This episode was filmed on April 2nd 2021.

For our most up to date coverage of the COVID-19 pandemic, be sure to check out the playlist linked in the description. [♪ INTRO]. Even though scientists have learned a whole lot about COVID-19, this pandemic has also highlighted the fact that there’s a lot we don’t know about our immune systems.

Like, one thing that’s really throwing researchers for a loop is that a fair number of people who catch the SARS-CoV-2 virus just… don’t show any signs of being infected. No one’s quite sure how prevalent these symptomless, or asymptomatic cases are. And that’s especially concerning for a disease that lands between five and thirty percent of people in the hospital!

What researchers are fairly sure of, though, is that there isn’t one answer to why people don’t feel the effects of SARS-CoV-2. And looking deeper into the many potential explanations will teach us a lot about how our bodies fight pathogens. Now, technically, everyone with COVID-19 starts out symptom-free, or pre-symptomatic.

No one is coughing the instant the first virus gets into one of their cells and convinces it to start churning out more viruses. There is an incubation period, and it can take anywhere from a few days to two weeks for people to start to feel an infection. Also, what ”feeling it” looks like varies.

It could be milder signs like a duller sense of taste or smell, all the way to life-threatening breathing difficulties or heart problems. Doesn’t matter where a person falls on that spectrum; even mild symptoms make a case count as a symptomatic infection. It’s also important to note that having an asymptomatic case of COVID-19 doesn’t mean there aren’t any effects on the body long-term.

Scientists are still keeping an eye on whether asymptomatic infections can trigger symptoms down the line. But being asymptomatic clearly lessens the odds of requiring emergency medical care off the bat. And one thing that stands out right away is that some groups of people tend to be less prone to severe cases, like kids.

As a group, people under the age of 18, and between the ages of 2 and 13 in particular, seem to be less likely to contract COVID-19 and less likely to experience symptoms if they do. And this might be because once a child's immune system is established, novelty is it's forte. Kids are newcomers to the world, so they haven’t encountered the myriad of disease-causing agents that grown-ups have.

And since SARS-CoV-2 is novel to everyone, kids seem to have some advantages that help them clear it more quickly and efficiently, often before they feel symptoms. The thing is, we’re not really sure yet what those advantages are. There hasn’t been enough research on how immune systems change with age to pinpoint exactly what might be at play.

Though, we might know a lot more in the coming years, as lots of researchers have been inspired by COVID-19 to look more closely at this! That said, one thing that does seem to change with age, which is very relevant to this virus in particular, is the distribution of ACE2 receptors. Those are the proteins that the SARS-CoV-2 virus uses to unlock and infect our cells.

They can be found in tissues throughout the body. But their presence in the nasopharynx is especially important, as that’s where respiratory viruses like SARS-CoV-2 usually enter our bodies, and where scientists believe these viruses can hang out and multiply. It’s possible, if kids have less ACE2 in those tissues, they can’t get a full-blown infection as easily, and that could have something to do with them not feeling symptoms.

And lo and behold, a May 2020 study in the. Journal of the American Medical Association found that the activity of the ACE2 gene was lower in children and increased with age. Now, other studies which, as of yet, have not been peer reviewed, have suggested that ACE2 in the nasal cavities drops again beyond the age of 60.

So, if those findings hold, this wouldn’t explain why that group tends to show more severe symptoms. But even in older people, the expression of ACE2 is highly dependent on environmental factors. For instance, grown-ups with respiratory allergies seem to have less ACE2 in their nasal passages.

So anything like that which affects where and how much ACE2 a person has may influence their likelihood of having an asymptomatic infection. And it’s not just about ACE2. Studies suggest the virus needs the help of another cell surface protein called TMPRSS2 to infect cells.

And kids also have fewer of those proteins in their nasal passages. This actually leads really well into some of the ideas researchers have for why some adults never show symptoms. You see, some people have variations of the ACE2 or TMPRSS2 genes that lead to fewer of these proteins in their nasopharynx; potentially to levels more like the amount seen in kids.

So they may stay asymptomatic simply because the virus can’t get a good foothold in them. And when it comes to the nose and throat, there are a lot of things that can affect whether a virus establishes itself. Like, the authors of a November 2020 paper in Frontiers in Immunology hypothesize that some people do a better job of creating a defensive coating of mucus in their nasopharynx.

