Life right now, for someone who studies respiratory virus infections, can be hectic and alarming. Akiko Iwasaki, a professor of immunology as well as molecular, cellular, and development biology at the Yale School of Medicine, hasn’t had a weekend or any break, really, for the last several weeks. Her lab has been scrambling, working nearly nonstop, to ensure that people around Yale, in New Haven, Connecticut, can be tested for COVID-19.
“It’s totally organic and grassroots,” she said, “because we don’t have enough kits coming from the federal government, not even from the state.” Her lab can test hundreds of people at a time—the capacity isn’t the problem. It’s all the red tape, the need to acquire the right sorts of approval for testing. “This should have been actually coordinated by the Centers for Disease Control in a rapid and uniform manner,” she said, “But it hasn’t. This has been an absolute nightmare for everyone.”
On the phone, in her office at Yale, Iwasaki seemed relieved to have cleared a major hurdle, and happy to be able to discuss a new paper she and her colleagues published in the Annual Review of Virology. The researchers describe the seasonality of respiratory viral infections, including SARS-CoV-2, the novel coronavirus responsible for the growing number of COVID-19 cases worldwide. This pandemic is all she’s been thinking about. “We can’t do any research that’s unrelated to COVID anymore,” she said.
What role did winter play in the spread of the pandemic?
Winter definitely plays a role because we know, by studying many other respiratory pathogens, that the winter months provide an ideal situation for viruses to transmit in the air. If you look at the influenza virus, the peak is in winter. Part of the reason for this is because we have low humidity indoors during winter, and that is an ideal condition for the virus to survive in the air. Another part is the fact that our defense against respiratory viruses declines in low-humidity settings. These things usually contribute to infection and transmission of influenza and other respiratory viruses.
Why does low humidity help the virus spread?
What happens when you cough or sneeze is that you expel the virus particle inside these droplets. When the droplet hits the air, and it’s very dry, it loses the water content and it becomes desiccated. Little dried particles float in the air, and they tend to persist in the air for hours. Whereas if the humidity is high, those droplets acquire water vapor from the air, and they become larger and they drop on the floor instead of infecting someone else. The low humidity basically allows these aerosolized particles to remain in the air for much longer because they don’t retain the water very well.
Did another winter factor come into play?
Likely sunlight, because it’s important to metabolize vitamin D. In the winter, people tend to stay indoors more often and they’re not getting enough sunlight. Vitamin D is well known to boost the immune system. That’s another winter factor that might affect the person’s ability to defend against the respiratory infection.
We’re not even at the peak of it. We are just bracing.
Will summer save us?
No, this doesn’t mean summertime will basically cure the virus. The aerosol transmission will likely reduce in the summer, but the direct transmission—as well as fomite transmission through things like skin cells and clothes—is still going to happen.
What sets this virus apart from common cold coronaviruses?
Definitely this virus is more virulent, more lethal. You don’t really die of the common cold, but this virus kills. The other difference is it seems we don’t have any prior immune response to this version of the coronavirus, so nobody has resistance. Whereas with the common cold, most of us have been exposed multiple times—we have antibodies and T-cell response, so the disease is much milder. This virus also has a very long incubation period. You might be infectious but you don’t know, because you don’t have any symptoms. That makes this virus very contagious, with the ability to spread well among humans. The key gap in the field is to try to understand what type of immune response is protective. We still don’t know exactly what we’re even aiming for with a vaccine. We don’t know which type of antibody responses confer protection versus which type will trigger worse disease. Similar for T-cell response, and so on. These are insights needed for therapy and vaccine strategies.
What makes it inherently lethal?
There’s a lot of theories. We don’t really understand it well. There’s some immune component to the disease. People who have severe COVID disease have what’s called a cytokine storm, and that’s basically an overdrive of the immune response that in itself is toxic to the person. It’s being stimulated without any breaks. The virus itself may not be causing the illness. We’re all trying to figure out why the storm happens. It’s possible that the immune system turns against itself. For instance, there may be some antibodies that are developing in a person that instead of blocking the virus replication, it might enhance the activation of the immune response. That could be leading to these severe cases of disease.
Why do viruses make us cough or sneeze?
There was recently a nice paper on the tuberculosis, which shows that the bacteria actually makes a metabolite that induces you to cough. That’s certainly a bacterial strategy to transmit from one person to another. Now, whether the virus encodes a similar kind of strategy is unclear right now. Mostly, coughing and sneezing is a host response to get rid of the virus. I think it’s still the case that we’re trying to get rid of the virus by coughing, but whether the virus is making us do that, I’m not sure if there’s any evidence for that.
How does a novel coronavirus differ from viruses that have been with us for a long time?
If you look at pandemic viruses that emerge as human-to-human transmission for the first time, they tend to be quite virulent, at least the ones that we understand, we know of. When a pandemic flu, or this COVID-19, first emerge in humans and start transmitting, they tend to have quite high virulence. What happens is that the virus will eventually be selected for its ability to replicate and transmit. Those features might be in conflict with virulence because if a virus makes you so sick that you’re not going out of the house and infecting other people, then the success of the virus dies right there. For viruses that have been circulating for many years, like the rhinovirus, you usually don’t get so sick to a point where you stay home and don’t interact with anyone. That sort of makes these viruses much more successful than if a virus were to kill you immediately. There’s a balance that the virus has to strike to become successful. Over the years, usually the virus that’s circulating in humans tends to have less virulence so that people go out, infect others. I’m not sure whether that’s going to happen to this particular virus.
