COVID-19 Chapter 1: Virology

couple of days. So over the course of that weekend, the first ten or so towns were quarantined and all the schools in the north were closed. What happened next is that the regions asked for and got an extension of the closure of the schools. So it's been three full weeks now since schools have closed, and there's another three weeks planned ahead of us. At least I'm at school teacher, so it's been not easy to cope with all of this. So the thing is, the schools stopped,

but the rest of the country went on. But things started moving fast. So we are now under this lockdown which means that we cannot leave our homes unless it's for either work reasons or basic needs. Kind of a soft lockdown, because we can actually move, but we have to provide some sort of declaration of written statement for the reason why we are out of our homes. Until the government came out with the lockdown, I think people

didn't really appreciate what that meant. And so it was just a few days before that that there were still parties going on and restaurants and so on for the let's say, for the lockdown we are under now. So if I was to you know, go out small without a good reason, So if police is going to stop you and check your statement, so if it's for worksons, they are going to call your workplace and that so there is a fine or you could face charges. You could go to jail, but that's only for extreme cases

after the last regulations. So this past week, I think that people are taking the thing more seriously and from what I see from my immediate vicinity and people I know, we are starting to embrace the social distancing and so we are moving to skype calls with friends and we're you know, the indoors life as much as you can, and as a school teacher I maybe have a slightly different perspective than most other people because we started from the very beginning to find ways to still keep doing

school in some form, but there wasn't really a plan for that, so a lot of it was left to our own you know, creativity and good will to do things. There are there are still issues with that. The first one is that it's very hard to keep in touch with all our students because of course not everybody is available, not everybody has the same resources, and it's hard and it's impact families, especially families where the parents are still working and so they need to take care of the children.

Traditionally here families are very close knit and this was something that often grandparents did. But parents are of course one of the most impacted categories for the yeah for the virus, so that that has raised some issues. We have one of those flash mobs on the balconies every day basically, you know, I mean a small town, so

there's not a lot of houses around here. Every day there's someone either playing songs or the other day they were tapping for the people in the medical professions, which are doing a great job and taking Dublin gifts to cover every everything. So that's that's good. There's this other thing that's going on now, which is the kids are making these rainbow paintings and with an action that is basic, everything will be fine in Italian and they are, you know,

sharing those pictures on the social media. This is bringing out a lot of you know, good things. I see that really people care, people care about their neighborhoods, people care about what's going on. That's a big thing. H h yah m m m hm hm h.

ever want about COVID nineteen yep. So we asked everyone out there for questions, and hundreds of you submitted your questions. So first of all, thank you so very much because that really helped us to figure out what you wanted to know and how to organize these episodes, and so we are so excited to bring you not one, but six of these episodes where we ask the experts to answer your questions.

which is a little bit of a mouthful. This is the official name for the virus that causes the disease, COVID nineteen. You can break that down to see where that comes from. It's coronavirus disease nineteen COVID nineteen. And so this is a virus that is new to humans and it emerged, as it turns out, or as it

likely turns out, in November twenty nineteen. Obviously, this is now a pandemic, and so we are going to talk in this episode about the biology of this new virus and some of the characteristics that have allowed it or facilitated it to reach pandemic proportions exactly.

DNA or RNA along with protein. Viruses can't replicate on their own, so unlike most bacteria, for example, which can multiply just by replicating their DNA and then dividing into two, viruses have to infect a cell of some kind, a host cell, and use that host cellular machinery to actually replicate their genetic material. So, in the case of SARS covy two, this is an RNA virus. It's a positive

strand RNA virus. So that means that once it gets into your cells, that viral RNA is released into our human cells, and then our cells do two things with this RNA number One, they start copying it directly as if it was our own RNA. And number two, what RNA does in normal cell is it codes for protein.

So our cells start to use this viral RNA to make the proteins that that viral RNA codes for, and then the replicated RNA plus those proteins get assembled into new little virus packets, okay, and those new viruses can then burst forth from the cell and go on to infect another cell, either in your body or in another host. So that's how RNA viruses work. DNA viruses do essentially the same thing, except that in order to make protein from DNA, your cells have to first translate it into

that RNA. So RNA viruses sort of skip that step, and as you'll hear our expert talk more about, they also tend to make more mistakes in that process of replication. But either way, viruses are using your host machinery to do this. They can't replicate outside of host cells.

there's an immune response, an inflammatory response. Sometimes there can be metabolic responses and I study those and sometimes those responses, depending on what they are, can mean the difference between getting rid of an infection and having a mild short illness versus having a chronic illness or a more severe disease.

