Professor Cliona O’Farrelly in her office at TBSI. © Trevor Butterworth

The following interview has been lightly edited for clarity

TBSI News: What do we know about innate immunity against COVID?

Cliona O’Farrelly: It’s been observed for hundreds of years that some people are resistant to infection: there are anecdotal stories from all sorts of communities about people being able to work amongst the sick and not get infected. When the adaptive immune system was discovered, it was assumed that protection came from its ability to make antibodies and T cells, a type of white blood cell that specifically kills infected cell. But we now think that our innate immune system, which is the non-specific system that kicks in early on in an infection, is effective enough in some people to keep the virus away without engaging the adaptive immune system.

TBSI News: It might be useful to explain the difference between the innate and adaptive.

Cliona: Let’s start with the more complicated one, the adaptive immune system. We know that when a person encounters a new infectious agent (or a vaccine), they’re able to make a new and specific immune response to it. How do we measure the specific response? Mostly by the presence of specific antibodies in the blood.

But we also know that we need specific T cells to make ‘good’ antibodies; these are T helper cells. We also generate specific T cells that kill off virally infected cells; these are killer T cells. We can make these specific T-cell populations against any ‘new’ microbe, hence the term ‘adaptive’ immune response.

As well as specificity, the other major feature of the adaptive immune response is that it has memory. Even though antibodies may wane after the infection is vanquished, there are memory T and B cells in your tissues that remember the specific infection (or vaccine) and they can reactivate when you get infected again (or for the first time after vaccination).

That’s the principle of vaccination — it stimulates your adaptive immune response to make specific T cells and B cells and antibodies. A second shot or a booster is to ensure you’ve lots of specific T cells and antibody-making cells in your tissues so that if you do encounter the virus again, they can go quickly into action.

That’s the adaptive immune response which is found in vertebrates and was always considered very sophisticated and ‘advanced’. 

But of course, any species can get infected by viruses and bacteria; so, it turns out that every species on the planet has mechanisms for fighting infection, most of which do not involve adaptive immunity. Species as primitive as slugs, sea urchins, or worms or long-living invertebrates like lobsters, or octopi are all equipped with a variety of innate mechanisms that can respond to bacteria and viruses. Even microbial species have mechanisms for defending themselves against other microbial species, so the ability to fight off infection has been evolving for as long as life itself has been evolving. These mechanisms have been conserved in species that evolved adaptive immune systems: Humans have many innate defence mechanisms in addition to our wonderful adaptive immune systems.

So, let’s imagine where these innate mechanisms would first go into action against SARS-CoV-2. The process would start in the epithelial cells lining the nose and throat: As soon as an epithelial cell detects the virus, its own molecular defense mechanisms go into action and try to get rid of it. If an epithelial cell can’t keep up with the virus getting inside and replicating, it then starts sending out danger signals to neighbouring immune cells through molecules called cytokines and interferons; this signaling activates local immune cells, such as macrophages and NK cells that swing into action, start killing infected cells, and if persistently activated, have ways of telling the whole body that it’s infected.

This sequence of defense is called the innate immune response.

At this stage, you’d start experiencing the symptoms of infection because both the macrophages and the continually-infected epithelial cells are also producing cytokines—protein messengers that call immune cells to the site of infection and activate them. These are the molecules that make us feel sick. They circulate throughout the body, causing the aches and pains of infection, raising our temperature, decreasing our appetites, and making us behave like sick people, and sometimes even causing depression.

This innate immune response might be enough to clear the infection. But if it doesn’t, the adaptive immune system is activated; then finally, hopefully, you clear the infection.

See Illustrating the Innate Immune Response to SARS-CoV-2 by Tianai Lou, a senior sophister in immunology

TBSI News: What were the scientific breakthroughs that led to this knowledge?

Cliona: Huge breakthroughs happened in the early ‘90s, when it was discovered that we have receptors for detecting pathogens, viruses, and bacteria that stimulate this innate immune response.

Ask any immunologist about their favorite textbook, and they will say “the Janeway”. So, Charlie Janeway, in a very famous lecture in 1989 predicted a novel biological method for detecting bacterial structures. Observation soon confirmed his predictions: There is a whole range of pathogen-recognition receptors, such as TLRs—Toll-like receptors. Discovering all of this was a really important steppingstone. Then natural killer cells were discovered, innate immune lymphocytes that are able to kill virally infected cells.

