Understanding why some people develop severe symptoms following a SARS-CoV-2 infection while others remain asymptomatic is one of the most pressing questions in COVID-19 research today. The answer is undoubtedly complicated and multifaceted and will take years of research.
One potentially crucial factor has now been identified by a team of researchers: prior exposure to coronaviruses.
This insight is based on research involving T-helper cells, a specialized white blood cell which is essential to the regulation of our immune response. The researchers found that one in three people with no prior exposure to SARS-CoV-2 nonetheless has T-helper cells capable of recognizing the virus. The likely reason for this is that SARS-CoV-2 shares certain structural similarities with other coronaviruses.
The work is published in Nature in the article, “SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.”
For their study, the researchers isolated immune cells from the blood of 18 COVID-19 patients. They also isolated immune cells from the blood of 68 healthy individuals who had never been exposed to the novel coronavirus.
The researchers then stimulated these immune cells using small, synthetic fragments of SARS-CoV-2 spike proteins. They then tested whether the T-helper cells would be activated by contact with these protein fragments. They found that this was the case in 15 out of 18 patients with COVID-19 (85%).
“This was exactly what we had expected. The immune system in these patients was in the process of fighting this novel virus, and therefore showed the same reaction in vitro,” explained one of the study’s three lead authors, Claudia Giesecke-Thiel, PhD, head of the flow cytometry facility at the Max Planck Institute for Molecular Genetics. She added: “The fact that not all patients with COVID-19 showed this T-helper cell response to viral fragments is probably due to the fact that T cells cannot be activated outside the human body during an acute or particularly severe phase of an illness.”
The team was, however, surprised to find memory T-helper cells capable of recognizing fragments of SARS-CoV-2 in the blood of healthy individuals. They were found in a total of 24 out of 68 healthy individuals tested (35%). In fact, the researchers noticed that the immune cells of COVID-19 patients reacted to different fragments of the viral envelope than the immune cells of healthy individuals. While the T-helper cells of patients recognized the spike protein in its full length, the T-helper cells isolated from healthy individuals were primarily activated by sections of the spike protein which showed similarity to corresponding sections found in the spike proteins of harmless “common cold” coronaviruses.
“This suggests that the T-helper cells of healthy individuals react to SARS-CoV-2 because of previous exposure to the endemic ‘common cold’ coronaviruses,” said Giesecke-Thiel. She further explained: “One of the characteristics of T-helper cells is that they are not only activated by a pathogen with an ‘exact fit,’ but also by pathogens with ‘sufficient similarity’.” Notably, the researchers were able to show that the T-helper cells isolated from healthy participants who reacted to SARS-CoV-2 were also activated by various “common cold” coronaviruses—displaying what is known as “cross-reactivity.”
What effects this cross-reactivity might have on a previously healthy person infected with SARS-CoV-2 was not addressed in the current study. “Generally speaking, it is possible that cross-reactive T-helper cells have a protective effect, for instance, by helping the immune system speed up its production of antibodies against the novel virus,” explained co-lead author Leif Erik Sander, MD, of Charité’s medical department, division of infectious diseases and respiratory medicine. He added: “In this case, a recent bout of the common cold would probably result in less severe COVID-19 symptoms. However, it is also possible that cross-reactive immunity could lead to a misdirected immune response and potentially negative effects on the clinical course of COVID-19. We know this can occur with dengue fever, for instance.”
Prospective studies will be needed in order to conclusively determine whether previous “common cold” coronavirus infections confer protection against subsequent infection with SARS-CoV-2—and whether this might explain the high variability in clinical manifestations. One such study, which will be led by Charité and conducted in collaboration with Technische Universität Berlin and the MPIMG, was just launched. Funded by the Federal Ministry of Health (BMG) and the Federal Institute for Drugs and Medical Devices (BfArM), the “Charité Corona Cross Study” will investigate the impact of cross-reactive T-helper cells on the course of COVID-19. The researchers will simultaneously follow COVID-19 risk populations over several months. Ultimately, the study aims to help predict the clinical course of COVID-19, both in people with and without previous SARS-CoV-2 infections.
Coronaviruses are responsible for up to 30% of all seasonal colds.
“Current estimates suggest that the average adult will contract an infection caused by one of the four endemic coronaviruses approximately every two to three years,” explained Andreas Thiel, PhD, a Charité researcher based at both the Si-M (‘Der Simulierte Mensch) and the BIH Center for Regenerative Therapies (BCRT). “If we assume that these cold viruses are capable of conferring a certain level of immunity against SARS-CoV-2,” he added, “this would mean that people who have had frequent exposure to such infections in the past, and who test positive for cross-reactive T-helper cells, should have better protection.”
The authors wrote that, “The presence of S-cross-reactive T cells in a sizable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming COVID-19 vaccine trials.”