Long-haulers and neurological damage

Tom Lane’s neurology research on coronaviruses in mice could yield answers

February 25, 2021

By Aaron Orlowski

On this episode of the UCI Podcast, Tom Lane, professor of neurobiology and behavior, discusses COVID-19 long haulers and the neurological complications arising from the virus. Steve Zylius/UCI Tom Lane’s lab photo: Steve Zylius/UCI

Half a million people have died of COVID-19 in the U.S. and countless millions have contracted the virus. Doctors have been concerned, first, with preventing death. But another threat is becoming clear: long-term neurological consequences such as brain fog, depression and anxiety.

Tom Lane, a Chancellor’s professor of neurobiology and behavior at UCI, has studied how coronaviruses neurologically affect mice for the last two decades. In this episode of the UCI Podcast, Professor Lane discusses COVID-19 long haulers, his current research using mice to look at COVID-19’s impact on the brain, and how people can prevent the disease’s neurological repercussions.

In this episode:

Tom Lane, Chancellor’s professor of neurobiology and behavior at UCI

Department of Neurobiology & Behavior

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Transcript

AARON ORLOWSKI, HOST

Loss of smell. Brain fog. Depression and anxiety.

A subset of COVID-19 patients known as long haulers are suffering health consequences months after the initial symptoms fade. And doctors are worried.

How are UCI researchers using mice to study COVID-19’s dire neurological effects? And what do we need to do to prevent the worst of them?

From the University of California, Irvine, I’m Aaron Orlowski. And you’re listening to the UCI Podcast. Today, I’m speaking with Tom Lane, who is a Chancellor’s professor of neurobiology and behavior at UCI.

Professor Lane, thank you for joining me today on the UCI Podcast.

TOM LANE

That’s great. Aaron, thank you so much for having me.

ORLOWSKI

COVID-19 cases are falling right now and more and more people are getting vaccinated. So it seems like we might be turning a corner, hopefully, on the disease, which is primarily an acute infection in the lungs. But there are also neurological symptoms that people with the virus have suffered and might suffer in the future. So what are some of those neurological symptoms that we see in people with COVID-19?

LANE

You know, I think you can break it down at the stage of the disease. And so usually people that are initially infected have headaches that can be either mild to severe. Then, I mean, everybody’s familiar with the loss of taste and smell. And then there are examples of mild cognitive problems, or delirium, and that can remain with individuals through the course of their infection. But the problem that I think I’m concerned about, and I think others in the field are concerned about, are this group of people called long haulers. You’ve gotten through COVID, but then 28 days later, or sometime later, you start experiencing a myriad of symptoms, some of them neurologic, and these could include depression, anxiety. A very common complaint is brain fog. Right. These patients also experienced extreme fatigue. So there’s a variety of different problems associated with COVID-19 that have a neurologic basis, which separates it from SARS-CoV-1 or MERS.

ORLOWSKI

Are there trends at this point that are visible about who suffers from these longer term neurological symptoms? Is it younger folks or older folks or some other group?

LANE

You always associate COVID with the co-morbidities. Right. Metabolic disorders, age being the primary one. Right. If you are older, you definitely have an increased risk of more severe disease. The neurologic complications don’t seem to fall in that category. You could be young and healthy and have neurologic complications that are much more severe than, say, an older person that has diabetes. So there doesn’t seem to be a clear path that’s at least evident now. Now, as time progresses, even though we’ve been into this for about a year now, that might fall into more defined categories. But no, there’s no clear indication of what might preclude or make somebody have more severe neurologic symptoms than another person.

ORLOWSKI

So at this point, from what we know, it really could be anybody.

LANE

Yes. Yeah. There are, I think things that will emerge in my opinion, are, what we’ve found out in the past six months or eight months, is that you have these things called experiments in nature. All right. And what I mean by that, there are some people that are just naturally more resistant to COVID. I mean, just very resistant, and others that are extremely susceptible, young people that should be just fine. And what we’ve learned, particularly with the latter, is cohorts of people that have innate deficiencies in their immune system that render them more susceptible to disease. Right. Conversely, you can also, and I’m anticipating that this will be happening over the next six months to a year, that we’ll find people that are very resistant to the disease and we can then study those individuals and find out what makes them that way. And I bring this up because if you have increased susceptibility to the disease that might lend itself to increased neurologic conditions. Right. Conversely, if you’re more resistant, you might be more resistant to the neurological aspects associated with the disease.

ORLOWSKI

Well, and this is a disease that primarily affects the lungs, or it affects the lungs first. We’ve all heard about the respirator shortages and people who need to get intubated. So what’s the mechanism by which it starts to affect the central nervous system?

