Virus World

A small subset of uninfected people also had SARS-CoV-2-fighting T cells, a finding that scientists are still trying to figure out. In May, researchers showed that people with mild forms of COVID-19, the disease caused by the SARS-CoV-2 virus, have circulating T cells that respond to the virus. Now, in a Science Immunology study published last week (June 26), a collaborating research team has determined that people who are sick enough with COVID-19 to be hospitalized in the intensive care unit also make SARS-CoV-2-reactive T cells. In both studies, the researchers found that a subset of healthy, unexposed people also had some of these T cells that react to the virus, perhaps due to previous exposures to other coronaviruses that cause symptoms of the common cold.

The latest study provides more solid evidence that there are SARS-CoV-2-specific T cells that are induced by the infection, says Antonio Bertoletti, who studies T cells at Duke-NUS Medical School in Singapore and was not involved in the work. This is important because researchers have put a lot of emphasis on antibodies, he adds, but it’s still not clear whether antibodies or T cells are more important for protection from the virus. Rory de Vries, a virologist and immunologist at Erasmus University Medical Center in the Netherlands, was visiting immunologist Alessandro Sette’s lab at the La Jolla Institute for Immunology in California to collaborate on another project when “all hell broke loose” with the pandemic, Sette tells The Scientist. Sette’s group had been developing tools to investigate adaptive immunity to SARS-CoV-2, but in California at that point, they didn’t have a COVID-19 patient population to try them in. As de Vries prepared to return home in March, Europe already had confirmed cases of SARS-CoV-2, so he took the tools the team had developed back to the Netherlands.

de Vries and colleagues collected blood from 10 COVID-19 patients—four women and six men admitted to the intensive care unit with acute respiratory distress syndrome requiring ventilation—and 10 healthy volunteers. The team exposed the study participants’ immune cells to a pool of predicted SARS-CoV-2 peptides in vitro to see whether or not the cells would react. The team determined that all of the ill patients had fewer overall T cells than the healthy volunteers, which was consistent with earlier findings from other groups. All patients had helper T cells and eight of 10 had killer T cells that targeted SARS-CoV-2 proteins. These reactive T cells showed up within about 10 days of symptom onset in the patients. The strongest responses were to the SARS-CoV-2 spike protein, but cells responded to membrane and nuclear viral proteins, too....

SARS-CoV-2 belongs to the betacoronavirus genus and has 79.5% identity to SARS-CoV. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its host entry receptor. The clinical manifestations of COVID-19 include pneumonia, diarrhea, dyspnea, and multiple organ failure. Interestingly, lymphocytopenia, as a diagnostic indicator, is common in COVID-19 patients. 

Xiong et al. found upregulation of apoptosis, autophagy, and p53 pathways in PBMC of COVID-19 patients. Some studies reported that lymphocytopenia might be related to mortality, especially in patients with low levels of CD3+, CD4+, and CD8+ T lymphocytes. Lymphocytopenia was also found in the Middle East respiratory syndrome (MERS) cases. MERS-CoV can directly infect human primary T lymphocytes and induce T-cell apoptosis through extrinsic and intrinsic apoptosis pathways, but it cannot replicate in T lymphocytes. However, it is unclear whether SARS-CoV-2 can also infect T cells, resulting in lymphocytopenia. To address this question, we evaluated the susceptibility of T lymphocytes to SARS-CoV-2 infection. To accomplish this, pseudotyped SARS-CoV and SARS-CoV-2 were packaged based on methods described previously.

Surprisingly, over several replicates, we saw that the T-cell lines were significantly more sensitive to SARS-CoV-2 infection when compared with SARS-CoV...

Published in Nature (April 7, 2020):

https://doi.org/10.1038/s41423-020-0424-9

New findings suggest past infections may offer some protection against the novel coronavirus. Immune warriors known as T cells help us fight some viruses, but their importance for battling SARS-CoV-2, the virus that causes COVID-19, has been unclear. Now, two studies reveal infected people harbor T cells that target the virus—and may help them recover. Both studies also found some people never infected with SARS-CoV-2 have these cellular defenses, most likely because they were previously infected with other coronaviruses.

“This is encouraging data,” says virologist Angela Rasmussen of Columbia University. Although the studies don’t clarify whether people who clear a SARS-CoV-2 infection can ward off the virus in the future, both identified strong T cell responses to it, which “bodes well for the development of long-term protective immunity,” Rasmussen says. The findings could also help researchers create better vaccines. The more than 100 COVID-19 vaccines in development mainly focus on another immune response: antibodies. These proteins are made by B cells and ideally latch onto SARS-CoV-2 and prevent it from entering cells. T cells, in contrast, thwart infections in two different ways. Helper T cells spur B cells and other immune defenders into action, whereas killer T cells target and destroy infected cells. The severity of disease can depend on the strength of these T cell responses.

Using bioinformatics tools, a team led by Shane Crotty and Alessandro Sette, immunologists at the La Jolla Institute for Immunology, predicted which viral protein pieces would provoke the most powerful T cell responses. They then exposed immune cells from 10 patients who had recovered from mild cases of COVID-19 to these viral snippets. All of the patients carried helper T cells that recognized the SARS-CoV-2 spike protein, which enables the virus to infiltrate our cells. They also harbored helper T cells that react to other SARS-CoV-2 proteins. And the team detected virus-specific killer T cells in 70% of the subjects, they report today in Cell. “The immune system sees this virus and mounts an effective immune response,” Sette says. 

The results jibe with those of a study posted as a preprint on medRxiv on 22 April by immunologist Andreas Thiel of the Charité University Hospital in Berlin and colleagues. They identified helper T cells targeting the spike protein in 15 out of 18 patients hospitalized with COVID-19. ..

Original Publication in Cell (May 14, 2020):

https://doi.org/10.1016/j.cell.2020.05.015