Mucus might act as a physical barrier between viruses and cells, so the viruses don’t get a chance to latch onto cells in the first place. It also seems likely that a person’s front line immune defenses, or innate immunity, plays a big role in whether or not they end up developing symptoms. Studies suggest that SARS-CoV-2 is able to fly in under the radar of some people’s innate immune systems.

Essentially, the virus might be able to buy itself enough time to set up shop before the immune system catches on to its presence. Meanwhile, in asymptomatic people, innate immune cells seem to be better at clearing out the virus quickly. Like, studies have found that a significant number of patients with life-threatening COVID-19 have problems with their interferons, proteins that help spot viruses and interfere with their replication.

By contrast, some asymptomatic people may have extra-robust interferons that throw a wrench into the virus’s plans early in the game. So, a person's unique blend of interferon genes may end up explaining whether they develop symptoms, and not just because the proteins interact with the virus directly. Interferon activity also alerts T cells.

These are white blood cells that play a central role in the other major branch of immunity: adaptive immunity. That’s the one that remembers threats and deploys specific weapons when it spots something it recognizes. And yep, it also probably plays a role in whether or not an infected person shows symptoms.

One way adaptive immunity might do this is by being “primed” to attack a virus because of previous exposure to other, similar viruses, like, in this case, the coronaviruses that cause colds. The idea here is that SARS-CoV-2 may look enough like these other viruses that people who’ve had infections, especially recently, have a bit of a pre-loaded adaptive response that helps them clear the virus out faster. And there has been some evidence to back this hypothesis.

For instance, one small study found that COVID patients who had recently had a cold-causing coronavirus infection were less likely to end up in intensive care. This may not extend all the way to showing no symptoms, though. And having your immune system primed like this has also been implicated in severe infections, so clearly we have more to learn.

Still, there are other ways the adaptive immune system could be suppressing a person’s symptoms. Like, research also suggests that T cells stay cooler under pressure in asymptomatic individuals. While they send up a loud alert, they also send out chill vibes.

So, basically, they tell the immune system “There’s a problem here, but don’t freak out, ok? We got this.” And that, too, could be a clue as to why some people don’t show symptoms. See, a lot of the symptoms of a viral infection have less to do with the virus than the immune response to it.

Just look at cold and flu viruses. Some people who catch them don’t feel a thing, while others get knocked down for days. And that could have more to do with their immune systems than the strain they caught.

For instance, in a 2016 study published in Clinical & Experimental Immunology, researchers intentionally exposed subjects to an influenza virus. Those that went on to exhibit symptoms had higher levels of immune signaling molecules, while the reaction was muted in those who got infected but didn’t feel sick. And researchers have seen similar muted responses in asymptomatic COVID-19 cases.

Like, a June 2020 study of people in China found higher circulating levels of antibodies and immune signaling proteins in people with symptoms. Another thing that doesn’t seem to happen in people who aren’t noticeably sickened by COVID-19 is a lot of disease resistance. That’s the term immunologists use to describe the degree of pushing back against a pathogen that the immune system does.

People whose innate and adaptive immune systems go ham on a pathogen tend to end up with more severe symptoms. Though, again, balance seems to be key. As we talked about earlier, not having an effective immune response can let a pathogen get a foothold and make it harder to oust later on.

And having an immune system that’s well-primed for attack, like from a previous infection, can help you clear out an invader quickly and quietly. But too strongly resisting a pathogen can cause collateral damage, especially if the virus has already managed to multiply a lot. Basically, a desperate attempt to kill an invader can kill healthy tissue, too.

So you want your immune system to do its job, but not be an overachiever. And this goes back to those cool under pressure T cells. It may be that many parts of the immune systems of people with asymptomatic COVID-19 don’t act desperately, no matter how bad things look.

They go about their business calmly and efficiently without panicking. But again, we don’t have a lot of specifics as to what that looks like on the cellular level. Immune systems are really complex, and there simply hasn’t been enough research on people with and without symptomatic infections to suss out all the moving molecular parts.

As you can see, the possible reasons for asymptomatic infections have been piling up. From slowing the virus from the get-go to gently dealing with a full-blown infection, one thing is clear: there isn’t just one answer as to why some people don’t get visibly sick. It might even seem like we’re turning up more questions than answers.

But that isn’t a bad thing! This mystery about asymptomatic COVID-19 has spurred a ton of research into the inner workings of our immune system. And as with all kinds of science, figuring out the right questions to ask is the first step to getting answers.

Thanks for watching this episode of SciShow! If you have any follow up questions about immunity or COVID-19, or just random questions about science, feel free to ask them in the comments! We love hearing what you want to know more about.