LANE

Yeah. You know, that’s a very good question, Aaron. And we’re beginning to get more insight into that. So originally most people, including myself, thought that the virus was neuro-invasive. And what I mean by that, is the virus is able to get into the brain and infect different cell types of the brain and replicate. And then this could induce neuro-pathology that leads to then neurologic complications. What is pretty clear now is that, you know, the virus can get into the CNS, the central nervous system, but not nearly to the levels that you would have thought, at least I would have thought. So I think to some extent, a lot of the acute symptoms that are occurring in response to COVID are a reflection of the cytokine storm that occurs in the lungs. And so cytokines are these proteins that are secreted by almost all nucleated cells of the body in response to infection. And these are soluble proteins and they can get into the central nervous system and cause a variety of problems.

ORLOWSKI

We could be finding out more in the future as research progresses about if it’s the cytokine storms that caused these longer term effects or if there’s a different cause.

LANE

That’s correct. Right. There are some really good studies that have come out over the past six months or so from very good groups around the country and around the world that have demonstrated that you can detect the virus in a subpopulation of neurons, as well as cells that line the vasculature of the central nervous system. And you can also detect viral RNA in some cases in the cerebral spinal fluid. And I think where the virus could persist in the CNS, if it does, that could certainly lead to potential long term effects. Right. What we don’t know is maybe the virus gets into the brain and replicates to high levels, but then the immune system is able to kick in and control it. Right. And we’re just not picking that up yet, because for example, in my laboratory, we’ve done a lot of post-mortem analysis on brains of patients that have succumbed to COVID and we can’t detect it. But this is after they’ve had the virus for a while and then they die. Right. But we don’t know what’s happening. You know, this is a snapshot in time. Right. So this then lends itself to the importance of animal models, right, to try to study these things.

ORLOWSKI

Well, and you’ve been working on animal models for quite some time studying the effects of coronaviruses on the neurological health of mice for something like 20 years. So you’re the expert for the moment. What led you to start studying this issue?

LANE

I originally did this when I was a postdoc at Scripps (Scripps Research Institute in La Jolla) and I was interested in viral infections of the central nervous system, but mainly I was very interested in the human demyelinating disease, multiple sclerosis. And there are a number of different mouse models of MS. And believe it or not, one of the really good ones is you can take mouse coronavirus and you inoculate susceptible mice with this mouse coronavirus, and they develop immune-mediated demyelinating disease, very similar to what you see in patients with MS. So I was really, I got into it because I was interested in auto-immune diseases. Right. And so multiple sclerosis being a big one.

But using a viral model, you have to understand a lot about the virus. Right. And so we’ve been doing that, that particular model since, let’s see, I started my postdoc in 1994 and I joined the faculty here in 1998, and so we’ve been running that model forever. Well, it seems like it. And it’s been a great model. So that’s how I got initially into doing the mouse coronavirus research in the central nervous system. And to be honest, when SARS-CoV-1 came out in 2002, in 2003, we kind of toyed with the idea of working in that field, but then it kind of came and went. And MERS-CoV is still around, but at that point I didn’t really have an interest in studying that in great detail. But then obviously in January of 2020 SARS-CoV-2 to hit. And we became very interested in looking at that. So now we’ve got a very vigorous research program studying SARS-CoV-2.

ORLOWSKI

Well and mice are frequently used in all sorts of medical studies. But for the ones that you’ve been working on, especially related to the coronavirus and coronaviruses, in what ways are mice a good model for the human brain? And in what ways are they fundamentally different?

LANE

They’re good for a number of reasons. A lot of the resident cell types in the brains of mice are similar for the most part to what you see in humans. And that’s good because you can look at innate immune responses that occur in the brain. In addition, lymphatic drainage, which is how the immune cells get from the periphery into the brain, are pretty much similar between mice and humans, not entirely. Some of the caveats, though, and this is particularly true for SARS-CoV-2, is that mice, for example, don’t have the receptor. They have ACE2, that’s angiotensin-converting enzyme 2, ACE2, but their ACE2 can’t bind the spike glycoprotein for SARS-CoV-2. Another example is measles virus. Measles is a horrible infection. We don’t really think about it anymore. But mice don’t have the receptor for measles virus. So you have to make transgenic mice. And what I mean by that is you have to engineer mice to express human ACE2,  for example, and study the immune response and potential CNS (central nervous system) involvement after experimental infection with SARS-CoV-2.

ORLOWSKI

And you just mentioned transgenic mice, and that’s something that you’ve been working on to study the effects of COVID-19 on the brain, developing these new mouse models. So what does it take to develop a new type of mouse for these kinds of studies?