So the viruses that I've been studying lately are ebolavirus, MERSED coronavirus, influenza virus, other hemorrhagic fever viruses, and of course, now like many of my colleagues, I'm also studying SARS coronavirus two our COVID nineteen.

a number of these viruses that have been discovered. They're called bat sars like coronaviruses, very clever original name because they are very much genetically like SARS coronavirus and now SARS coronavirus too. We do know that this virus, probably based on our analysis of the genome, evolved from a rus one of these batsars like coronaviruses. We don't know if there was another animal involved in the spread of this virus from its wildlife reservoir the animal that had

it in the wild to humans. What we do know is that this spillover, which is the transmission of a virus from its wildlife reservoir into humans, was probably a single event, meaning that there weren't multiple instances of animals infecting people. After the first patient or patients weren't infected with this from whatever animal it came from, it's been

transmitted human to human ever since. The reason why it's important to understand eventually if this came directly from a bat or if it came from a different animal is that both STARS classic and MERS coronaviruses were amplified in an intermediate species, so both stars and mers are thought to have also originated in bats. However, SARS classic was transmitted into humans most likely from an animal called a civet,

and murrs. Coronavirus is known to be transmitted primarily from dromedary camels to humans, so we don't know if there was another animal in between the bat and the human that also was involved in the spillover from its wildlife reservoir.

early January. So we've been able to analyze the genome of this virus since before we actually were able to even isolate the virus. So we can look at the genome of this virus, and we can look at the specific individual changes in one isolate of the virus versus another, and by looking at those changes, we can deduce how many different viruses came out of the bats versus went

from person to person. There are specific genetic signatures that are associated in many cases with bat coronaviruses and coronaviruses that are transmitted with in bats, including some sequences that are part of the envelope glycoprotein which is called spike, and that molecule is on the surface of the virus and it allows the virus to enter a cell that

it's going to infect. That protein spike has changes sometimes that are specific to bats versus specific to humans, and we can look at that as well to determine how recently the virus emerged from a bat versus emerged from a human.

which we call pathogens. Those pathogens in some people will cause very mild disease and in some will cause very severe disease, and we're seeing that in terms of the fairly broad range of disease presentations of COVID nineteen. So the ability to get into the cell is just one part. And of course, in order to cause disease, a virus has to be able to infect the cell. So those proteins on the surface of the cell or on the surface of the virus particle called spike. Spike binds the

host cellular receptor, which is in humans. The molecule we know about anyways is called ACE two, and ACE two is on a variety of different tissues, but there's a lot of it in your lungs, which is why this causes a pulmonary disease. So certainly in that sense, the virus spike protein is involved in determining that this is

going to be a pulmonary disease. Similarly, we know that ACE two is expressed in the gastrointestinal tract, and there have been reports that infectious virus has been found in the stool of some patients. Also, people have reported diarrhea, which may again suggest that the ability to infect the intestine because of that receptor binding the spike protein on the surface of the virus particle allows this virus to

cause a gastrointestinal disease. But when you're talking about what is the difference between a virus in two different people, causing a mild cold like illness in one person versus causing severe pneumonia in another, that difference is often related to to the host response, and that can be determined

by a lot of different things. It can be determined by genetics, It can be determined by the health state of that individual, which we again already know as a risk factor because people with pre existing medical conditions are

more susceptible to severe disease. So really a lot of the disease is likely caused by a sort of out of control inflammatory response in infected tissues, and that largely depends on the person who's infected, as well as their overall health condition and sometimes the circumstances in which they're infected.

whether this finding is actually valid. Are there multiple strains of stars kov two?

the virus makes mistakes. We call these mutations. Many of these mutations are silent, they don't have any effect on the way the virus works. Many more of them will have a negative effect on the way the virus works and make it so that the virus can't work essentially, and some of them will confer an advantage. These mutations occur randomly, so there has to be a selection pressure

to maintain mutations from generation to generation. And some of these advantages can be an enhancedability to replicate in various host cells. It can be the ability to evade the host immune response. It can be something that would make the virus more capable of infecting cells or capable of inducing a response that would lead to more severe disease.

