Understanding the immune system’s response to COVID-19

Understanding the immune system’s response
Christine Tham (left) places the cells in an incubator overnight; as most of the work had to be carried out during Singapore's circuit breaker period, the team came up with innovative solutions to keep the discussion going (right)

Hepatitis B expert Professor Antonio Bertoletti and his team at Duke-NUS were about to get the first readings for what was initially a side project. They were investigating what T cells, a key part of the immune system, could tell them about COVID-19 infection.

When Kamini d/o Kunasegaran arrived at the lab one morning in early April to start her shift, she was in for a surprise. Just looking at the wells of the ELISpot assay (a test used to count cells) that her colleague Christine Tham had set up the day before, she could tell they had hit something.

“When Kamini showed me the ELISpot, my first reaction was ‘Something has gone wrong’,” said Dr Anthony Tan, a senior research fellow in the Bertoletti Lab.

Before this project, the team had been devoting their energy to coaxing T cells that could recognise hepatitis B from peripheral blood. Present at a rate of just one per 10,000 T cells, isolating just ten hepatitis B-specific T cells in a sample counted as a success.

“But this time, the ELISpot lit up like a Christmas tree,” said Kamini, a senior research assistant.

“We didn’t even need to put it under the microscope to see that we had lots of SARS-CoV-2-specific T cells,” added Tham, a research fellow in the Bertoletti lab.

This finding turned the team’s focus away from chronic hepatitis B infection, which Bertoletti jokingly calls his first love, and signalled the start of a three-month-long race to study the T cells that recognise the novel coronavirus.

The 96-well ELISpot, a test used to quantify cells in a sample, that launched a frenzied three-month project

T cells, along with antibodies, form the immune system’s second line of defence. Unlike the first defence, which is triggered as soon as anything non-human is detected in the body, the second line of defence is tailored to the specific threat and can take a while to kick in.

While the first wave tries to stem the invasion, fragments of the intruder are delivered to the lymph nodes, where specialist T cells await. Once the right type of T-cell specialist has been identified, the body produces countless clones. The clones are split into two battalions: killer T cells, which blow up the infected cells, and helper T cells, which recruit another set of white blood cells — called B cells — to produce specific antibodies. While killer T cells destroy, antibodies sweep up any free-floating viral particles.

“Antibodies and T cells need to work together to control an infection,” said Professor Antonio Bertoletti from Duke-NUS’ Emerging Infectious Diseases Programme.

“But they are not like a shield that keeps the virus out completely,” he added. Nonetheless, the better the immune system recognises the virus, the faster it will be at containing and eliminating the virus.

That is why Bertoletti shakes his head in frustration at the fears triggered by reports of re-infection. Naturally, people will get infected again during a pandemic, but Bertoletti insisted that it is the progress of their disease that matters.

The hunt for COVID-19 T cells
Completing the research during circuit breaker meant that only a skeletal team could be in the lab, working seven days a week while the rest who worked from home crunched the data. But having worked on T cells for decades and studied the T-cell response to the 2003 SARS virus, Bertoletti's team had an idea about where to start their work.

“One reason why we were able to publish our paper so quickly was that we have a fantastic partnership with the clinical side of our Academic Medical Centre. They [the clinicians] were able to provide us with suitable and prompt access to patients’ profiles during our study,” he said.

Bertoletti’s team have years of experience coaxing T cells
Bertoletti’s team are experts at coaxing T cells from the peripheral blood of hepatitis B patients

On 15 July, the team published their findings in Nature, switching the spotlight from antibodies to T cells. Being notoriously hard to study, T cells’ role in mitigating COVID-19 infection had received less attention. The paper even prompted a blog post from Dr Francis Collins, Director of the US National Institutes of Health.

In the paper, the team showed that individuals, even those who had no symptoms, had SARS-CoV-2-specific T cells after their recoveries from the infection.

“There were T cells, even in asymptomatic individuals who had very low levels of antibodies,” said Bertoletti. Whether these individuals were asymptomatic because of their T-cell responses remains an unanswered question, which may have implications for vaccine development.

What is more, two other groups — those who had never been infected with SARS-CoV-2 and those who had been infected with SARS in 2003 — both had T cells that could attack COVID-19.

Seventeen years on, the memory T cells in SARS survivors still recognised key parts of the SARS-CoV-1 virus, including the nucleocapsid protein, which keeps the virus’ RNA stable, and two non-structural proteins, which are important in virus replication. These proteins are almost identical in SARS-CoV-2, which could mean that SARS survivors may be protected from severe COVID-19 infections.

“This finding, in particular, has attracted a huge amount of interest from the scientific community because it shows that coronaviruses can induce long-lasting immunity that might have a protective effect. This is an area of huge controversy and with great impact on the management of the COVID-19 pandemic,” said Bertoletti. At press time, the study ranked in the 99th percentile of all tracked journal articles of a similar age and topped the 844 tracked Nature articles of a similar age, according to the publisher's metrics

What’s next?
Bertoletti’s work is a first step in understanding how the immune system fights COVID-19. Next, the team is working on an easy-to-use test that will help researchers to measure large numbers of T cells that attack specific threats, such as SARS-CoV-2.

They are also engineering SARS-CoV-2-specific T cells by cloning the parts of T cells that recognise the virus and fitting them to other T cells. If T cells prove to be protective against severe COVID-19 infection, these engineered T cells could be a possible therapy for COVID-19 infection.

While Bertoletti and his team are focusing on COVID-19 for the foreseeable future, Bertoletti is still fond of his work on hepatitis B: “I’m not quite ready to separate from hepatitis B yet. But since this pandemic has struck the world so unexpectedly and there is so much to learn about this virus, this work, from a researcher’s perspective, is extremely exciting! My first love will have to wait for now.”
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