LANE

You know, it’s not hard making new strains of mice, a lot of people are doing it. There are a number of different transgenic mouse models for studying SARS-CoV-2 infection. All of them employ making animals that overexpress or express the human ACE2. You can then experimentally infect these animals. By far and away, the most common strain that’s used is called a K18 mouse. This was developed in 2007 by Stanley Perlman at the University of Iowa. Stanley is one of the leading investigators in coronavirus pathogenesis around the world. And he made these animals to study SARS-CoV-1. And so it was a good model, but there are problems with it. And the main problems are: One, you have overexpression of human ACE2. So it’s not at physiological levels that you would see in humans. Furthermore, the expression of the trans-gene in these mice, and I’m not getting too complicated, here, it doesn’t mirror what you see in humans. Right. So you have overexpression in the lungs, but you don’t have human ACE2 being expressed in other organs that you see in humans. So if you really want to model human disease, you’re not going to get it very accurately. And then, finally, following experimental infection with SARS-CoV-2 in these K18 mice, you can, in about half the mice that are infected, you get this really robust CNS infection, which we know is probably not the case that’s happening in humans. So it’s a good model for studying lung pathology. And it’s a good model for studying new or novel drugs that can either block viral replication in the lungs or dampening inflammation. But it’s not a perfect model. And then there are no perfect models.

But what we’re doing, in collaboration with Dr. Grant MacGregorDr. Kim Green and Dr. Eric Pearlman here at UCI, is we’re making a new mouse where we’re expressing human ACE2 in organs that are expressed humans. And then the second thing, in this new strain of animal that we’re making, we’re eliminating all mouse ACE2. And why that’s important is because in the K18 strain, you have human ACE2 that’s overexpressed and then you also have mouse ACE2. And so what ACE2 does under normal circumstances is it regulates blood pressure. And so you have this massive overexpression of ACE2, so you have a lot of problems with vascular integrity in these animals. So what we’re attempting to do is make a mouse that reflects human ACE2 expression, and therefore we can potentially more accurately model acute disease as well as chronic disease. So that’s our goal. And we’re getting there, the mice are coming along. We hope to get a colony in the next two months or so to start doing infections.

ORLOWSKI

Well, and I think it’s important to at least touch on why it’s vital to have these kinds of animal models. Why is this kind of research important when we are ultimately trying to improve human health?

LANE

The reason we like mice is that we can do a lot of genetic manipulations. So for example, I indicated earlier in our conversation that within the past six months, a population of humans that have deficiencies in their immune system tend to be more susceptible to disease. Well, we can model that in a mouse. Right. Because we can ablate these specific genes that might be associated with immune control of virus in the animal, and then more accurately study how the virus spreads in those animals and more importantly, develop new interventional therapies to potentially help control the virus from replicating and spreading. So that’s why an animal model is extremely important.

ORLOWSKI

Well, and we’ve talked about a number of different coronaviruses and you’ve examined different coronaviruses over the course of your career. So how is SARS-Co-2 different than the previous ones that have existed in that you’ve looked at?

LANE

We’re SARS-CoV-2 stands apart from SARS-CoV-1 and MERS-CoV is, one, it’s a true pandemic, which never really was the case with either SARS-CoV-1 or MERS-CoV. The other insidious aspects of SARS-CoV-2 is that unlike MERS and SARS-CoV-1, you can be asymptomatic and spread the virus. Right. With SARS-CoV-1, you were very sick and spreading the virus. That’s why most people that became infected were their care workers, hospital workers, or family members. Right. So that’s a big difference. And then secondly, we know what the spillover reservoir was for SARS-Cov-1 and MERS-CoV. For SARS-CoV-1, bats. Well, bats seem to be the main source of all of these coronaviruses. Right. But then at some point for SARS-CoV-1 and MERS-CoV, the virus jumped into civet cats and camels, respectively, and then that’s how it’s spread to humans.

SARS-CoV-2, we don’t really know what the spillover reservoir is. Rght. So that makes it very challenging to control the virus. So these are fundamental key aspects that separates SARS-CoV-2 from the other MERS-CoV and SARS-CoV-1. And then the neurologic complications with SARS-CoV-2 make it much different than the previous outbreaks that occurred. And that’s where, I think, the work that we’ve done with our mouse coronavirus, we hope to find some intersection there that allows us to build on what we’ve done over the past two decades to understand what might be happening to these people with SARS-CoV-2.

ORLOWSKI

And what do we know about how SARS-CoV-2 interacts with other neurological diseases such as Alzheimer’s?