So right now we don't know what a lot of those theoretical mutations would be that could make the virus more virulent, capable of infecting more cells, or more pathogenic, capable of causing more intense disease. The paper that you mentioned is controversial because essentially it's grouping these two viruses into what they're calling strains. But what are normal groupings of RNA viruses that have replicated in multiple hosts. What makes a virus a strain a different strain often depends

a lot on which virus you're talking about. In this case, if we're talking about two different genotypes or virus genomes that encode virus genes that result in differential disease or more severe disease in one person versus less in another. Whether that's a strain or not is sort of up

for debate. What I think is controversial about this paper is that essentially they were just grouping a variety of different clinical isolates of the virus and then going back to the clinical data that have been recorded about those patients and making assumptions that these genetic changes is that distinguished these two groups were responsible for any differences they

found in the patient's conditions. That is, it's really hard to say, first of all, the group the viruses and the L group versus I think, what is it the S group. Yeah, the differences between those viruses, they're not all it's not just two viruses. They're groups of viruses that cluster together when you look at their genomes and

compare them. So it's really difficult to say that any one of the specific genomic changes that are characteristic of either group are directly responsible for causing increased or decreased disease. Severity gotcha.

So the only way to really look at that is either through human volunteers or patients who at least could be identified very early after infection and then followed over time we call longitudinal observations, or by looking in animal models to try to understand the various mechanisms of pathogenesis. My personal suspicion and again this plays to my bias

for the host response. But when you're looking at humans who are genetically diverse, you will see the same virus, the same idea dental strain of a virus cause two

different types of disease and two different individual people. So even when you're looking at a fairly large patient population and you're just making correlations between certain clinical features that were recorded by their doctors during clinical care, as well as the genomic sequence of their disease, you're not really able to look at any of those mechanisms that might

distinguish a host from one from another. So you can look at the differences in the virus, but you're never going to know what's different from one person to the next. So it's really difficult to conclude, even on a data set of hundreds or thousands of patients, that a genetically different strain of a virus is the only thing that is causing one person's disease to be more severe than another's, Right, Right, that makes sense.

of this virus and mRNA viruses. Can you say anything to our listeners about whether there's a risk of this virus mutating into something more deadly, and especially maybe also in the context of control measures or how behavior might influence viral evolution.

Every RNA virus will have. The normal mutation rate for an rnavirus is about one in every thousand units of the genome that gets copied is a mistake or mutation. Coronaviruses actually have an enzyme that does some limited proofreading, so their mutation rate is lower than many other RNA viruses, but it's still higher than for enzymes that replicate DNA, so it still has a relatively high mutation rate, and there will be mutations every single time the genome is copied.

In terms of mutating to become more virulent or more lethal, it's really really difficult to predict that because mutations don't stick around unless there's some sort of selection pressure. It's hard to imagine what the selection pressure would be to make the virus more lethal. If anything, viruses are selected to become less lethal only because viruses can't replicate without a host, and if you kill your host before they can transmit the virus to another host, that pretty much

cuts off that virus's evolutionary chain. So I think that it's likely certainly that the virus could mutate or has mutated, and there will be mutations every time the virus copies itself within a single person. Much less is transmitted to another person. But it's very difficult to say that the virus would be evolving on its own the capacity to

be more lethal. Now, however, if there is an antiviral drug developed, for example, and that targets a specific part of a viral protein, then it's possible that that would be a selection pressure for the virus to evolve resistance. That's one example of how viruses can become more lethal by evading countermeasures. If there's a vaccine, it's possible that the parts of the virus the vaccine recognizes could be

a pressure for those parts to mutate. The way that your immune system works for most vaccines is by making antibodies, and those antibodies recognize a shape on the surface of the virus. So if you think of a virus as a three dimensional sort of ball that's covered with spikes. Antibodies would recognize the shape of those particular spikes. It's possible that a virus could evolve a slightly different shaped spike that those antibodies from a prior infection or from

