The coronavirus at 1: A year into the pandemic, what scientists know about how it spreads, infects, and sickens 

The coronavirus behind the pandemic presents some vexing dualities.

It’s dangerous enough that it dispatches patients to hospitals in droves and has killed more than 1.6 million people, but mild enough that most people shrug it off. It blocks one arm of the immune system from responding as it takes hold, but lures other parts into dangerous hyperdrive. It homes in on cells high up in the airway — think the nose and throat — but also burrows deeper into the lungs, maximizing infectiousness without ceding how sick it can make people.

“It’s sort of right in that sweet spot,” said Kristian Andersen, an infectious disease expert at Scripps Research Institute.

A year into the pandemic, STAT is outlining a portrait of SARS-CoV-2 based on what scientists learned as the virus raced around the world, crippling some economies, societies, and health systems in its wake.

How the virus cracks open cells and wards off the body’s first-line attack. How it can spread before people start feeling sick. How it’s changed since the dawn of the pandemic, and what, if anything, that means. How the omnivorousness of the disease it causes, called Covid-19, reaches not just the lungs but into the heart, brain, gut, and beyond.

How this virus has caused the damage it has, unlike other respiratory viruses that also prey on our impulses to get together — to pack into crowds, to laugh, to sing — and use them as stepping stones in their mission to infect cells and make copies of themselves.

There are still lots of questions about SARS-2, as scientists call the virus for short, from basic biological queries to multifaceted mysteries, like why certain people get so sick. But for a virus that’s sometimes portrayed as bestowed with superpowers, experts point out that SARS-2 is in many ways, well, pretty normal.

That’s not to minimize the harm it can inflict, or to gloss over the tricks it has up its sleeve. But SARS-2 shares lots of features with viruses scientists have seen before, if perhaps to more extreme ends.

“It’s got its own character, so to speak, but there’s nothing really out of the ordinary, it’s not that weird,” said Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago. But she stressed: “This is still a pretty intimidating virus.”

Meet SARS-2

It’s Coronavirology 101: These RNA viruses have spike proteins that look like geysers spurting out of the surface and that latch onto a receptor called ACE2 on human cells. This allows the virus to enter the cell and, by taking over some of the cell’s own machinery, to churn out copies of itself. These descendants then burst out of the cell and seek out new cells to infect.

Though it’s tempting to anthropomorphize viruses, they’re not really alive in the ways we normally imagine that state of being. They’re more like replicating Roombas, moving forward with a single purpose — though, instead of vacuuming, they’re fixated on multiplying.

The single advantage that’s propelled SARS-2 on its around-the-world quest: People can pass it to others before they start feeling sick or even if they never show symptoms. Together, this accounts for more than 50% of new cases, according to the Centers for Disease Control and Prevention.

This is not the case with the two other coronaviruses, MERS and the original SARS, that in recent decades have spilled from animals into people and raised global alarms. Those infections are much deadlier than the one caused by SARS-2 — MERS in particular — but people are only contagious once they show symptoms. It’s much easier to stop a virus when you have a clear sign of who is infected. (There are four other known coronaviruses that infect humans, but they cause common colds.)

“It’s a very clever virus,” Susan Weiss of the University of Pennsylvania said about SARS-2. “If a virus infects someone and kills someone immediately, it can’t spread easily.” But with SARS-2, people who appear healthy can go about their lives while transmitting the virus — a feat Weiss called “diabolical.”

How SARS-2 does this remains unknown. The virus seems to build up in high levels before the immune system catches onto its presence, which is what triggers symptoms like fever. If there’s lots of virus in a person’s nose and throat, it could be easily “shed” to others through breathing (and talking, yelling, and laughing).

SARS-2 had the upper hand in another way too: We were sitting ducks. Because it was a new virus, essentially everyone was “naïve” to it — science-speak for being susceptible to an infection.

But there’s a curious fact about SARS-2 transmission: Many cases dead end. While some people pass the virus to one person, like a spouse or parent, researchers have found that so far, some 10% to 20% of cases have propagated the majority of new infections, often in superspreading events. That creates a vulnerability in the virus: Experts know which settings foster such transmission — like crowded and stuffy indoor places where people aren’t wearing masks — so interventions can be designed to minimize that.

Indeed, with comprehensive strategies, many countries have contained the virus, or at least suppressed its spread. That’s another thing we know now that wasn’t clear in the early days: It’s possible to control SARS-2. In fact, what experts say they’ve been most surprised by is not the pathogen’s wiliness or what an infection does, it’s the human failures that have opened the door for its rampant run.

“The reason there’s a pandemic has everything to do with us,” Andersen said.

What happens when the virus arrives

For all the genetic overlap between the new coronavirus and the original SARS virus (hence the name SARS-2), there are differences that experts say could explain why the younger virus, with its 30,000 genetic “letters,” spreads more efficiently.

