Recent data on hantaviruses and perspectives for research

The members of the genus Hantavirus are the only representatives of the family Bunyaviridae not transmitted by arthropod vectors but by small mammals. Hantaviruses transmitted by rodents (Order Rodentia) have been discovered at first because of their pathogenicity for humans. The first phylogenetic studies suggested a co-evolution between each hantavirus and its rodent reservoir species. However, further exploration of more animal reservoirs has evidenced that hantaviruses also circulate among insectivores (Order Soricomorpha) and bats (Order Chiroptera), without associated human pathology or even transmission demonstrated up to now. Documented co-circulation of the same hantavirus among sympatric rodent species and new phylogenetic data outlining host-switching events between closely related hantaviruses are currently weakening the concept of strict co-speciation. In addition, the closer analysis of clinical cases invites to moderate the dogma of a clearly distinct pathology in humans between Old World (Europe-Asia) hantaviruses that would provoke Haemorrhagic Fevers with Renal Syndrome (HFRS) and New World (Americas) hantaviruses that would result in a Cardio- Pulmonary Syndrome (HCPS). These topics are discussed because they open interesting perspectives for trans-disciplinary research, from compared immunology between mammals up to modelling of reservoir dynamics in natural environment and sociology of human populations at risk. The most recent data concerning the circulation and pathogenicity of hantaviruses in Europe and in the world are also presented as well as the new technologies for the serological and genetic investigations to discover without a priori new viruses « sleeping » in animal reservoirs and to evaluate their potential for future emergence(s) in manLes virus du genre Hantavirus sont les seuls représentants de la famille des Bunyaviridae qui ne sont pas transmis par des vecteurs arthropodes mais par des petits mammifères. Les hantavirus transmis par les rongeurs (Ordre Rodentia) ont été les premiers découverts en raison de leur pouvoir pathogène chez l’homme. Les premières études phylogénétiques ont suggéré une coévolution entre chaque hantavirus et son espèce de rongeur réservoir. Toutefois, l’exploration d’autres réservoirs animaux a montré que des hantavirus circulent aussi chez les insectivores (Ordre Soricomorpha) et les chauvessouris (Ordre Chiroptera), sans qu’aucune transmission pathogène à l’homme n’ait pu être mise en évidence jusqu’à aujourd’hui. Des observations naturelles de cocirculation d’un même hantavirus au sein de plusieurs espèces de rongeurs sympatriques, ainsi que de nouvelles données phylogénétiques qui soulignent des changements d’hôte (host-switching) entre hantavirus très proches, remettent actuellement en cause la cospéciation stricte. De même, l’observation plus fine de cas cliniques suggère de modérer le dogme d’une maladie distincte chez l’homme, les hantavirus de l’Ancien Monde (Europe- Asie) provoquant une fièvre hémorragique à syndrome rénal (FHRS) et ceux du Nouveau Monde (Amériques) conduisant à une hantavirose à syndrome cardio-pulmonaire (HSCP). Ces points sont discutés car ils ouvrent d’importantes perspectives en matière de recherche transdisciplinaire, depuis l’immunologie comparée chez les mammifères jusqu’à la modélisation de la dynamique des réservoirs dans leur milieu naturel, en passant par la sociologie des populations à risque. Les données récentes sur la circulation et le pouvoir pathogène des hantavirus en Europe et dans le monde sont aussi présentées, ainsi que les nouveaux outils d’investigation sérologique et génétique permettant la découverte sans a priori de nouveaux virus « dormants » dans des réservoirs et l’évaluation de leur potentiel d’émergence chez l’homm

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Phylogeography of Puumala orthohantavirus in Europe

Puumala virus is an RNA virus hosted by the bank vole (Myodes glareolus) and is today present in most European countries. Whilst it is generally accepted that hantaviruses have been tightly co-evolving with their hosts, Puumala virus (PUUV) evolutionary history is still controversial and so far has not been studied at the whole European level. This study attempts to reconstruct the phylogeographical spread of modern PUUV throughout Europe during the last postglacial period in the light of an upgraded dataset of complete PUUV small (S) segment sequences and by using most recent computational approaches. Taking advantage of the knowledge on the past migrations of its host, we identified at least three potential independent dispersal routes of PUUV during postglacial recolonization of Europe by the bank vole. From the Alpe-Adrian region (Balkan, Austria, and Hungary) to Western European countries (Germany, France, Belgium, and Netherland), and South Scandinavia. From the vicinity of Carpathian Mountains to the Baltic countries and to Poland, Russia, and Finland. The dissemination towards Denmark and North Scandinavia is more hypothetical and probably involved several independent streams from south and north Fennoscandia