Around the same time, cytokines, the innate immune molecules that stimulate, mediate, and amplify the inflammatory response, were being discovered. Diverse populations of innate immune cells capable of responding to pathogens and producing cytokines were being discovered. Antimicrobial peptides were being found in all sorts of species. We discovered that many cells of the body are able to produce anti-microbial peptides and cytokines and that cytokines could induce changes in behavior because they make us sleepy, and tired, and depressed. You can imagine why this was really important from an evolutionary point of view: a sick animal needed to stay hidden somewhere quiet; otherwise, it might get eaten.

TBSI News: What was your path to studying innate immunity in viral infection?

Cliona: I have a background in liver immunology. I worked for years in St. Vincent’s Hospital, which is a national liver transplant center. I started there in 1993, which was the year of the first liver transplant. I was fascinated to discover that livers could be transplanted without tissue matching. Being an immunologist, I thought you could not have a successful transplant unless the tissue from the donor was compatible with the tissue of the receiver. If it wasn’t, the immune system of the receiver would likely reject the organ. We call this HLA matching. HLA stands for “human leukocyte antigen,” and HLA typing means looking for variations between the respective immune systems of donors and receivers to determine if a transplant from one to the other will likely be accepted or rejected based on the likely immune response to the new organ or tissue.  

Ironically, I had been the first person in Trinity to set up HLA typing in 1977, the first year of my PhD, and so I was particularly intrigued to discover years later that doctors didn’t do HLA typing for the liver. Their excuse was that they couldn’t, because there were so few donor organs that you couldn’t reject any of them. But it turned out that one of the real reasons was that a transplanted liver is not rejected as easily as a heart or kidney. Despite no HLA matching, people who received liver transplants only needed one tenth of the immunosuppression drugs than the recipients of other organs needed.

My thinking led me to wonder whether there was there something about the immune system in the liver that might be responsible for this tolerance. The response I got was “there is no immune system in the liver”. But I had been studying the gut, and people were making great discoveries about the special immune system in the gut; so, I went looking at the liver. Almost immediately, we found huge populations of lymphocytes and, in particular, natural killer cells, innate immune cells important for killing viruses and ‘altered/abnormal [malignant] cells. These discoveries started me thinking that the liver was a very important innate immune organ.

Now, we need to step back and look at what was also happening around the same time, namely, the anti-D scandal. Hundreds of Irish women had been given anti-D immunoglobulin in 1977–79 that was contaminated with Hepatitis C. Some background information — anti-D is given to pregnant women who have a rhesus negative blood type as a precaution. If their babies turned out to be rhesus negative too, the

As hepatitis C infects the liver, I was really interested in how the liver responded to the virus. As it turned out, almost 50 percent of the women who had been given the highly contaminated anti-D did not become infected. Neither did they have antibodies. The question was why not?

One interpretation was that they had not, in fact, been infected. I thought they might have a particularly effective Innate immune system in their liver that kept the virus away; however, I was told it would be impossible to research this hypothesis because I would never be sure that these women had actually been infected with the virus. But I think there was also a political reason for discouraging me: If I went looking and then discovered that what these women had been told wasn’t true, that they had, in fact, been infected, it would cause a new scandal. And nobody wanted to deal with that!

But I still thought, “this is a really important question”! So, I wrote a grant for Science Foundation Ireland (SFI); it got rejected. I wrote another one; it, too, got rejected. Finally, on the third go, SFI gave me a grant to recruit some of these women and to study what had happened to them.

TBSI News: How did you solve the challenge of finding these women?

Cliona: With huge difficulty. Even though the IBTS (national blood service) had their details, for ethical reasons, we weren’t allowed to approach them through the IBTS, because it would be disruptive and perhaps disturbing to the women to receive a letter from them.

So we launched a national media campaign. Thankfully, the response was tremendous and 700 rhesus-negative women who had received anti-D contacted us. Of these, we found 33 who had received what we knew were highly contaminated vials of anti-D.

Our hypothesis was that the innate immune response of these women was strong enough to keep the virus away. And, after years of work, numerous challenges, a wonderful collaboration with the Pasteur Institute in Paris and the hard work of an amazing PhD student Jamie Sugrue, we now have evidence that these resistant women have a particularly effective interferon response — which is explained in a paper we have just sent off for publication and two reviews we have just published.

