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Molecular characterization of Influenza D virus - host interactions

English title Molecular characterization of Influenza D virus - host interactions
Applicant Dijkman Ronald
Number 179260
Funding scheme Project funding
Research institution Institut für Infektionskrankheiten Universität Bern
Institution of higher education University of Berne - BE
Main discipline Molecular Biology
Start/End 01.08.2018 - 31.12.2022
Approved amount 700'000.00
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All Disciplines (3)

Discipline
Molecular Biology
Medical Microbiology
Cellular Biology, Cytology

Keywords (4)

Host - pathogen interaction; Influenza virus; Airway epithelium; Innate immunity

Lay Summary (German)

Lead
Im Jahr 2011 wurde ein neues Mitglied der Orthomyxoviridae-Familie, das Influenza D Virus, in einem breiten Spektrum von Nutztierarten identifiziert. Darunter befinden sich auch Rinder, eine Art, die zuvor niemals als anfällig für eine Influenzavirusinfektion angesehen wurde.
Lay summary

Die zugrundeliegenden Parameter, die das breite Wirtsspektrum des Influenza D Virus beeinflussen, sind weiterhin unklar. Angesichts der Interspeziesübertragungen und des Zoonosepotentials, und allgemein der wichtigen Bedeutung von Influenzaviren für die Veterinär- und Humanmedizin ist die molekulare Charakterisierung der Influenza D Virus – Wirt Wechselwirkungen wichtig. Das vorgeschlagene Forschungsprojekt soll detailliertes Wissen über das Wirtsspektrum des Influenza D Virus einschließlich seines Zoonosepotentials, sowie über die angeborene Immunantwort des Wirts bei verschiedenen Arten liefern. Darüber hinaus bietet es einen umfassenden Überblick über grundlegende Aspekte der Molekularbiologie des Virus, dem Zusammenspiel des Influenza D Virus mit der angeborenen Immunantwort des Wirts, und die mögliche Rolle von viralen Proteinen in der Umgehung der angeborenen Immunantworten und deren möglichen Einfluss auf das breite Wirtsspektrum dieser Viren. Diese Erkenntnisse sind unabdingbar, um die grundlegenden Parameter für die erfolgreiche Etablierung von Influenza D Virus in verschiedenen Tierarten und möglicherweise dem Menschen zu verstehen.

Direct link to Lay Summary Last update: 09.04.2018

Lay Summary (English)

Lead
In 2011, a novel member of the Orthomyxoviridae family, Influenza D virus, was identified among a broad spectrum of livestock species, including cattle, a species that previously never was considered to be susceptible to influenza virus infection.
Lay summary

The underlying determinants affecting the broad host tropism of influenza D virus remain elusive. Considering the zoonotic potential, interspecies transmission and the important veterinary and public health significance of influenza viruses, the molecular characterization of the interaction of influenza D virus with its host’s is warranted. The proposed research will provide detailed knowledge on the host tropism of influenza D viruses, including their zoonotic potential, and on the host innate immune responses of different species. Moreover, it provides a comprehensive overview on basic aspects of the molecular biology of the virus, the interplay of Influenza D virus with the host’s innate immune responses, and on the putative role of viral proteins in antagonizing the host innate antiviral response and its effect on the broad species tropism of the virus.This knowledge is crucial to understand the basic parameters of the successful establishment of Influenza D virus among different livestock species and in possibly humans.

Direct link to Lay Summary Last update: 09.04.2018

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
196062 Rapid Evaluation and Development of Cellular and Animal Tools to fight SARS-CoV-2 01.08.2020 Special Call on Coronaviruses

Abstract

Background: Influenza viruses are notorious pathogens that frequently cross the species barrier with often severe consequences for both animal and human health. In 2011, a novel member of the Orthomyxoviridae family, Influenza D virus (IDV), was identified in the respiratory tract of pigs with influenza-like symptoms and subsequently also in cattle, a species that previously never was considered to be susceptible to influenza virus infection. Epidemiological surveys among livestock demonstrated that Influenza D virus is worldwide distributed among cattle, swine, goat and sheep, but the most striking is the detection of influenza D virus directed antibodies among humans with occupational exposure to livestock. Influenza D virus is phylogenetic closely related to the human influenza C virus that utilize the same cellular receptor determinant, however, influenza C virus infections are predominantly restricted to humans, whereas the novel influenza D virus has a promiscuous host tropism. The underlying molecular viral and host determinants affecting the broad host tropism of influenza D virus remain elusive, and considering the zoonotic potential, interspecies transmission and the important veterinary and public health significance of influenza viruses, the molecular characterization of influenza D virus - host interactions is warranted.Working hypothesis and aims: In cattle and swine the respiratory epithelium has shown to be the main entry port of IDV and is an important barrier to infection. Herein the innate immune system has a major protective role as the first line of defence in the barrier function. My hypothesis is that the receptor determinant (9-O-Ac-Neu5Ac) of IDV is distributed in a cell-type specific fashion and that this influences the dynamics of the host innate immune response, and that this may differ among host species. In addition, I hypothesize that the non-structural 1 (NS1) protein of IDV is a potent virulence factor that plays an important role in antagonising the innate immune response and, like other influenza viruses, influences the host range. As a first step toward identifying viral traits involved in the broad host tropism of the newly emerging influenza D virus we will determine the (i) cell and host tropism and (ii) innate immune response at the primary site of replication using in vitro respiratory epithelium models of cattle, swine, and human. Furthermore, we will (iii) molecular characterize the NS1 protein on its role in innate immune response antagonism in those different species. In combination, with the other aims we will perform a (iv) novel complementary genome-wide CRISPR-based screen to identify host determinants impeding influenza D virus replication.Expected significance: The proposed studies will provide detailed knowledge on the host tropism of influenza D virus and innate immune response during viral infections among different species and will reveal whether IDV possess zoonotic potential. Moreover, it provides a comprehensive overview on the innate immune system among livestock and the role of IDV NS1 protein as an important antagonist of this system. This knowledge is indispensable to understand the basic parameters of the successful establishment of IVD among different livestock species and will be highly instructive when assessing the risk of other influenza virus family members in animals and humans.
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