For one, the exact part of the SARS-2 spike protein that docks onto cells — called the receptor binding domain — attaches more easily to the ACE2 receptor than the one on SARS-1 does. This could mean that people need to be exposed to less virus for an infection to take hold.

And unlike SARS-1, SARS-2 has what’s called a furin cleavage site, which helps the virus pass into cells. “That’s what makes SARS-2 SARS-2,” Andersen said about the differences.

But Weiss, a member of the coterie of researchers who have been studying coronaviruses for decades, cautioned that the virus’ biology might not fully explain why it spreads the way it does. Perhaps SARS-2 just hangs out in the nose longer than MERS or SARS. The point, Weiss said, is that genetics can’t always explain what’s observed.

“Small differences in genetics can make a big difference in behavior, but to translate that to anything at this point in a way that makes sense, we just don’t know,” she said.

The immune response

When a pathogen invades, you want your immune system to get into gear. You rally an array of protections: first, a general defense, and then fighters that get more targeted as they learn the new enemy’s specific traits. But the immune system can also overdo it. When people get severely sick from Covid-19, it’s often not because of the virus itself — it’s the immune system ramping up so violently it sends them into respiratory distress and sometimes kills them.

SARS-2 seems to present a nasty combo. It can interrupt the immune response you want, and also cloak itself in ways that send other parts out of control.

All viruses — all viruses that make us sick, that is — have some ability to blunt the immune system’s first responders. They typically block what are called interferons from emitting a “suit up, there’s a pathogen here” signal — one that would otherwise help slow down viral replication.

“But maybe,” said Yale University immunologist Akiko Iwasaki, “SARS-CoV-2 is super effective” at dampening interferons. This could allow the infection to go from a toehold to a full footprint.

As it’s “antagonizing” the interferon Bat-Signal, SARS-2 also allows another arm of the immune system involving inflammatory molecules called chemokines to run free. From there, the cycle of immune mayhem only builds, as the body’s reinforcements overcompensate for the initial defensive lapses.

“To me, all the consequences of developing Covid-19 stem from that particular attribute,” said Benjamin tenOever, a virologist at Mount Sinai’s Icahn School of Medicine.

Other infections also lead to harmful immune responses, but “what makes Covid so unusual” is the intensity of the resulting inflammation, tenOever said. When that occurs deep in the lungs at the site of the infection, fluid can leak in, making it harder for people to breathe.

Of course, this dangerous immune response only occurs in a subset of patients. In most of these battles between the virus and the host (that’s us), the host’s defenses can overcome the pathogen. In those who shake SARS-2 off quickly, perhaps enough of that initial immune response slips past the virus’ anti-interferon actions and wipes out the virus. In other cases, it might take a bit of time for the immune system to kick into proper gear and mount the fighters that can target SARS-2, but they’ll eventually fend off the infection.

So why is it that some people get severe Covid-19? Age is a key factor; because older people have sleepier immune systems to start, the blunting of the initial response is even more impactful and allows the dangerous spiral to begin. But even for octogenarians, the most likely result is that they’ll survive the infection. Genetics, other health conditions, sex hormones, and perhaps how people are exposed to SARS-2 could all factor in — which explains why there are such varying responses.

“There are some 75-year-olds who look like 20-year-olds, and there are going to be some 20-year-olds who look like 75-year-olds,” Iwasaki said.

For some people, it seems that even after the infection the immune system has trouble relaxing to baseline. That is what experts believe is happening in “long haulers,” those who recover from Covid-19 — often just after a mild case — but who have lingering complications. Some might have even generated molecules called autoantibodies that, instead of going after an invader, attack what’s left behind by cells destroyed by the infection.

Other acute viral infections can also lead to long-term effects, but Covid-19 has touched so many millions so quickly that thousands are now struggling with symptoms like headaches, fatigue, and forgetfulness, months after their initial bout.

The illness

If SARS-2 spreads so well because it infects cells in the upper airway, it makes people so sick because it can also migrate deeper in the lungs. (Respiratory viruses tend to target one spot or the other.) But thinking of Covid-19 as just a respiratory infection belies its protean nature.

People with Covid-19 have had heart complications or trouble in their guts and kidneys. Early on, as patients complained they couldn’t smell or taste, it became clear it was having some impact on the nervous system.

It’s difficult to tease out whether Covid-19 is particularly eclectic. So many people have gotten it that we’re seeing the full scope of what the infection can do, including the outlying cases. Other viruses can also cause a range of different-looking illnesses.

“If you infect enough people who are all going to respond differently, you’re going to see a lot of different presentations,” said Angela Rasmussen, a virologist at the Georgetown Center for Global Health Science and Security. “Individual hosts can yield a whole slew of outcomes.”

