viruses Review Morbillivirus Experimental Animal Models: Measles Virus Pathogenesis Insights from Canine Distemper Virus Renata da Fontoura Budaszewski 1,2 and Veronika von Messling 2,* 1 Laboratório de Virologia, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Porto Alegre 91540-000, Brazil; [email protected] 2 Veterinary Medicine Division, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen 63225, Germany * Correspondence: [email protected]; Tel.: +49-6103-777-400 Academic Editor: Richard K. Plemper Received: 11 August 2016; Accepted: 30 September 2016; Published: 11 October 2016 Abstract: 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. Keywords: morbillivirus genus; canine distemper virus; animal models; pathogenesis 1. Introduction Morbilliviruses are enveloped, negative-stranded RNA viruses which cause a moderate to severe respiratory and gastrointestinal disease and long-lasting immunosuppression in their respective hosts. Despite the availability of a safe and cost-effective vaccine, the Measles virus (MeV) remains one of the leading causes of death among young children in developing countries [1]. MeV infections are also associated with neurological complications that may occur during the acute disease phase, but also many years later, due to long-term persistence in the central nervous system (CNS). Since humans are the only reservoir for MeV, it is a promising target for global eradication, and a world-wide eradication campaign is ongoing [1]. The successful eradication of the closely related Rinderpest virus (RPV) in 2011 demonstrates the general feasibility of this approach [2]. However, decreasing adherence to vaccination in industrialized countries has resulted in a re-emergence of the disease. The increase in outbreaks in North America and Europe in recent years has led to these regions missing eradication targets, endangering the success of the overall campaign [3]. To develop new prophylactic and therapeutic strategies that support these efforts, a better understanding of MeV pathogenesis and immune interference is required. While the narrow host range, which includes only humans and non-human primates, makes MeV eradication possible, it also limits the characterization of its pathogenesis. A surrogate model based on the study of the Canine distemper virus (CDV)—a closely related morbillivirus that infects a broad range of carnivores including ferrets or dogs—represents an attractive alternative. CDV causes a similar overall pathogenesis in its different hosts, but the disease severity varies from moderate in Viruses 2016, 8, 274; doi:10.3390/v8100274 www.mdpi.com/journal/viruses Viruses 2016,, 8,, 274 2 of 12 dogs, to completely lethal in highly susceptible species, such as ferrets and many wild carnivores [4,5].dogs, toThe completely clinical lethalsigns ininclude highly susceptiblefever, often species, a characteristic such as ferrets rash, and diarrhea, many wild nasal carnivores discharge, [4,5]. conjunctivitis,The clinical signs and include generalized fever, immunosuppression, often a characteristic thereby rash, diarrhea, reproducing nasal the discharge, disease spectrum conjunctivitis, seen inand MeV generalized patients immunosuppression,(Figure 1). Furthermore, thereby acute reproducing and delayed the neurologic disease spectrum complications seen in are MeV frequently patients observed(Figure1). [6]. Furthermore, This review acute will and provide delayed an neurologicupdate on complications the contribution are frequentlyof these models observed to our [ 6]. understandingThis review will provideof the anroutes update of on theinfection, contribution receptors, of these tissue models totropism, our understanding mechanisms of theof immunosuppression,routes of infection, receptors, and viral tissue persistence tropism, in mechanisms the CNS, and of immunosuppression, also an update on the and progress viral persistence that has beenin the made CNS, in and drug also and an updatevaccine on development. the progress that has been made in drug and vaccine development. Figure 1. Morbilliviruses ( (MeaslesMeasles virus virus (MeV)(MeV) in in blue, Canine distemper virus (CDV)(CDV) in in red) display similar tropism and tissue distribution in their respective hosts. 