Influenza viruses are among the many most probably triggers of future pandemics. A analysis staff from the Helmholtz Centre for An infection Analysis (HZI) and the Medical Middle — College of Freiburg has developed a way that can be utilized to check the interplay of viruses with host cells in unprecedented element. With the assistance of their new improvement, they’ve additionally analyzed how novel influenza viruses use different receptors to enter goal cells. The outcomes have been just lately revealed in two papers within the journal Nature Communications.
Viruses don’t have any metabolism of their very own and should subsequently infect host cells as a way to replicate. Contact between the virus and the cell floor is an important first step, which might additionally forestall infections if entry into the cells is blocked. “The interplay with a bunch cell is dynamic and transient for influenza viruses. As well as, related processes happen on the nanoscale, requiring super-resolution microscopes for a extra exact investigation. Utilizing typical approaches, it has subsequently not been doable to research this essential first contact in additional element,” says Prof. Christian Sieben, head of the junior analysis group “Nano An infection Biology” at HZI, explaining the problem the staff has confronted.
In collaboration with Prof. Mark Brönstrup’s division “Chemical Biology” at HZI, his staff has developed a common protocol to research how viruses talk with host cells. To do that, the scientists immobilized viruses individually on microscopy glass surfaces. Cells have been then seeded on high. In typical experiments, the viruses are added on high of pre-seeded cells. “The benefit of our ‘upside-down’ experimental setup is that the viruses work together with cells however don’t enter them — the crucial second of preliminary cell contact is thus stabilized and will be analyzed,” says Sieben.
Utilizing the instance of a seasonal influenza A virus, the researchers used high-resolution and super-resolution microscopy to indicate that contact between the virus and the cell floor triggers a cascade of mobile reactions. First, the mobile receptors accumulate regionally on the virus binding web site. This is because of the truth that the receptors transfer extra slowly by way of the cell membrane close to the binding web site and are subsequently extra plentiful regionally. Subsequently, particular mobile proteins are recruited and eventually the actin cytoskeleton is dynamically reorganized.
Nevertheless, the researchers utilized their technique not solely to a longtime influenza A mannequin, but additionally to a novel influenza pressure of animal origin: the H18N11 virus, which is present in bats in Central and South America. Not like most influenza viruses, which bind to glycans — i.e. carbohydrate chains on the cell floor — for an infection, the H18N11 virus has a distinct goal. “This virus binds to MHC class II complexes — protein receptors which can be usually discovered on sure immune cells,” says Dr. Peter Reuther, analysis group chief from the Institute of Virology of the Medical Middle — College of Freiburg. He’s learning the cell entry of bat-derived H18 influenza A viruses.
Utilizing single-molecule monitoring, the researchers have been capable of present for the primary time that MHCII molecules cluster particularly on the cell floor upon contact with the virus — a course of that’s important for the virus to enter the cell. The groups from Braunschweig and Freiburg have thus characterised a brand new mannequin of influenza A an infection: the binding to MHCII instead receptor and the related dynamic reorganization of the cell floor. “The discovering that influenza viruses don’t bind solely to mobile glycans opens up new views for analysis into these pathogens,” says Reuther. “Significantly in view of their zoonotic potential, it’s essential to higher perceive these different receptors.”
The virus-cell binding step can be the main focus of the EU undertaking COMBINE, which was launched at first of 2025 and is coordinated by HZI researcher Sieben. In COMBINE, scientists from 5 European international locations are investigating the virus entry means of newly rising viruses, particularly these with pandemic potential. “This course of is a possible goal for antiviral therapies. The methodology now we have developed to research the virus entry course of will be utilized to many different viruses,” says Sieben. The brand new outcomes not solely present detailed insights into the biology of influenza viruses. Additionally they present a methodological foundation for investigating the entry mechanisms of potential pandemic pathogens in a extra focused method — and thus figuring out new targets for antiviral therapies.
