Evolution and interspecies transmission of canine distemper virus—an outlook of the diverse evolutionary landscapes of a multi-host virus

This article belongs to the Special Issue MorbillivirusesCanine distemper virus (CDV) is a worldwide distributed virus which belongs to the genus Morbillivirus within the Paramyxoviridae family. CDV spreads through the lymphatic, epithelial, and nervous systems of domestic dogs and wildlife, in at least six orders and over 20 families of mammals. Due to the high morbidity and mortality rates and broad host range, understanding the epidemiology of CDV is not only important for its control in domestic animals, but also for the development of reliable wildlife conservation strategies. The present review aims to give an outlook of the multiple evolutionary landscapes and factors involved in the transmission of CDV by including epidemiological data from multiple species in urban, wild and peri-urban settings, not only in domestic animal populations but at the wildlife interface. It is clear that different epidemiological scenarios can lead to the presence of CDV in wildlife even in the absence of infection in domestic populations, highlighting the role of CDV in different domestic or wild species without clinical signs of disease mainly acting as reservoirs (peridomestic and mesocarnivores) that are often found in peridomestic habits triggering CDV epidemics. Another scenario is driven by mutations, which generate genetic variation on which random drift and natural selection can act, shaping the genetic structure of CDV populations leading to some fitness compensations between hosts and driving the evolution of specialist and generalist traits in CDV populations. In this scenario, the highly variable protein hemagglutinin (H) determines the cellular and host tropism by binding to signaling lymphocytic activation molecule (SLAM) and nectin-4 receptors of the host; however, the multiple evolutionary events that may have facilitated CDV adaptation to different hosts must be evaluated by complete genome sequencing. This review is focused on the study of CDV interspecies transmission by examining molecular and epidemiological reports based on sequences of the hemagglutinin gene and the growing body of studies of the complete genome; emphasizing the importance of long-term multidisciplinary research that tracks CDV in the presence or absence of clinical signs in wild species, and helping to implement strategies to mitigate the infection. Integrated research incorporating the experience of wildlife managers, behavioral and conservation biologists, veterinarians, virologists, and immunologists (among other scientific areas) and the inclusion of several wild and domestic species is essential for understanding the intricate epidemiological dynamics of CDV in its multiple host infections

Signal-regulatory protein alpha is an anti-viral entry factor targeting viruses using endocytic pathways

Signal-regulatory protein alpha (SIRPA) is a well-known inhibitor of phagocytosis when it complexes with CD47 expressed on target cells. Here we show that SIRPA decreased in vitro infection by a number of pathogenic viruses, including New World and Old World arena-viruses, Zika virus, vesicular stomatitis virus and pseudoviruses bearing the Machupo virus, Ebola virus and SARS-CoV-2 glycoproteins, but not HSV-1, MLV or mNoV. Moreover, mice with targeted mutation of the Sirpa gene that renders it non-functional were more suscepti ble to infection with the New World arenaviruses Junı´n virus vaccine strain Candid 1 and Tacaribe virus, but not MLV or mNoV. All SIRPA-inhibited viruses have in common the requirement for trafficking to a low pH endosomal compartment. This was clearly demonstrated with SARS-CoV-2 pseudovirus, which was only inhibited by SIRPA in cells in which it required trafficking to the endosome. Similar to its role in phagocytosis inhibition, SIRPA decreased virus internalization but not binding to cell surface receptors. We also found that increasing SIRPA levels via treatment with IL-4 led to even greater anti-viral activity. These data suggest that enhancing SIRPA’s activity could be a target for anti-viral therapies

The Fusion Protein Signal-Peptide-Coding Region of Canine Distemper Virus: a Useful Tool for Phylogenetic Reconstruction and Lineage Identification

Canine distemper virus (CDV) (Paramyxoviridae, Morbillivirus) is the etiologic agent of a multisystemic infectious disease affecting all the terrestrial carnivore families, with high incidence and mortality in domestic dogs. The hemagglutinin (H) gene has been widely employed to characterize field strains, permitting the identification of the nine CDV lineages worldwide. Recently, it has been established that the fusion protein signal peptide coding region (Fsp) is extremely variable, suggesting its usefulness for characterization studies. However, the divergence among global strains and its phylogenetic resolution has not been evaluated yet. Herein, we constructed two datasets with the Fsp coding region and H gene sequences of the same strains belonging to eight CDV lineages, and used them to compare both genomic regions through phylogenetic and likelihood mapping analyses. The phylogenetic analysis revealed that both datasets clustered the strains in eight CDVs lineages. The amino acid divergence inter-lineages showed values for Fsp peptide four-fold higher than the H protein. The likelihood mapping study revealed that both datasets displayed strong phylogenetic signals in the region of well-resolved topology. These features indicated that the Fsp coding region is useful for evolutionary analysis as it allows the straightforward identification of CDV lineages.Fil: Nicolas Sarute. UNIVERSIDAD DE LA REPUBLICA.Fil: Gallo Calderon, Marina. CONSEJO NAC.DE INVEST.CIENTIF.Y TECNICAS. OFICINA DE COORDINACION ADMINISTRATIVA PQUE. CENTENARIO. INST.DE CS. Y TECNOLOGIA "DR. CESAR MILSTEIN".Fil: Ruben Perez. UNIVERSIDAD DE LA REPUBLICA.Fil: la Torre, Jose. CONSEJO NAC.DE INVEST.CIENTIF.Y TECNICAS. OFICINA DE COORDINACION ADMINISTRATIVA PQUE. CENTENARIO. INST.DE CS. Y TECNOLOGIA "DR. CESAR MILSTEIN".Fil: Martín Hernández. UNIVERSIDAD DE LA REPUBLICA.Fil: Lourdes Francia. UNIVERSIDAD DE LA REPUBLICA.Fil: Yanina Panzera. UNIVERSIDAD DE LA REPUBLICA