Phylogeography of Puumala orthohantavirus in Europe

Puumala virus is an RNA virus hosted by the bank vole (Myodes glareolus) and is today present in most European countries. Whilst it is generally accepted that hantaviruses have been tightly co-evolving with their hosts, Puumala virus (PUUV) evolutionary history is still controversial and so far has not been studied at the whole European level. This study attempts to reconstruct the phylogeographical spread of modern PUUV throughout Europe during the last postglacial period in the light of an upgraded dataset of complete PUUV small (S) segment sequences and by using most recent computational approaches. Taking advantage of the knowledge on the past migrations of its host, we identified at least three potential independent dispersal routes of PUUV during postglacial recolonization of Europe by the bank vole. From the Alpe-Adrian region (Balkan, Austria, and Hungary) to Western European countries (Germany, France, Belgium, and Netherland), and South Scandinavia. From the vicinity of Carpathian Mountains to the Baltic countries and to Poland, Russia, and Finland. The dissemination towards Denmark and North Scandinavia is more hypothetical and probably involved several independent streams from south and north Fennoscandia

Report of the First Meeting of the Middle East and Eastern Europe Rabies Expert Bureau, Istanbul, Turkey (June 8-9, 2010)

Rabies is a threat in all parts of the world where animal reservoirs persists, including Eastern Europe and the Middle East. Rabies experts from seven Middle East and Eastern European countries (Croatia, Egypt, Georgia, Iran, Serbia, Turkey, and Ukraine) met for two days in Istanbul, Turkey (June 8-9, 2010), to exchange information on the epidemiological situation concerning human and animal rabies in their respective countries and to discuss strategies for rabies elimination and control. They decided to establish a regional network, the Middle East and Eastern Europe Rabies Expert Bureau (MEEREB), a regional network of experts, to increase collaboration in rabies prevention and control at the local, regional, and global levels

Experimental Infection of Squirrel Monkeys with Nipah Virus

We infected squirrel monkeys (Saimiri sciureus) with Nipah virus to determine the monkeys’ suitability for use as primate models in preclinical testing of preventive and therapeutic treatments. Infection of squirrel monkeys through intravenous injection was followed by high death rates associated with acute neurologic and respiratory illness and viral RNA and antigen production

A One Medicine Mission for an Effective Rabies Therapy

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients

Rabies virus matrix protein interplay with eIF3, new insights into rabies virus pathogenesis

Viral proteins are frequently multifunctional to accommodate the high density of information encoded in viral genomes. Matrix (M) protein of negative-stranded RNA viruses such as Rhabdoviridae is one such example. Its primary function is virus assembly/budding but it is also involved in the switch from viral transcription to replication and the concomitant down regulation of host gene expression. In this study we undertook a search for potential rabies virus (RV) M protein's cellular partners. In a yeast two-hybrid screen the eIF3h subunit was identified as an M-interacting cellular factor, and the interaction was validated by co-immunoprecipitation and surface plasmon resonance assays. Upon expression in mammalian cell cultures, RV M protein was localized in early small ribosomal subunit fractions. Further, M protein added in trans inhibited in vitro translation on mRNA encompassing classical (Kozak-like) 5′-UTRs. Interestingly, translation of hepatitis C virus IRES-containing mRNA, which recruits eIF3 via a different noncanonical mechanism, was unaffected. Together, the data suggest that, as a complement to its functions in virus assembly/budding and regulation of viral transcription, RV M protein plays a role in inhibiting translation in virus-infected cells through a protein–protein interaction with the cellular translation machinery

A five-year perspective on the situation of haemorrhagic fever with renal syndrome and status of the hantavirus reservoirs in Europe, 2005-2010

Hantavirus infections are reported from many countries in Europe and with highly variable annual case numbers. In 2010, more than 2,000 human cases were reported in Germany, and numbers above the baseline have also been registered in other European countries. Depending on the virus type human infections are characterised by mild to severe forms of haemorrhagic fever with renal syndrome. The member laboratories of the European Network for diagnostics of Imported Viral Diseases present here an overview of the progression of human cases in the period from 2005 to 2010. Further we provide an update on the available diagnostic methods and endemic regions in their countries, with an emphasis on occurring virus types and reservoirs