Covid-19: How to Get a Virus to Give Up Its Secrets

In an age of wonders, the greatest may live behind laboratory doors.

Imagine working with viruses like SARS-CoV-2 that are perhaps just 100 nanometers in diameter. Illuminating their close-held mysteries, probing their genetic sequences for weaknesses, and investigating the human body’s response—those are Sabra Klein’s challenges. From where to get viral samples and what to look for, to big-picture challenges like quantifying the difference in immune responses between men and women, Klein, PhD ’98, MS, MA, a Molecular Microbiology and Immunology professor, offers a brisk master class in virus investigation. 

What do you think about when you think about the virus? 

You know, the virus is just trying to survive and reproduce and be transmitted. Just as we are basically trying to survive, reproduce, and have babies.

How do you get samples of the virus?

We get the virus from those nasal swab samples that are used to determine if somebody has been infected or not. When you take that nasal scraping, you’re going to get a little bit of that virus material. There can be viral genomes and viral particles in there. 

Do you buy these virus samples from a company?

They can come in kits, but we’re in the middle of a pandemic doing testing at a level that we have never experienced before. So that is when having card-carrying, hard-core molecular biologists around can be fantastic. [Professor] Andy Pekosz, my next-door neighbor in MMI, has provided homemade kits with the appropriate media in a tube that you would need for the nasal swab.

You’re basically finding chunks of the virus genome?

When you take that nasal scraping, you're going to get a little bit of that virus material. We can design what are called primers. They’re going to match a genetic component of the virus. So, when they find their match, they’re going to “sit down.” We then have an entire process to then amplify and measure what those primers recognize.

What are you looking for?

The way virologists try to get the virus to give up its secrets is to start looking at genetic sequences. And by comparing them, we can study the mutations. Does it change the ability of that virus to infect cells, the growth of that virus? Does it make the virus a little hardier? And if so, what different immune responses might need to be in place to kill the virus?

You’re also seeing what other virologists around the world are finding, right?

Everybody sequencing these viruses is putting them onto publicly accessible databases. Then you can see certain mutations start popping up around the world. Then we realize, “wow, this mutation is really taking hold.” And we can study in the laboratory why that mutation resulted in a survival advantage.

Tell us more about what you do with the virus in the lab.

What I’m particularly interested in is the other side of this: How we protect ourselves or don’t protect ourselves. And when the immune response is beneficial to us versus when it is not. Why is that happening in some individuals more than others? That’s what we’re very interested in.

You also look at blood samples from people who are infected. What can you learn from those? 

We can look at proteins that they’re making to protect themselves and the antibodies that recognize things like the spike protein. We can look at cytokines that are often used by immune cells to communicate with each other. Cytokines recruit other cells to a site of infection. They convey an awful lot of information and are integral in orchestrating an immune response to something like SARS -CoV-2.

Do you see your goal as to accumulate knowledge that could lead to a more effective vaccine or to a new drug therapy ?

As a basic scientist, I’m trying to understand the pathogenesis of the virus. All that means is we want to understand, over the course of infection, what the mechanisms are that are causing such severe disease. Is it the virus replicating out of control? Is it the inflammation that we induce as a result of the presence of the virus?

You study how women and men respond differently to infections. Are you looking at that in terms of SARS-CoV-2?

We are so actively looking at that.

Women typically have a stronger immune response than men. Could this stronger immune response later in the course of infection actually be more harmful to women than to men?

Yes, that would be my hypothesis. It may be that some of the long-term implications of greater immunity may be showing up in people who are long-haulers. That hasn’t been shown yet, but my hypothesis is that women are more likely to be long-haulers.

What would be the ultimate for you in terms of your research making a difference?

I will feel like I have made a real difference once we start seeing these vaccine trial data disaggregated and analyzed to compare men and women. A recent publication showed that the vaccine is equally efficacious in men and women. But I haven’t seen any of the immune response data or adverse reaction data disaggregated and broken down by sex. That’s so important because this is a vaccine that we know is going to result in more adverse reactions than what we see with our seasonal influenza vaccine. Once companies start disaggregating data and are comparing between men and women and then maybe even thinking dosages could be different between men and women, then I’d know my work is done.

Right. You've studied this for a long time with the influenza virus—that women don’t need the same size dose as men.

Maybe you don’t need as large a dose to induce enough immunity in women to still protect them and not cause these adverse reactions. You might not have to give as much to each individual, so you may be able to spare some doses that could be used for others.