Influenza A virus exploits transferrin receptor recycling to enter host cells
Significance
We still have an incomplete understanding of the proteins influenza A virus (IAV) uses to enter the host cell. The team led by GCIR member Prof. Mirco Schmolke, demonstrates in this article published in the Proceedings of the National Academy of Sciences (PNAS), that IAV entry is diminished in the absence of transferrin receptor 1 (TfR1). Consequently, pharmacological targeting of TfR1 efficiently interferes with IAV replication. While this process could be mediated by an interaction of IAV HA with glycosylated TfR1, a “headless” TfR1 mutant still functions as a host entry factor for IAV in trans. The “revolving door” model provides a plausible explanation as to why IAV is capable of entering such a broad range of cell types in culture and why the adaptation of the zoonotic avian IAV to mammalian cells involves primarily an adjustment to attachment factors rather than the entry machinery.
Abstract
Influenza A virus (IAV) enters host cells mostly through clathrin-dependent receptor-mediated endocytosis. A single bona fide entry receptor protein supporting this entry mechanism remains elusive. Here the authors performed proximity ligation of biotin to host cell surface proteins in the vicinity of attached trimeric hemagglutinin-HRP and characterized biotinylated targets using mass spectrometry. This approach identified transferrin receptor 1 (TfR1) as a candidate entry protein. Genetic gain-of-function and loss-of-function experiments, as well as in vitro and in vivo chemical inhibition, confirmed the functional involvement of TfR1 in IAV entry. Recycling deficient mutants of TfR1 do not support entry, indicating that TfR1 recycling is essential for this function. The binding of virions to TfR1 via sialic acids confirmed its role as a directly acting entry factor, but unexpectedly even headless TfR1 promoted IAV particle uptake in trans. TIRF microscopy localized the entering virus-like particles in the vicinity of TfR1. These data identify TfR1 recycling as a revolving door mechanism exploited by IAV to enter host cells.
This work was funded by: Fondation privée des HUG, Novartis Research Foundation, Swiss National Fund, the Fondation de Reuter and CARIGEST.
Why is it important to study the entry mechanism of flu viruses?
Influenza viruses are major pathogens affecting human and animal health. They cause an acute respiratory infection and kill half a million people worldwide every year, mostly among high-risk groups including the very young, the elderly pregnant women, immunocompromised patients, and those with serious medical conditions. An Influenza virus infection begins with the binding of the virus particle to sugar structures on the surface of host cells. After this the virus rolls along the surface to find a suitable entrance point, presumably defined by distinct host surface proteins. In collaboration with teams from the UNIGE Faculty of Medicine, the Geneva University Hospitals and the University of Lausanne, the team of Prof. Schmolke identified transferrin receptor 1 early on in their project as a lead candidate. It functions like a revolving door that continuously transports carrier-bound iron into our cells. They demonstrated that influenza viruses hijack this revolving door to start their infection cycle. From a fundamental point of view this is an exciting new aspect of influenza virus biology. Importantly, chemical blocking of transferrin receptor recycling in human lung tissue models inhibits a wide range of influenza virus isolates including clinical strains. While there is still a long way from translating these findings into patient care, blocking transferrin receptor 1 might be a suitable strategy to treat influenza virus infections in the future.
25 May 2023
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