2. Morbillivirus Morbillivirus Taxonomy Taxonomy and and Life Life Cycle Cycle Morbilliviruses belong belong to to the the ParamyxoviridaeParamyxoviridae familyfamily as as a a member member of of the the MononegaviralesMononegavirales order.order. In addition to to MeV, CDV, andand RPV,RPV, thethe MorbillivirusMorbillivirus genusgenus currentlycurrently includes four species, namely the Cetacean morbillivirus (CeMV), the Phocine distemper virus (PDV),(PDV), the the PestePeste-des-petits-ruminant‐des‐petits‐ruminant virus (PPRV) andand thethe recently recently added addedFeline Feline morbillivirus morbillivirus(FeMV). (FeMV). Phylogenetically, Phylogenetically, the the CDV CDV and and PDV PDV are are the themost most closely closely related related (Figure (Figure2), suggesting2), suggesting that that the the PDV PDV emerged emerged from from the the CDV CDV several several thousands thousands of years ago by contactcontact withwith terrestrialterrestrial carnivorescarnivores [[7].7]. The The CeMV forms forms a separate branch that includes isolates from dolphins and porpoises, while the MeV is most closely related to the ruminant morbilliviruses: RPVRPV and and PPRV. PPRV. The The RPV RPV has been has suggestedbeen suggested as the progenitor as the progenitor virus of the virusMorbillivirus of the Morbillivirusgenus [8]. genus [8]. All morbilliviruses shareshare the the same same particle particle structure structure and and genome genome organization. organization. Viral Viral particles particles are arepleomorphic, pleomorphic, with with a diameter a diameter of approximately of approximately 150 nm. 150 They nm. consist They of consist a lipid of envelope a lipid composed envelope composedof the fusion of (F)the andfusion attachment (F) and attachment (H) transmembrane (H) transmembrane glycoproteins glycoproteins and are lined and by are the lined matrix by (M)the matrixprotein. (M) The protein. viral genomicThe viral RNA genomic is encapsidated RNA is encapsidated by the nucleoprotein by the nucleoprotein (N), and forms,(N), and together forms, withtogether the with phosphoprotein the phosphoprotein (P) and the(P) polymeraseand the polymerase (L) protein, (L) protein, the ribonucleoprotein-complex the ribonucleoprotein‐complex (RNP), which(RNP), is which surrounded is surrounded by the viral by envelope the viral during envelope the buddingduring the process budding at the process plasma at membrane the plasma [9]. membraneThe morbillivirus [9]. The genome morbillivirus size lies genome at around size lies 16,000 at around nt, and 16,000 the genome nt, and contains the genome six transcription contains six transcriptionunits arranged units linearly arranged in the order linearly 3’leader-N-P-M-F-H-L-5’trailer, in the order 3’leader‐N‐ whichP‐M‐F are‐H‐ separatedL‐5’trailer, by which intergenic are separatedregions. The by transcription intergenic regions. units give The rise transcription to at least eightunits proteins,give rise sinceto at least the P eightgene proteins, also encodes since the the C Pand gene V proteinsalso encodes by use the of C an and alternate V proteins open by reading use of an frame alternate and RNA open editing,reading respectivelyframe and RNA [10]. editing, respectivelyThere is [10]. considerable homology on the amino acid and even nucleotide level, which results in high levelsThere of structural is considerable and functional homology conservation on the amino among acid morbilliviruses. and even nucleotide On the level, one hand, which this results allows in highthe application levels of structural of structural and data functional available conservation for MeV proteins among to morbilliviruses. those of other morbillivirusesOn the one hand, [11 ,this12], allowsand on the the application other hand, of it enablesstructural the data use ofavailable chimeric for viruses MeV proteins or in vitro to trans-complementationthose of other morbilliviruses for the [11,12],characterization and on the of other functional hand, domainsit enables [ 13the,14 use]. of chimeric viruses or in vitro trans‐complementation for the characterization of functional domains [13,14]. Viruses 2016, 8, 274 3 of 12 Viruses 2016, 8, 274 3 of 12 Figure 2.2. Phylogenetic tree, basedbased onon completecomplete genomesgenomes ofof morbilliviruses.morbilliviruses. Molecular Evolutionary Genetics Analysis 6 (MEGA6) was used for phylogeny inference according to the maximummaximum