This finding was just coming together when COVID hit, and it was inevitable that we wondered whether we’d see people with similar super innate anti-viral immunity who remain uninfected by SARSCoV2. I was convinced that we would find viral-resistant people amongst COVID-exposed individuals, and just as I was having that thought, one of the world’s leading immunologists, Jean-Laurent Casanova, wrote an article in Cell describing how he was embarking on a major global study to look at the genetic reasons for why people become seriously ill in viral infection and why others remain uninfected. He was inviting researchers from across the globe to join the project — the COVID Human Genetic Effort. In one short paragraph he said he was also interested in resistance. So, I contacted him, and told him about our experience with the Hepatitis C virus, and he invited us and Ireland to join the COVID Human Genetic Effort.

TBSI News: So that’s how it all started…

Cliona: That’s how it all started. There are at least 90 different groups worldwide. We meet every second Monday for fantastic discussion.

TCD and St. James’s Hospital are now part of a COVIDHGE subgroup interested in viral resistance that has embarked on a genetic analysis of resistant people. About 20 research groups are recruiting people, and we now have about 450 DNA samples for analysis. Trinity got a grant from SFI to be part of this collaboration. We’ve recruited 30 people from healthcare workers at St. James’s Hospital who have shown likely resistance. The criteria set by the consortium are that the resistor needs to have shared a room and, ideally, a bed with somebody who was PCR-positive. We need to have proof that the contact person was PCR-positive at the time.

We have tested their adaptive immune response, and we know that they do not have a T-cell response, meaning that they did not get infected. But we do know they made a T-cell response to their vaccines so they can make an adaptive immune response; they just didn’t need to when they first encountered the virus their innate immune systems were good enough to keep it away. The big question now is how many people have innate immune protection against SARS-CoV-2.

TBSI News: What were the scientific breakthroughs that led to this knowledge?

Cliona: Huge breakthroughs happened in the early ‘90s, when it was discovered that we have receptors for detecting pathogens, viruses, and bacteria that stimulate this innate immune response.

Ask any immunologist about their favorite textbook, and they will say “the Janeway”. So, Charlie Janeway, in a very famous lecture in 1989 predicted a novel biological method for detecting bacterial structures. Observation soon confirmed his predictions: There is a whole range of pathogen-recognition receptors, such as TLRs—Toll-like receptors. Discovering all of this was a really important steppingstone. Then natural killer cells were discovered, innate immune lymphocytes that are able to kill virally infected cells.

Around the same time, cytokines, the innate immune molecules that stimulate, mediate, and amplify the inflammatory response, were being discovered. Diverse populations of innate immune cells capable of responding to pathogens and producing cytokines were being discovered. Antimicrobial peptides were being found in all sorts of species. We discovered that many cells of the body are able to produce anti-microbial peptides and cytokines and that cytokines could induce changes in behavior because they make us sleepy, and tired, and depressed. You can imagine why this was really important from an evolutionary point of view: a sick animal needed to stay hidden somewhere quiet; otherwise, it might get eaten.

TBSI News: What was your path to studying innate immunity in viral infection?

Cliona: I have a background in liver immunology. I worked for years in St. Vincent’s Hospital, which is a national liver transplant center. I started there in 1993, which was the year of the first liver transplant. I was fascinated to discover that livers could be transplanted without tissue matching. Being an immunologist, I thought you could not have a successful transplant unless the tissue from the donor was compatible with the tissue of the receiver. If it wasn’t, the immune system of the receiver would likely reject the organ. We call this HLA matching. HLA stands for “human leukocyte antigen,” and HLA typing means looking for variations between the respective immune systems of donors and receivers to determine if a transplant from one to the other will likely be accepted or rejected based on the likely immune response to the new organ or tissue.  

Ironically, I had been the first person in Trinity to set up HLA typing in 1977, the first year of my PhD, and so I was particularly intrigued to discover years later that doctors didn’t do HLA typing for the liver. Their excuse was that they couldn’t, because there were so few donor organs that you couldn’t reject any of them. But it turned out that one of the real reasons was that a transplanted liver is not rejected as easily as a heart or kidney. Despite no HLA matching, people who received liver transplants only needed one tenth of the immunosuppression drugs than the recipients of other organs needed.