a vaccine would then not be able to recognize. So that is another way in which a virus could potentially evolve to become more lethal in the sense that it would be able to again evade a countermeasure that we had developed for it. Will that happen? I don't know. A lot of that depends on the types of antivirals that we find are able to work against this virus, as well as the vaccine strategies that are being tested right now, how well they work and how well they

are able to induce immunity. We do know from some other viruses though, that certainly antiviral drug resistance is something that happens. We know that from influenza evolving to be resistant to osul tamavir or tama flu. We know that influenza, normally it's a surface antigens or the proteins that are recognized by vaccines change all the time, so that's why

we have to get a flu shot every year. So there are certainly examples in the wild world of virology that viruses can do this, But on its own, I don't think that there's any particular pressure that I've seen anyways that would cause SARS coronavirus to spontaneously evolve greater lethality or virulence.

doesn't work. It's also thought that some of these so called nucleoside analog drugs can also activate components of your innate anti viral immune system, making yourselves more capable of responding to and resisting viral infection. So that's thought to be the mechanism of ac action for remdesevir as far

as I know. So, these these nucleoside analogs don't always work for some RNA viruses, but there is data in non human primates suggesting that rendesevir is effective at treating MRS coronavirus, and now so people have showed I think in vitro at least that it's capable of reducing virus tiders of STARS coronavirus too. So we do know that these nuclear side analogs can be effective against certain RNA

virus infections. We just won't know if it's effective in people until the clinical trials have been completed.

the envelope. So either alcohol based hand sanitizers or soap will disrupt that membrane. If you disrupt that membrane, wash it away, there's no more spike, the virus can't get into your cells. The virus is intactivated. Soapy water is more effective than hand sanitizer because that also has the added effect of physically washing things off of your hands. So, in addition to disrupting the membrane and making any viruses or some bacteria or other microorganisms that have a membrane

that can be disrupted by soaper, hand sanitizer. That's great, but in general, there may be other things. There may be non envelope viruses on your hands. Soap and water washes them away physically so that they're no longer on your hands at all, whether it disrupts the envelope or not. For that reason, washing your hands is by far the best thing you can do to reduce your own risk,

besides practicing, of course, social distancing. Hand washing is better than hand sanitizer, although it is important to note that for this particular virus, hand sanitizer as long as it's sixty percent alcohol or more, will work in between hand washes.

similar properties for remaining infectious on various surfaces. So they looked at experimentally generated aerosols, which for STARS coronaviruses is only an issue for the most part in hospital settings where there are aerosol generating procedures. But they showed that for both of these the aerosol half life is only

about three hours. So that's good news in that you know, if somebody that you love or care about is working in a hospital or an ICU or is getting treated there, these aerosols are not going to persist for days at a time in the environment. They also looked at survival of the virusrus on copper, stainless steel, plastic, and cardboard, and the virus lasts the longest on stainless steel and plastic, so it lasts forty eight to seventy two hours, and

it can potentially be there for longer than that. But what's important to note is that there was a three log reduction, so a thousand times less virus that was infectious after seventy two hours. So even though you can detect infectious virus on surfaces plastic or stainless steel surfaces, after three days, it's a greatly reduced amount of virus

compared to stars. Classic SARS coronavirus two lasted longer on cardboard. However, it didn't last longer than twenty four hours, so before everybody gets worried about getting packages in the mail or opening letters or calling ordering stuff from Amazon. It also was essentially undetectable after twenty four hours, so cardboard is probably not a surface that's going to retain the virus

for days and days at a time. What we don't know is that the effect that temperature and humidity and other environmental conditions would have on this, because they didn't look at that in this paper. However, the same group had previously done work with MRS coronavirus and that showed that temperature and humidity were also really, really important factors in terms of the virus being able to persist and

remain infectious on various surfaces. So my take home from this is that I assume that the virus under ideal conditions can last for a couple days on surfaces, So I just try to again wash my hands and where I can disinfect shared communal surfaces like tables. Take precautions to avoid being exposed to virus that may be on shared surfaces, but it's probably not going to persist in the environment for more than a couple days.

infection too. So if you are touching your hands to your nose, the inside of your nose, your nostrils is a mucous membrane. It's a mucosal surface. Mucus itself acts as a barrier that prevents virus particles from coming into contact with the cells that are in your nose to infect them. That's going to be different than in your mouth and in your eyes, and all of these different mucosal surfaces that could potentially be infected. There are inherent mechanisms,

barrier mechanisms that protect those surfaces from being infected. So it's not enough to necessarily have one infectious virus particle. You may have to have a certain number of those infectious virus particles to overcome these other obstacles to infection that your body has. We don't really know what that is.