LANE

That’s a great question, Aaron. It’s interesting because there have been recent reports in the literature that indicate that patients with dementia have an increased susceptibility to COVID-19. There are a number of potential reasons why. One can just be social. Right. Because if you have a family member that has dementia or is in a memory care facility, having those individuals constantly wear masks and social distance is challenging. My mom had dementia. It was very — you know, just getting these people to do these things, it’s very hard. And then, secondly, what we do know in patients with dementia and then later with Alzheimer’s — which you actually diagnose upon autopsy — is that there’s an increase in permeability of the blood-brain barrier. And under normal circumstances, this blood-brain barrier is an amazing guard to protect the brain and central nervous system from infection. All right. But if you have an increase in the permeability — that is opening up of, you know, holes, if you will, in the blood-brain barrier — that allows a lot of bad actors to get into the brain. So potentially the virus might have greater access to the CNS of patients with dementia and that can potentially make things much worse. And so we’re now trying to model that in my laboratory as well, working with transgenic models of Alzheimer’s disease and in this scenario we’re doing infections with our mouse coronavirus, but we’ll ultimately start developing unique transgenic models to do SARS-CoV-2 infection.

ORLOWSKI

Yeah. Well, Professor Lane that research will be incredibly valuable for humanity as we move forward and hopefully tame and end this virus. As you look at the picture of where we’ve come in the last year and the tragedy that has already befallen the entire globe with millions of people getting infected and half a million dying here in the U.S., what are you most worried about for the future with this virus? What do we not know that concerns you?

LANE

I think the one thing I’m most concerned about given the incredible number of people worldwide that have been infected by the virus, you know, 175 million, or something like that, as of now. The majority of these people survive. Right. But a lot of these people have these long hauler symptoms. Right. And that can be an incredible burden on the medical community, not just the neurologic complications, but other organ systems. Right. Chronic fatigue, etc, etc. You’re not only talking about increased care over — we don’t know how long, this could be years, decades, etc, etc. Furthermore, you’re going to lose these people from the job field. Right. I mean, these are people that can’t consistently go to work. So that’s a big issue that I think we might have to be dealing with down the road.

To tell you the truth, I’m not so worried about these variants that are emerging, that people are very concerned about. Right. Viruses evolve. That’s what they do. But if you look back, as early as March 2020, there was a variant that came out, one single amino acid change that seemed to enhance replication of the virus in the lungs. Right. But then that became the prominent strain. And what everybody’s worried about now is particularly like, I think it’s a South African strain, that if you take convalescent serum from patients that had COVID, it doesn’t work very well in neutralizing this new strain of virus. But it seems to be that following at least Moderna and Pfizer vaccinations, you generate still a pretty good antibody response, and that can help in controlling the virus, the South African strain, and probably these others.

And the other thing that doesn’t seem to get mentioned very often is we have no idea what these variants are doing for the T cell responses. Right. You, for any virus, and this is true for coronaviruses, following immunization, you’re going to get antibodies generated, but you’re also most likely getting a very good T cell memory response. And these T cells might be very effective at controlling these variants. So I think that we just have to take our time and see what happens over the next year, years, and see, do we have to make new vaccines? Maybe. Do I think it’s going to be like the flu every year, we’re going to get a vaccine? I think the verdict’s not out yet. And the big picture, then, I’m more worried about these people that are surviving, the infection that he can have a lot of these post-COVID symptoms and what the duration of these will be, and what the burden of that will be on the medical system.

ORLOWSKI

Well, and as you’ve stated, there’s so much that we don’t know about the specific long term effects and what’s going to happen with these emerging variants, but there are some things that we can do that are probably common sense to prevent some of these long term effects. So what do we need to do today to tame this virus and prevent as many of these effects as possible?

LANE

Vaccination. We need to get as many people vaccinated as quickly as possible. For those individuals that have had COVID and then are experiencing some of these long hauler symptoms that are neurologic in nature, so brain fog, etc, etc, that it’s hard for me to say, I’m not a clinician, I’m a PhD. And so I’m not a neurologist, but I can tell you that these symptoms and these conditions are being taken very, very seriously by neurologists around the country, if not the world. Right. In fact, there’s a new diagnosis for it’s called Post-Acute Sequelae of COVID. And I think, you know, certain universities, and I think UCI is moving in this direction as well, are setting up special groups of neurologists to actually focus on these people. So I think as time goes by, we’ll understand better on how to manage these symptoms, but right now it’s still relatively unclear. But the main thing is, if you want to avoid this, you don’t want to get infected. So get the vaccine. And no matter what the new emerging strains are, get the vaccine.

ORLOWSKI

Professor Lane, thank you so much for joining me today on the UCI Podcast.

LANE

All right, Aaron, thank you for having me.