Can a conflict between viruses be a good thing for us?
A prevalence of a single virus will prevent the prevalence of another virus in the population. This is kind of well studied for rhinovirus and influenza. Rhinovirus usually happens in the fall, and when that drops, then you see a rise in the influenza virus. It’s thought that part of the reason for this viral conflict comes from the fact that immune responses, when they’re generated against a single virus, will be cross-protective to other viruses. That’s the innate immune response that I was talking about. The early immune response that happened during an infection will produce this alarm signal against all viruses. Let’s say if you’re infected with the rhinovirus right now, you may not be as susceptible to COVID-19 as if you weren’t. That’s the conflict that a person might have within themselves.
Definitely this virus is more virulent, more lethal. You don’t really die of the common cold, but this virus kills.
Theoretically, could a possible treatment be for people to go catch colds?
That’s kind of a radical way to defend against this virus, because you pretty much have to have the cold all the time in order for it to work. There are probably better ways to deal with this, rather than catching a cold.
Is this coronavirus especially good at getting by our antiviral defenses?
It’s not clear what kind of invasion mechanisms they have. Looking at the fact that the vast majority of people who are infected have very little to no symptoms, I would think that they are able to somehow circumvent the immune response, but exactly how they do this, we don’t know. Largely all viruses have mechanisms to block the host immune response, particularly these early immune responses that happen within infected cells. Every virus that I’ve studied so far codes for genes that block the ability of the cells to either recognize the infection or alert the other cells that there is an infection. Sometimes they block the whole immune process. I wouldn’t be surprised if this virus has come up with some way to evade immune detection.
Can you explain what innate and adaptive immunity are and how they relate to this coronavirus?
The innate immune response is the first line of defense that we have against viruses, and that happens within minutes to hours to a few days into the infection. Every cell type, every cell in the body, is equipped to mount certain types of immune response against pathogens like viruses. When a cell is infected, they can detect the presence of the virus using sensors. Every cell has sensors that detect the presence of the virus. When the sensors are triggered, it creates an alarm signal. The alarm signal is also known as cytokines or interferons. When these alarm signals are released, the neighboring cells detect this alarm signal through their receptors and induce an antiviral state. This happens in response to any virus. That is the sort of innate immune defense, and that’s mediated by any cell types in the body. Whereas the adaptive immune response is mediated by only one type of cell, known as lymphocytes. Lymphocytes come in different flavors. There are B cells and T cells. B cells ultimately generate antibodies that are specific to the virus. Antibodies are critical in removing and getting rid of the virus ultimately. The T cells become killer cells and they start killing the infected cells. The source of the virus is eliminated that way. The combination of the killer T cells and antibodies is what ultimately clears the virus infection, and that’s the adaptive immune system.
What explains why infants and young children seem to be more resilient against COVID-19?
I suspect that their immune response is such that they’re not leading to the second phase that I was talking about where there’s cytokine storm and toxic immune overdrive. Children may not be engaging in that type of response. Again, this is a big key question that we need to investigate. We don’t know the answer to this question yet.
In early March many thought, like Elon Musk, that panicking about the virus was dumb. What was your sense of the threat coronavirus posed in early March?
I didn’t think it was dumb at all. In fact, we’re not even at the peak of it. We are just bracing. In a week or so, we will see the peak death rates coming. We’re not even close to being done.
Why don’t some carriers of the virus get sick?
Those people, interestingly, are completely resistant to the disease aspect of COVID-19, but they are factories of the virus. How exactly these people become these so-called super-spreaders, it’s unknown. The super-spreaders are a well-known phenomenon for any kind of infectious disease. The biology of the super-spreader is unclear. It’s likely that they’re somehow not triggering the inflammatory responses that make people feel sick, such as a cytokine storm. It’s not a good state for the population because these are the people responsible for outbreaks, but if you are the super-spreader, I don’t think it’s too bad. I’m not so sure what kind of harm you’re really inflicting yourself, just being a viral factory. I’d love to meet people like that and study them. It’s really hard to identify who the super-spreaders are, so they haven’t been studied very well.
What can we learn from super-spreaders?
That is the entire field of study called disease tolerance. Disease tolerance, instead of trying to reduce the virus load, is to prevent the toxic effect of a viral infection. What a super-spreader might be undergoing is disease tolerance. They’re immune to the effect of the viral infection, presumably because they don’t create the cytokine storm or activation, like overdrive of the immune response. It’s definitely a strategy that people are thinking about using to treat severe cases of the COVID virus.
Where do you stand on the mask question? Should people without symptoms wear them proactively?
I have mixed feelings about that because we need to reserve the masks for healthcare workers who really need them. If we had an unlimited supply of masks, yes, I would say everyone should be wearing masks when they go outside, but because of the shortage, I hesitate to say that. People are making homemade masks, which isn’t perfect for preventing transmission, but it’s better than nothing.
Do you see yourself as fortunate, amid this pandemic, for having already been interested in respiratory viral infections?
I sometimes wonder if I’m fortunate or unfortunate. If I were a plant biologist, say, maybe I could read a book and write papers, do other things other than COVID-19. On the other hand, I am in a privileged position because I’m already an expert in the field and I can contribute to society in a way that others can’t.
Brian Gallagher is an associate editor at Nautilus. Follow him on Twitter @BSGallagher.
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