environment. Respiratory epithelial cells have recently gained wide use as a cell model for studying the pathogenesis of human, murine or swine respiratory pathogen infections. However, studies of the pathogenic mechanisms of canine pathogens have been hindered by the lack of reliable respiratory cell lines. Here, we cultured primary canine bronchiolar epithelial cells (CBECs), whose characteristics were confirmed by their expression of the epithelial cell-specific marker cytokeratin 18, and have provided protocols for their isolation and ex vivo expansion. Further, we established immortalized CBECs containing the human telomerase reverse transcriptase (hTERT) gene via transfection of primary CBECs with the recombinant plasmid pEGFP-hTERT. Immortalized bronchiolar epithelial cells (hTERT-CBECs) retain the morphological and functional features of primary CBECs, as indicated by reverse transcriptase polymerase chain reaction, proliferation assays, karyotype analysis, telomerase activity assay, and Western blotting, which demonstrate that hTERT-CBECs have higher telomerase activity, an extended proliferative lifespan, and a diploid complement of chromosomes, even after Passage 50. Moreover, this cell line is not transformed, as evaluated using soft agar assays and tumorigenicity analysis in nude mice, and can therefore be safely used in future studies. The isolation and establishment of stable hTERT-CBECs is of great importance for use as an in vitro model for mechanistic studies of canine pathogenic infections.

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Transcriptional Changes in Canine Distemper Virus-Induced Demyelinating Leukoencephalitis Favor a Biphasic Mode of Demyelination

Cited by 27 publications

References 54 publications

Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus

Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus

New Aspects of the Pathogenesis of Canine Distemper Leukoencephalitis

Establishment and characterization of a telomerase-immortalized canine bronchiolar epithelial cell line

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