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Characterisation of epithelial cells infection by morbilliviruses.

Wong, Xiao Xiang (2012). Characterisation of epithelial cells infection by morbilliviruses. Mémoire. Québec, Université du Québec, Institut National de la Recherche Scientifique, Maîtrise en virologie et immunologie, 94 p.

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Résumé

Measles (MeV) and Canine distemper vints (CDV) are closely related members of the genus Morbillivints in the Paramyxoviridae family. They are transmitted by aerosol droplets, and cause a moderate to severe disease characterized by rash, fever, respiratory and gastrointestinal signs and immunosuppression in their respective hosts. The virus initially targets immune cells expressing its primary entry receptor: the signaling lymphocyte activation molecule (SLAM; CD150). After massive replication in lymphoid tissues, the virus spreads to epithelial tissues in organs throughout the body, which coïncides with the appearance of clinicat signs. The virus is finally released into the respiratory tract, and transmitted to a new host. Recent studies have refined the current mode!of MeV pathogenesis, proposing that virus replication in epithelial cells is not necessary to initiate an infectious cycle or for viral dissemination, but required for shedding and transmission. To validate this new mode!, we took advantage of a more severe disease phenotype seen in CDV-infected ferrets. We hypothesized that the mechanism of interaction with the epithelial cell receptor is conserved between MeV and CDV, and that the same H protein region is involved in this interaction. To test our hypothesis, we first introduced the mutations conferring an epithelial cell receptor (EpR)-blind phenotype from MeV H to the CDV H protein (V478S, P493S and Y539A). Protein transport to the cell surface was slightly reduced for one of the mutant H proteins, but nevertheless, they ali retained wild-type fusion capacity in SLAM­ expressing cells. We then produced a recombinant CDV expressing aH protein carrying the respective EpR-blind mutations. Ali mutant viruses replicated with similar efficacy as the wild-type CDV in SLAM-expressing celis, but poorly in canine and ferret epithelial cells, illustrating their inability to infect epithelial cell. The tropism and pathogenesis of the EpR-blind CDV was finaliy evaluated in ferrets. Infection with wild-type CDV causes a lethal disease in these animais, and recapitulates the clinicat signs of measles in humans. Ferrets infected with the EpR-blind CDV had similar viralloads and experienced a similar extent of immunosuppression as wild-type infected animais. However, they did not show any signs of clinicat disease such as rash, fever or weight loss. More importantly, no virus was detected in the epithelial tissues of the trachea, lungs orbladder. Taken together, our data from the ferret mode!supports and strengthens the previous MeV pathogenesis study in macaques by Leonard et al. We have shown that the infection of epithelial cells has little or no role in establishing infection and systemic spread, but rather contributes to the development of clinical disease, virus shedding and transmission to a new host. The implication of structurally conserved H protein residues in epithelial cells entry, further suggests that morbilliviruses share a common epithelial receptor. In this perspective, approaches that interfere with the entry into epithelial cells may constitute a novel strategy for controlling the transmission ofthese highly contagious viroses, and may therefore contribute to the global eradication of MeV.

Type de document: Mémoire
Directeur de mémoire/thèse: von Messling, Veronika
Mots-clés libres: rougeole ; morbillivirus ; maladie ; mev ; cdv ; virus ; carre
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 09 nov. 2015 19:31
Dernière modification: 18 déc. 2015 16:35
URI: http://espace.inrs.ca/id/eprint/2040

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