Love Triangle Reveals Potential Antiviral Targets
3D print of influenza virus. The virus surface (yellow) is covered with proteins called hemagglutinin (blue) and neuraminidase (red) that enable the virus to enter and infect human cells. Image credit: NIH
The connection between an influenza virus surface protein and a host cell lipid has been discovered by researchers at the University of Maine and the National Institutes of Health. Confirmation of direct interaction between the protein and lipid could lead to new antiviral therapies.
The UMaine-led research team is now testing a hypothesis that a certain region within the protein hemagglutinin (HA) — its cytoplasmic tail — could be the site of interaction with the host cell lipid PIP2. Because of the stability of the HA tail, there is potential for a targeted treatment that could continue to work, despite the frequent mutations of other parts of HA, according to the scientists, who reported their findings in the Biophysical Journal.
“Our findings show for the first time a connection between the influenza virus surface protein HA (the H in H1N1) and the host cell lipid PIP2,” says UMaine professor of physics Samuel Hess, the team’s lead scientist. “With further single-molecule microscopy experiments, we are now testing the hypothesis that a certain region within HA could be the site of interaction with PIP2.”
HA has two roles, according to the Centers for Disease Control and Prevention website. The surface protein allows a flu virus to enter a healthy cell and acts as an antigen that can trigger an immune response that protects the host from reinfection by the same flu strain. That makes HA one of the active components of inactivated flu vaccines. According to the CDC, most seasonal flu vaccines are designed to target HA of the flu viruses that research suggests will be most common during flu season.
Video credit: The University of Maine
PIP2 controls a large number of cellular functions through signaling pathways it can modulate. Many of these pathways control the actin cytoskeleton, a structural framework for cell shape, motility and membrane organization. During flu infection, manipulation of such signaling pathways by the virus can allow it to suppress innate immune responses, keep infected cells alive, and increase the rate of assembly and escape of new viral particles.
Many proteins that have been seen together with HA are known to control the actin cytoskeleton, and they also have known binding to PIP2, but the connection was not previously explained.
Using confocal and super-resolution microscopy, the latter a patented technology developed by Hess, the researchers imaged HA and PIP2 in several living cell types and observed that they sometimes occupied the same regions in the plasma membrane defining the cell exterior. HA and PIP2 also were observed affecting each other’s motions. Having HA present caused PIP2 to move more slowly, reverse direction more frequently, and be more highly confined into clusters. Having PIP2 present caused the density of HA to increase. A high density of HA on the surface of the virus is necessary for viral entry into uninfected cells through a process called membrane fusion.
Video transcript, by Sam Hess:
The big challenge is that people still get sick from the flu. The virus mutates every year, so the vaccine is playing catch‑up to that. We’d really like to have something that could fight the flu even though it’s changing, even though it’s mutating.
We’ve developed a technique called super‑resolution microscopy. It allows us to see what’s happening at the molecular scale, inside of a cell it’s either being infected by the flu or has some parts of the flu virus present. We discovered that one of the components, which is called HA or hemagglutinin, it’s the H in H1N1, is connected to a lipid that’s part of a host cell.
This lipid’s called PIP2. While many lipids are passive players, this particular one is able to signal or control signaling in the cell. That’s one thing that the virus could exploit. We discovered that the HA and the PIP2 are together in the same region and also that they affect each other, how they move, how they concentrate, and how they cluster.
That discovery means that there’s probably an interaction of some kind between these two things — the HA and the PIP2. If we could attack that interaction and break it up, then that could stop the virus from being able to manipulate the cell. We think that the HA and the PIP2 are interacting through the tail on the HA, which is a very short region. It’s very much consistent from strain to strain. I mean you could screen a bunch of different drugs to see if something is able to block that interaction.
This is a super‑resolution image of HA, the flu protein in green, and PIP2, which is the cell lipid. That’s colored in pink. There are areas where the two are together. It makes a strongly white cluster.
If you attack part of the virus that changes each year, then your strategy has to change as the virus changes. If you attack part of the virus that’s invariant, that’s conserved from year to year, and that’s what the tail is, it’s consistent, then either the virus gets killed by or isn’t able to replicate because of the drug, or the virus mutates something that it needs. Then it dies on its own.
It’s a connection that’s never been seen before. If we can block that interaction, then we have something that the virus can’t mutate out of. I think of this as like a bad relationship, three people that are competing. The HA is stealing PIP2 away from those other proteins, like a bizarre love triangle.
I think it’s really exciting. Some people were quite surprised. I know some of my colleagues have heard what we found. They’re already planning some of the parts of their lab’s work to use this and investigate this finding further.
The flu causes tens of thousands of deaths per year in the United States. The available drugs for treating the flu are quite limited. The viruses that are circulating have resistance. Some of them have resistance to the available drugs.
All it takes is a few mutations to get us from the strains that are going around now into a 1918‑type flu. That type of virus would be a disaster. It was a disaster. We’d like to have some more options for fighting off something like that.
This article has been republished from materials provided by The University of Maine. Note: material may have been edited for length and content. For further information, please contact the cited source.
Curthoys, N. M., Mlodzianoski, M. J., Parent, M., Butler, M. B., Raut, P., Wallace, J., . . . Hess, S. T. (2019). Influenza Hemagglutinin Modulates Phosphatidylinositol 4,5-Bisphosphate Membrane Clustering. Biophysical Journal, 116(5), 893-909. doi:10.1016/j.bpj.2019.01.017
Image sourced from https://3dprint.nih.gov/
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