'I Am a Scientist Working With Severe Cases of COVID-19'

Before the pandemic, I was studying immunology in the field of virus infections. I am a professor of immunobiology and molecular, cellular and developmental biology at Yale School of Medicine, and an investigator of the Howard Hughes Medical Institute. With my team at Yale's Iwasaki lab, we had been studying how the immune system detects viruses and how innate and adaptive immune systems are connected. Based on these insights, we are designing better vaccines.

We had been studying viruses including herpes, influenza and Zika for years, so when SARS-CoV-2 (COVID-19) hit we were prepared to tackle the questions it provoked. At the end of February, we started pivoting our work to focus on COVID-19. Our first effort was mostly focused on testing, because in the early stages of the virus there was no real testing capacity in the U.S.

With a number of collaborators, we helped set up a polymerase chain reaction (PCR) based testing strategy, and carried out numerous PCR testing in the lab to help identify COVID-19 infected patients and healthcare workers.

In parallel, my lab quickly moved into studying immunology, which is our specialty.

Now, in September in Connecticut, there are very few COVID-19 cases. But back in March and April we were seeing cases spiking in the state. So, we had this unique opportunity to start enrolling patients at Yale New Haven Hospital, which was seeing many cases of COVID-19, as part of our Yale IMPACT (Implementing Medical and Public Health Action Against Coronavirus CT) study. We were able to do white blood cell analysis on 113 patients to study and follow them over time to understand the changes in their immune responses in real time, and that work has resulted in a study that was published in Nature.

Our aim was to study the immune response in different people; those who were having a moderate case of COVID-19 and are recovering from the infection, and those who were having a severe response to the COVID-19 virus, some of whom unfortunately did pass away from this disease.

Every four days or so, we would take their nasopharyngeal swabs (samples of secretions from the nose and throat) and blood and analyse what was happening, and that led to very interesting insights. Firstly, with the virus load that we measure from the patients' nose, we observed the severe and moderate patients started off with similar levels. But then, though the moderate patients were able to clear the virus eventually, the severe patients never really could.

So the first thing we noticed was that one of the elements that distinguished between moderate and severe cases of the disease was the inability to control the virus in the severe case. The second thing we learned when we collected patients' plasma and observed their cytokines.

Cytokines are small proteins important in cell signalling because they transmit information from one cell to another.

The COVID-19 viral load in severe patients was associated with increased levels of these proteins. They can have a positive or a negative effect on the body's immune response to a disease, depending on the information they are transmitting between cells.

It turns out that there are a number of distinct features that are associated with the COVID-19 patients we observed and that interestingly correlate with their recovery from this disease. I was really floored when I saw these features, because there were some unusual things that we had not anticipated seeing.

Essentially, we saw that patients who eventually recovered had proteins (growth factors) in their blood that were encouraging their cells to repair. Growth factors can repair the damaged tissue in blood vessels and lung cells that happens during viral infection. In contrast, the patients who went on to have really severe cases of COVID-19 had proteins in their blood that were misfiring in all sorts of strange ways, and in some cases, reacting as if there was a parasite in the body!

It's pretty unusual during a viral infection to have anti-parasite responses going off—but many of the very severe patients we monitored exhibited these.

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This illustration shows the structure of coronaviruses, including the spikes that adorn the outer surface of the virus. Centers for Disease Control and Prevention

Compared to other viruses we have been studying over the years, we had never seen this kind of anti-parasite response coming up. So, it's likely that this virus is doing something to the host that is disorienting them in some way that allows this type of misfiring to occur. We don't know what that is yet, it may be intrinsic to the virus or it may be somehow the host is being triggered by some features of this virus that is elevating all kinds of these cytokine proteins. It may even be a body's way of trying to recover from infection.

When the patients were clustered based on their cytokine levels, they separated out into three clusters. We observed that patients who recovered didn't have much in the way of these misfiring proteins, but the second cluster of severe cases and the third cluster of very severe cases both did, and the third cluster had very rapid decline with the disease. That third cluster included patients who had the greatest numbers of misfiring proteins.

When I first saw these unusual signatures, I thought there was some technical glitch. So I asked the scientists to make sure they repeated this analysis multiple times, and these signatures kept coming up. But then during the course of study we started seeing other pre-prints, scientific papers that have not yet been peer-reviewed, that were reporting these anti-parasite responses also. So we knew we weren't alone in seeing this, and now we have seen several studies that confirm this.

One of the things that we reported is that even during the first 12 days of COVID-19 symptom onset there are certain proteins mentioned above that correlate with worse COVID-19 disease outcome. So, by measuring these early, we can inform clinicians that a patient, if they exhibit such cytokine proteins, is someone to pay attention to versus others who may look just as sick but aren't exhibiting in the same way.

In addition, we found bio-markers that we can use to look at patients to help predict what might happen. It's very useful to have this information because you can prepare Intensive Care Unit (ICU) beds in anticipation, as well as to potentially give these patients more suitable treatment.

Way before our COVID-19 study came out I had been tweeting about targeting inflammasomes because we have seen evidence of that activation in multiple papers. Inflammasomes are one type of inflammation that happens during a severe infection.

As the name suggests, inflammasomes are a very toxic form of inflammation. It is a large protein complex that forms inside the cell in response to bacterial and viral infection. Inflammasomes can transform cytokine proteins such as IL-1b and IL-18 into active forms. It can also cause "fiery death" of cells, which is known as pyroptosis. We found clear signatures of inflammasome activation that correlated with worse disease and death from COVID-19.

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Professor Akiko Iwasaki is a professor of immunobiology and molecular, cellular and developmental biology at Yale School of Medicine, and an investigator of the Howard Hughes Medical Institute. With her team she has been investigating the body's immune response to COVID-19. Robert Lisak

My lab had the knowledge and tools to react before COVID-19 hit, and it is an amazing privilege to be able to work on a pandemic to try and help people. We feel very energized because we are helping people and there are tangibles that come out of this type of research. Things are happening in real time; people are reaching out to me with different ideas for clinical trials based on what we have found. It's really exciting that a study result can trigger clinical trials in a very rapid manner, and be able to predict what might happen using a mouse model we developed to mimic COVID-19.

I feel honored to be working in this area. The pandemic has given me an opportunity to communicate science because more people are now interested. This real interest in immunology and vaccines is also an opportunity for me to educate the public about the immune system. Immunology is becoming extremely important now that public health measures have failed in many countries. Now, we really need the immune system to be able to kick in with the right vaccines to protect us.

I hope that our insights will help people cope with this infection better and eventually, recover. We continue to investigate this virus and have recently released research into whether immune responses to COVID-19 differ between the sexes.

To help just even one person survive this virus would be the most gratifying thing a scientist could hope for.

Professor Akiko Iwasaki focuses on the mechanisms of immune defense against viruses at mucosal surfaces, which are a major site of entry for infectious agents. She is a professor of immunobiology and molecular, cellular and developmental biology at Yale School of Medicine, and an investigator of the Howard Hughes Medical Institute. Professor Iwasaki has received numerous awards and honors for her work and is also well known for her Twitter advocacy on women and underrepresented minorities in the science and medicine fields. You can follow her on Twitter @VirusesImmunity

All views expressed in this piece are the writer's own.

As told to Jenny Haward.