To some experts, SARS-2 seems to possess a notable ability for reaching beyond the lungs, perhaps a result of the virus itself, the ensuing inflammation, or some combination of the two. When inflammatory molecules flood the lungs, for example, some slip into the bloodstream, along with debris from destroyed cells. They can travel to other parts of the body and lead to tissue-damaging inflammation there as well as blood clots.

“You get a lot of things circulating in the blood that have no business being there,” said tenOever, the Mount Sinai virologist.

Direct infection could also be driving some of the damage. Iwasaki, for example, described what she saw as “an unusual amount of [nervous system] involvement” from Covid-19, caused by “not just inflammation, but invasion” of the virus into the brain.

ACE2 receptors line tissues throughout the body, leaving them open to infection if the virus can reach them. Studies of blood haven’t shown high viral levels, but perhaps in some people some virus is hitching a ride through the lymphatic system or the bloodstream to other organs. (One potential factor for why younger children don’t appear to get infected as older people do is because the number of ACE2 receptors remains relatively low until puberty.)

Covid-19 is not just heterogeneous in presentation, but in severity. One in five people who get it never feel sick at all, while another one in five will get severely or critically ill. Experts say the fact that the vast majority of people will recover just fine has made it harder to get everyone to take it seriously — and in turn to take precautions to protect themselves, their communities, and health system capacities. Experts wonder if people might act differently if SARS-2 had a mortality rate like SARS of nearly 10%, as opposed to 1% or less.

“People are like, my cousin got it and he was fine,” said virologist Juliet Morrison of the University of California, Riverside. “Well, you might have a genetic propensity to develop more serious disease, or you might have an underlying risk factor you don’t know about. Seeing how it’s presented in one individual or even the majority of the population does not mean you’ll have the same disease presentation.”

What happens to most people

Alarming headlines about reinfections and fading antibodies have suggested that perhaps our immune systems aren’t upholding their duty to protect us from a second Covid-19 case after we recover from an infection. But experts say most people are responding to this virus like other infections of its ilk. They are generating antibodies and T cells that can target SARS-2 should it appear again. And even if antibody levels fall off over time, it doesn’t mean they can’t be whipped up should an exposure occur.

In other words, this is what’s supposed to happen.

“In the vast majority of people who have milder disease or asymptomatic infection, this virus acts just like any other respiratory infection,” Iwasaki, the Yale immunologist, said. “It’s likely contained within the upper respiratory tract or it’s quickly cleared from the lungs.”

Immune responses aren’t uniform, and protection will wane at different rates; it could be months for some people but years for others. But the expectation is that people who contract SARS-2 again will generally have milder illness in subsequent rounds — perhaps even asymptomatic infections. The immune system may not block the infection entirely, but it can prevent people from getting sick.

It’s not known how many cases of reinfection there have been — experts presume many asymptomatic and mild cases go uncounted — though they’re generally thought to be rare as of now. But the first documented reinfection in the U.S. raised concerns because the person got sicker the second go-round. It’s not entirely clear why that happened, but one explanation is that if someone has a mild initial case, the virus might be vanquished before the body has a chance to rally a robust response — meaning there aren’t those immune defenders sticking around for when the virus appears again.

For now, that appears to be an outlier.

“The vast majority of people who recover from an infection without complications are likely mounting a good protective response,” Iwasaki said.

A changing virus

Viruses evolve. And already, one mutation for the spike protein, referred to as D614G, appears to have made the virus more transmissible (though it doesn’t seem to have had an impact on how sick it makes people).

It’s not that the original variant was a lackluster transmitter, experts say, and it’s not that D614G cannot be corralled. But the mutation might have given the virus an extra push, helping it emerge as the dominant line as it tore from China to Europe to the United States and beyond.

“D614G has not helped the situation, but the virus was spreading well before,” said Jesse Bloom, an evolutionary virologist at Fred Hutchinson Cancer Research Center.

The concern with mutations is that they might cause the virus to “escape” the protection conferred by vaccines. The leading vaccines were designed based on the genes encoding the spike, so it’s possible that changes there could reduce the immunizations’ effectiveness.

While coronaviruses don’t mutate as quickly as flu or HIV and have proofreading systems, they do pick up changes as they go. But it’s not just the mutation rate that’s important, the University of Chicago’s Cobey noted. It’s also how “tolerant” the spike protein is to the mutations. If a change occurred that meant the vaccines were no longer effective — but also changed the spike so that it could no longer bind to cells — it wouldn’t matter.

Essentially, it’s not just the number of mutations the virus picks up; they have to be the right mutations to make a difference — changes that give that variant an advantage over other ones so it takes off.

Experts say that it could take a while for that to happen with SARS-2, but that it’s something they’ll be keeping an eye on. Already, international efforts to monitor emerging variants are underway. If an escape does happen, the vaccines could likely be tweaked to match the changes.

“I don’t think this is something to be alarmed about,” Bloom said. “We just need to pay attention.”