My thinking led me to wonder whether there was there something about the immune system in the liver that might be responsible for this tolerance. The response I got was “there is no immune system in the liver”. But I had been studying the gut, and people were making great discoveries about the special immune system in the gut; so, I went looking at the liver. Almost immediately, we found huge populations of lymphocytes and, in particular, natural killer cells, innate immune cells important for killing viruses and ‘altered/abnormal [malignant] cells. These discoveries started me thinking that the liver was a very important innate immune organ.

Now, we need to step back and look at what was also happening around the same time, namely, the anti-D scandal. Hundreds of Irish women had been given anti-D immunoglobulin in 1977–79 that was contaminated with Hepatitis C. Some background information — anti-D is given to pregnant women who have a rhesus negative blood type as a precaution. If their babies turned out to be rhesus negative too, the

As hepatitis C infects the liver, I was really interested in how the liver responded to the virus. As it turned out, almost 50 percent of the women who had been given the highly contaminated anti-D did not become infected. Neither did they have antibodies. The question was why not?

One interpretation was that they had not, in fact, been infected. I thought they might have a particularly effective Innate immune system in their liver that kept the virus away; however, I was told it would be impossible to research this hypothesis because I would never be sure that these women had actually been infected with the virus. But I think there was also a political reason for discouraging me: If I went looking and then discovered that what these women had been told wasn’t true, that they had, in fact, been infected, it would cause a new scandal. And nobody wanted to deal with that!

But I still thought, “this is a really important question”! So, I wrote a grant for Science Foundation Ireland (SFI); it got rejected. I wrote another one; it, too, got rejected. Finally, on the third go, SFI gave me a grant to recruit some of these women and to study what had happened to them.

TBSI News: How did you solve the challenge of finding these women?

Cliona: With huge difficulty. Even though the IBTS (national blood service) had their details, for ethical reasons, we weren’t allowed to approach them through the IBTS, because it would be disruptive and perhaps disturbing to the women to receive a letter from them.

So we launched a national media campaign. Thankfully, the response was tremendous and 700 rhesus-negative women who had received anti-D contacted us. Of these, we found 33 who had received what we knew were highly contaminated vials of anti-D.

Our hypothesis was that the innate immune response of these women was strong enough to keep the virus away. And, after years of work, numerous challenges, a wonderful collaboration with the Pasteur Institute in Paris and the hard work of an amazing PhD student Jamie Sugrue, we now have evidence that these resistant women have a particularly effective interferon response — which is explained in a paper we have just sent off for publication and two reviews we have just published.

This finding was just coming together when COVID hit, and it was inevitable that we wondered whether we’d see people with similar super innate anti-viral immunity who remain uninfected by SARS-CoV-2. I was convinced that we would find viral-resistant people amongst COVID-exposed individuals, and just as I was having that thought, one of the world’s leading immunologists, Jean-Laurent Casanova, wrote an article in Cell describing how he was embarking on a major global study to look at the genetic reasons for why people become seriously ill in viral infection and why others remain uninfected. He was inviting researchers from across the globe to join the project — the COVID Human Genetic Effort. In one short paragraph he said he was also interested in resistance. So, I contacted him, and told him about our experience with the Hepatitis C virus, and he invited us and Ireland to join the COVID Human Genomic Endeavor.

TBSI News: So that’s how it all started…

Cliona: That’s how it all started. There are at least 90 different groups worldwide. We meet every second Monday for fantastic discussion.

TCD and St. James’s Hospital are now part of a COVIDHGE subgroup interested in viral resistance that has embarked on a genetic analysis of resistant people. About 20 research groups are recruiting people, and we now have about 450 DNA samples for analysis. Trinity got a grant from SFI to be part of this collaboration. We’ve recruited 30 people from healthcare workers at St. James’s Hospital who have shown likely resistance. The criteria set by the consortium are that the resistor needs to have shared a room and, ideally, a bed with somebody who was PCR-positive. We need to have proof that the contact person was PCR-positive at the time.

We have tested their adaptive immune response, and we know that they do not have a T-cell response, meaning that they did not get infected. But we do know they made a T-cell response to their vaccines so they can make an adaptive immune response; they just didn’t need to when they first encountered the virus their innate immune systems were good enough to keep it away. The big question now is how many people have innate immune protection against SARSCoV2.

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