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Novel receptors for host cell entry of influenza A viruses

English title Novel receptors for host cell entry of influenza A viruses
Applicant Stertz Silke
Number 204166
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 01.11.2021 - 31.10.2025
Approved amount 954'527.00
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Keywords (3)

Virus receptors; Virus entry; Influenza virus

Lay Summary (German)

Lead
Influenzaviren sind die Erreger der Influenza, einer fieberhaften Atemwegserkrankung des Menschen, die eine große Belastung für die menschliche Gesundheit und die Weltwirtschaft darstellt. Während mehrere Merkmale zum zoonotischen Potenzial von Influenzaviren beitragen, sind die virale Rezeptorspezifität und die Rezeptorverteilung in einem Wirt von besonderer Bedeutung. Dieser Aspekt soll hier untersucht werden.
Lay summary

Mit Ausnahme des Fledermaus- Influenza A Viren (IAV) erkennen alle IAV Sialinsäure als Rezeptor für die Anheftung. Unterschiede in der Sialinsäurepräferenz haben sich als wichtige Determinante für zoonotische Infektionen erwiesen. Allerdings klafft in unserem Verständnis des IAV-Eintritts noch eine große Lücke: Während wir detaillierte Kenntnisse über die Anheftung des Virus über Sialinsäure haben, sind die Internalisierung des Virus, insbesondere die Internalisierungsrezeptoren, nur unzureichend definiert, und es kann nur vermutet werden, dass IAV proteinhaltige Rezeptoren für die Aufnahme binden könnten. Mit den hier vorgeschlagenen Arbeiten wollen wir alternative Eintrittswege für aviäre und humane IAV aufdecken und charakterisieren. Darüber hinaus erwarten wir, neue Internalisierungsrezeptoren für IAV zu identifizieren und ihre Rolle für humane und aviäre IAV-Stämme zu bewerten.

Unsere Forschung hat somit das Ziel, unser Verständnis des IAV-Eintritts in Wirtszellen zu vertiefen. Da die Verwendung von Rezeptoren zwischen IAV-Stämmen unterschiedlich sein kann, könnte die Identifizierung und Charakterisierung von neuen Rezeptoren auch einen bisher unbekannten Aspekt der zoonotischen Übertragung von IAV aufdecken.

 
Direct link to Lay Summary Last update: 28.09.2021

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
176170 Host proteins required for influenza virus entry as novel antiviral targets 01.11.2017 Project funding
189939 Infectivity of influenza viruses in expiratory aerosols under ambient temperatures and humidities (IVEA) 01.06.2020 Sinergia

Abstract

Influenza viruses are the causative agent of influenza, a febrile respiratory disease in humans that poses a large burden on human health and on worldwide economy. Influenza A viruses (IAV) are the most relevant members of the influenza viruses as they infect a broad spectrum of hosts and possess zoonotic potential. While several features contribute to the zoonotic potential of IAV, viral receptor specificity and receptor distribution in a host are of particular relevance. With the exception of bat IAV, all IAVs recognize sialic acid, the terminal glycan on many host cell glycoproteins and glycolipids, as receptor for attachment. Differences in sialic preference (sialic acid with an a2’,3’- versus a2’,6’-linkage to the penultimate sugar) have been established as a major determinant of zoonotic infections. However, a large gap remains in our understanding of IAV entry: While we have detailed knowledge about virus attachment via sialic acid, virus internalization, in particular the internalization receptors, are only poorly defined and it can only be hypothesized that IAV may bind proteinaceous receptor for uptake. The hypothesis of proteinaceous IAV receptors was recently supported by findings from our group and others that bat IAV cannot recognize sialic acid but instead uses major histocompatibility (MHC) class II complexes, such as HLA-DR, to enter host cells. However, thus far HLA-DR-dependent entry seemed restricted to bat IAV and it is unclear if non-bat IAVs can use proteinaceous receptors. Here, we propose to investigate the function of HLA-DR-dependent entry for non-bat IAV. Furthermore, we propose novel approaches to identify the internalization receptor(s) for IAV. Specifically, we aim to •Assess the functional role and the subtype and host specificity of HLA-DR-dependent entry in non-bat influenza virus infections (aim A)•Elucidate the HLA-DR-dependent IAV entry pathway from virus attachment to viral fusion (aim B)•Identify the IAV internalization receptor(s) using proximity labelling of internalizing influenza viruses combined with single cell transcriptomics of primary human airway cultures (aim C)With the work proposed here we expect to reveal and characterize HLA-DR-dependent entry as an alternative entry route for non-bat IAV. Furthermore, we expect to identify novel internalization receptors for IAV and assess their role for a broad set of human and avian strains of IAV. Thus, our research has the potential to revise our understanding of IAV entry from a sialic acid-centric view to a much more complex one, in which sialic acid-dependent and sialic acid-independent entry pathways exist and which distinguishes between attachment and internalization receptors. As receptor usage can differ between IAV strains, the identification and characterization of proteinaceous receptors could also reveal a thus far unknown aspect of zoonotic transmission of IAV.
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