A recessive Trim2 mutation causes an axonal neuropathy in mice

We analyzed Trim2A/A mice, generated by CRISPR-Cas9, which have a recessive, null mutation of Trim2. Trim2A/ A mice develop ataxia that is associated with a severe loss of cerebellar Purkinje cells and a peripheral neuro-pathy. Myelinated axons in the CNS, including those in the deep cerebellar nuclei, have focal enlargements that contain mitochondria and neurofilaments. In the PNS, there is a loss of myelinated axons, particularly in the most distal nerves. The pathologically affected neuronal populations – primary sensory and motor neurons as well as cerebellar Purkinje cells – express TRIM2, suggesting that loss of TRIM2 in these neurons results in cell autonomous effects on their axons. In contrast, these pathological findings were not found in a second strain of Trim2 mutant mice (Trim2C/C), which has a partial deletion in the RING domain that is needed for ubiquitin ligase activity. Both the Trim2A and the Trim2C alleles encode mutant TRIM2 proteins with reduced ubiquiti- nation activity. In sum, Trim2A/A mice are a genetically authentic animal model of a recessive axonal neuropathy of humans, apparently for a function that does not depend on the ubiquitin ligase activity

TRIM2, a novel member of the antiviral family, limits New World arenavirus entry

Tripartite motif (TRIM) proteins belong to a large family with many roles in host biology, including restricting virus infection. Here, we found that TRIM2, which has been implicated in cases of Charcot-Marie-Tooth disease (CMTD) in humans, acts by blocking hemorrhagic fever New World arenavirus (NWA) entry into cells. We show that Trim2-knockout mice, as well as primary fibroblasts from a CMTD patient with mutations in TRIM2, are more highly infected by the NWAs Junin and Tacaribe virus than wild-type mice or cells are. Using mice with different Trim2 gene deletions and TRIM2 mutant constructs, we demonstrate that its antiviral activity is uniquely independent of the RING domain encoding ubiquitin ligase activity. Finally, we show that one member of the TRIM2 interactome, signal regulatory protein alpha (SIRPA), a known inhibitor of phagocytosis, also restricts NWA infection and conversely that TRIM2 limits phagocytosis of apoptotic cells. In addition to demonstrating a novel antiviral mechanism for TRIM proteins, these studies suggest that the NWA entry and phagocytosis pathways overlap.Peer reviewe

Detección del virus Distemper canino por RT-PCR en tiempo real y caracterización genética de aislamientos del Río de la Plata mediante el análisis de los genes de la hemaglutinina y la proteína de fusión

Orientador: Dra. Yanina Panzera y Ruben Pérez

Evolution and Interspecies Transmission of Canine Distemper Virus-An Outlook of the Diverse Evolutionary Landscapes of a Multi-Host Virus

Canine distemper virus (CDV) is a worldwide distributed virus which belongs to the genus Morbillivirus within the Paramyxoviridae family. CDV spreads through the lymphatic, epithelial, and nervous systems of domestic dogs and wildlife, in at least six orders and over 20 families of mammals. Due to the high morbidity and mortality rates and broad host range, understanding the epidemiology of CDV is not only important for its control in domestic animals, but also for the development of reliable wildlife conservation strategies. The present review aims to give an outlook of the multiple evolutionary landscapes and factors involved in the transmission of CDV by including epidemiological data from multiple species in urban, wild and peri-urban settings, not only in domestic animal populations but at the wildlife interface. It is clear that different epidemiological scenarios can lead to the presence of CDV in wildlife even in the absence of infection in domestic populations, highlighting the role of CDV in different domestic or wild species without clinical signs of disease mainly acting as reservoirs (peridomestic and mesocarnivores) that are often found in peridomestic habits triggering CDV epidemics. Another scenario is driven by mutations, which generate genetic variation on which random drift and natural selection can act, shaping the genetic structure of CDV populations leading to some fitness compensations between hosts and driving the evolution of specialist and generalist traits in CDV populations. In this scenario, the highly variable protein hemagglutinin (H) determines the cellular and host tropism by binding to signaling lymphocytic activation molecule (SLAM) and nectin-4 receptors of the host; however, the multiple evolutionary events that may have facilitated CDV adaptation to different hosts must be evaluated by complete genome sequencing. This review is focused on the study of CDV interspecies transmission by examining molecular and epidemiological reports based on sequences of the hemagglutinin gene and the growing body of studies of the complete genome; emphasizing the importance of long-term multidisciplinary research that tracks CDV in the presence or absence of clinical signs in wild species, and helping to implement strategies to mitigate the infection. Integrated research incorporating the experience of wildlife managers, behavioral and conservation biologists, veterinarians, virologists, and immunologists (among other scientific areas) and the inclusion of several wild and domestic species is essential for understanding the intricate epidemiological dynamics of CDV in its multiple host infections.http://scienti.colciencias.gov.co:8081/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0000153095https://scholar.google.com/citations?user=o3Y7mZwAAAAJ&hl=eshttps://orcid.org/0000-0002-1447-145