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Entry and reassortment potential of the newly discovered bat influenza A-like viruses

English title Entry and reassortment potential of the newly discovered bat influenza A-like viruses
Applicant Stertz Silke
Number 164065
Funding scheme Project funding
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Medical Microbiology
Start/End 01.04.2016 - 30.04.2019
Approved amount 120'000.00
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Keywords (3)

influenza virus; virus entry; zoonotic infections

Lay Summary (German)

Lead
2012 und 2013 wurden komplette Genomsequenzen von Influenza-ähnlichen Viren, die provisorisch H17N10 und H18N11 genannt wurden, durch Next-Generation Sequencing in südamerikanischen Fledermäusen identifiziert. Allerdings konnte bisher kein infektiöses Virus isoliert oder durch Reverse Genetik hergestellt werden und somit war die Untersuchung dieser neuartigen Viren bisher nicht möglich.
Lay summary

Uns ist es nun gelungen, chimäre Viren zu generieren, die die sechs internen Segmente der Fledermausviren, sowie die Oberflächenproteine HA und NA von konventionellen Influenzaviren besitzen. Wir konnten zeigen, dass diese chimären Viren nicht mit konventionellen Influenzaviren reassortieren können und dass dies unter anderem an einer unbekannten Inkompatibilität des Nukleoproteins liegt. Im Gegensatz zu allen bekannten Influenzaviren binden Hemagglutinin (HA) und Neuraminidase (NA) dieser Fledermausviren nicht an Sialinsäure und daher sind der zelluläre Rezeptor und der Mechanismus des Eintritts in die Wirtszelle ebenfalls unbekannt. In diesem Kollaborationsprojekt möchten wir die wichtigen offenen Fragen zur Identität des Rezeptors und den Blockaden bei der Reassortierung beantworten und schlussendlich die authentischen Fledermaus-Influenzaviren generieren.

Direct link to Lay Summary Last update: 11.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Entry of influenza A virus into host cells — recent progress and remaining challenges
Sempere Borau Milagros, Stertz Silke (2021), Entry of influenza A virus into host cells — recent progress and remaining challenges, in Current Opinion in Virology, 48, 23-29.

Associated projects

Number Title Start Funding scheme
176170 Host proteins required for influenza virus entry as novel antiviral targets 01.11.2017 Project funding

Abstract

In 2012 and 2013, two complete genome sequences of influenza A-like viruses, provisionally designated H17N10 and H18N11, were identified by next-generation sequencing in bat specimens. Despite considerable progress there are many questions that remain to be addressed: To date, no infectious viruses have been isolated or produced by reverse genetics, although we have succeeded in generating chimeric viruses containing six internal genes from these bat viruses and the surface glycoproteins HA and NA from conventional influenza A viruses (IAV). We could show that these chimeric viruses and conventional IAV cannot reassort and obtained preliminary data that this is due, amongst other reasons, to an ill-defined incompatibility of the viral nucleoprotein. Finally, unlike all conventional IAVs, the hemagglutinin (HA) and neuraminidase (NA) protein of these bat viruses do not bind to sialic acids, leaving the identity of the cellular receptor(s) and the complete entry mechanism obscure. In a collaborative effort, we want to address the major open questions, the identity of the entry receptor and the barriers to reassortment with conventional IAV, and generate full infectious bat IAV. Specifically, we aim to a) identify the cellular receptor(s) of bat influenza A-like viruses and determine whether it is specifically expressed in bats, b) study the role of both HA and NA during viral infection, c) challenge our hypothesis that NP co-evolved differently between prototypic IAV and bat influenza A-like viruses resulting in virus subtype-specific packaging of the viral segments, and d) generate authentic H17N10 or H18N11 viruses in vitro for further studies in vivo. This study has the potential to uncover the entry mechanism of bat influenza A-like viruses, the role of NP in genome packaging, the function of the atypical HAs and NAs, and finally the spill-over potential of these viruses to other animals.
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