Flu season is always right around the corner, and although it’s predictable, it’s also deadly.

Seasonal flu can kill more than  half a million people every year by some estimates, and every year,  it’s a roll of the evolutionary dice with a chance of – sorry – another pandemic. And we actually have a pretty good  idea of how the flu kills you – what we don’t have is a way to stop it.

However, researchers have presented  a novel drug candidate that, while it won’t stop you from getting the flu, might just stop you from dying from it. [♪ INTRO] First, a quick refresher on the flu. You probably know it as a winter disease – it’s most common around October  to December in the Northern hemisphere, and then around April  to July in the Southern hemisphere. The culprit of this winter  woe is the influenza A virus.

It’s sphere-shaped and covered  in two kinds of spikes, hemagglutinin and neuraminidase – but  we’ll call them, for short, H and N. H and N work together so the  virus can infect human cells. H latches onto a molecule on the surface of cells, while N helps the virus cut itself in.

Different versions of those spikes  give each virus variant its name, like H1N1 and H3N2, the two main  types that are – at the moment – responsible for seasonal flu in humans. Then there’s H5N1, a type of  avian influenza or “bird flu,” which makes the news distressingly often. It gets attention because it is more  deadly than most and is likely to cause a pandemic if it can just work out  how to spread from person to person.

But regardless of the strain,  the flu can kill in three ways. About one third of flu-related deaths  are caused by organ failure during the infection, and another third are  due to a second, bacterial infection. The remaining third of deaths  are caused by the way the immune system reacts to the viral  infection – or rather, overreacts.

Now, a study published in the journal  Nature presents a possible drug that could protect people  from that immune overreaction. But to understand how it works, we need to get a flu’s-eye-view of the situation. The virus needs to infect cells  so that it can make more viruses that can infect more cells and  make more viruses, and so on.

Specifically, it infects the cells  that line the inside of your lungs. But those cells aren’t just  looking out for themselves. They need to protect you,  too.

So they will literally self-destruct if it might  help you get over the flu. The thing is, you need those cells to breathe. And too much self-destruction leads  to severe lung injury and death.

Your cells rely on a protein called RIPK3, which is a pretty metal name,  to make the tough decisions. And RIPK3 gives the cell two options:  the easy way, or the hard way. First, the easy way: Apoptosis,  often called “programmed cell death.” When RIPK3 shows up, its  presence activates some other cellular machinery that  causes the cell to collapse.

Like expert stagehands disassembling  a set, a bunch of enzymes cut apart the cells’ proteins and DNA, and  a unique signal on the cell surface sends the message that other cells  can absorb and recycle the pieces. It’s a pretty low-key event that doesn’t cause too much trouble for your immune system. Easy peasy ay-poh-squeezy.

Cool, so, what’s “the hard way”? Well, that’s when RIPK3 brings  out the big guns: necroptosis. Unlike apoptosis, necroptosis  is an inflammatory cell death.

The dead cell gunk isn’t packaged  up as nicely as it is in apoptosis, and the process releases chemicals that signal Hey! This part of the body is in distress. In response, extra fluid and  cells from the blood collect around the damaged cells to  try to contain the damage, which is why an inflamed area gets puffy and red.

And the immune system sends a flood of even more inflammatory molecules called cytokines. And these, of course, can be useful in small doses to help clear away infections. But with too many cytokines,  you can get a cycle of more and more inflammation, which damages organs and is linked to lethal cases of the flu.

You may remember how we all had to learn the phrase “cytokine storm” during COVID? It’s pretty much the same thing. Under most circumstances,  RIPK3 won’t cause necroptosis unless apoptosis is blocked for some reason.

But during an influenza infection, RIPK3 causes both apoptosis and necroptosis at the same time. So, for years, scientists  have been fiddling with RIPK3 to find a way that it can still  cause apoptosis, but not necroptosis and all the inflammation that comes with it. Luckily, RIPK3 causes those two kinds  of cell death in two different ways.

For necroptosis, RIPK3 functions as  a type of protein called a kinase. Kinases do a very specific  thing: they add a chemical tag called a phosphate group to another molecule. That phosphate group touches off some kind of signal and causes something to happen.

In the case of RIPK3, that signal tells the cell: Ok, boys, we’re doing this the  hard way. And necroptosis begins. For apoptosis, though, it’s simpler.

RIPK3 doesn’t need its kinase activity – it doesn’t pass a phosphate group to anyone. It just rolls out of bed and shows up. So the thinking goes, if you can  stop RIPK3’s kinase activity, but still have it be there, you  get apoptosis without necroptosis.

And in April 2024, a study in  the journal Nature presented an experimental drug called UH15-38  that can do exactly that… in mice. They tested a bunch of similar  molecules until they found one that interacts with a key part of  RIPK3 that does the kinase-ing. Then, they gave it to a group  of mice with flu infections.

For four days, some mice received UH15-38, and others received either other  drug candidates or a control. Mice that received the drug saw less  lethality and less lung injury from necroptosis after a flu infection  compared to those without the drug. No inflammatory cytokines.

And the cells that line the lungs were largely safe and sound. Lastly, the researchers confirmed  that UH15-38 can prevent necroptosis after a flu infection  in human cells in the lab. And in an especially good piece  of news, for the mice at least, UH15-38 was useful at least  5 days following infection, unlike other antivirals that need to be given within 2 days to have much impact.

Meaning we might have way more time to get it to somebody who needs it. This is really exciting  progress toward a treatment that could protect people  from deadly flu infections. But, of course, there is a lot  of work to do before something like this hits the shelves at your local pharmacy.

This study all took place  either in lab dishes or in mice, and drugs need to go through  clinical trials in people, and official approval,  before they reach you and me. And this drug is also specific to the flu. It wouldn’t be able to protect  people from severe cases of COVID-19, for example, because even though  the way the infection goes down in your lungs is really similar,  necroptosis works differently in COVID.

Still, this is a huge step forward  for a drug that we badly need. If we could have this drug  ready for the next flu pandemic, or even just the next bad  flu season, it could make a big difference toward saving many, many lives. [♪ OUTRO]