I don't think that anybody has looked at that, And because the animal model work is still in development, we can't really look at that in the context of a controlled experiment where we would be able to look at different amounts of virus on different surfaces and see which animals got infected and then how sick they got.

That concerns me greatly because initially I felt, you know, I was concerned about this, but I felt that if we were on top of it in terms of surveillance and testing, then we could really limit and contain spread.

In January, when there were a few patients coming into the United States with travel history who were identified and rapidly sequestered, and there didn't seem to be a ton of secondary transmission, I felt pretty calm that we were responding to this correctly, identifying and isolating patients, which is what you should do. Doing contact tracing back when it

was manageable to do that. Then it turns out through genomic analysis that it looks like here in Seattle anyways, we've had community transmission since that first patient arrived, and potentially transmission from other patients who may not have even been identified. And some of this has been the absolutely unacceptable slow rollout of effective testing and the continued failure

to adequately increase testing capacity and throughput. I think that that has really really harmed our ability to contain this outbreak.

And while where we can, we should still make efforts to contain it by doing contact tracing and isolation and quarantine on these tried and true public health methods, part of our focus now has to be mitigation, and that has to be the so called flattening the curve, trying to limit and reduce spread or the speed of spread to avoid overwhelming hospitals, Trying to make sure that there is a safety net in place for people who can't afford to work from home, who don't have sick leave,

who may not have adequate insurance. We need to make sure that all of those things are addressed so that we can at least mitigate the effects that this is going to have on our healthcare systems and on our public health as a country and really as a as a species on this planet. We really need to have all hands on deck, including full engagement from the public.

And I'm concerned that with the amount of misinformation that our federal leadership has provided, the constant still downplane of the seriousness of this situation, I'm very concerned that some of these measures won't even work. And I'm not so much concerned for myself. I'm not in a high risk category. I do have asthma, but I still, you know, I don't think that I would be personally likely to die

from this. But of course I'm concerned about all those other people who do have pre existing health conditions, who are immunosuppressed, who are older, who have underlying medical conditions that would cause them to have a bad outcome, or other people who may not even have coronavirus, but are unable to access medical treatment that they need for other

things because our hospital systems are overwhelmed. So my concerns, really, my concerns about the virus are the least of my concerns for this with regard to this public health crisis, awesome.

cause the common cold. But this is a similarity that SARS CoV two shares with its closest relative, if viruses have relatives, and that is SARS classic SARS.

show notes. But what we still don't have a great handle on is what exactly that means for transmission, because we don't know how many viral particles it takes to actually make you sick, or how different environmental conditions like temperature and humidity, how these might affect the longevity of

the virus. But what we'll touch on in another episode in more detail, is that we don't even know how much virus people are shedding, So really, the best thing you can do is just kind of assume that your saliva and the saliva of everyone around you is infectious. So wipe down surfaces, wash your hands before you touch your face. These are the basic steps that will protect you not only from getting this virus but also from

spreading it to others. And it'll also do those things for so many other viruses too.

drastic ways. There's been a lot of talk about this is going to mutate to be airborne, and we'll talk in more detail in a future episode about what respiratory droplet versus airborne transmission really means, but in general, it's very uncommon for viruses to mutate in that drastic of a fashion to change their mode of transmission.

But even if there are different strains, we don't know if that will actually result in different virulence or infectivity between those strains, because so much of what goes into disease severity is related directly to our individual host response, and so it's really hard to tease apart the individual effects of certain virus strains and how much a particular viral strain is going to affect us or cause disease

or be more infectious than another. And so that's something I think is really important to remember as this talk of strains comes into the news is that this is also something that's going to probably take a bit to figure out whether there are any differences in the infectivity or virulence among any of the strains that we might detect.

And then the other paper that we mentioned in our interview that referred to the L and S strains of SARS CoV two is by tang at All and that's also from twenty twenty and it is titled on the Origin and Continuing Evolution of SARS CoV two.