BERLIN — The answer to why some cases of COVID-19 are worse than others is the subject of intense research efforts. A new study aims to address this issue after finding that more than one-third of people who were never exposed to the virus possess immune cells capable of recognizing SARS-CoV-2. Scientists suggest that these cells could be the result of prior infection with other “common cold” viruses.
The study is led by scientists at Charité – Universitätsmedizin Berlin and the Max Planck Institute for Molecular Genetics (MPIMG). Published in Nature, the research looks at the presence of an immune cell called a T-helper cell in the blood of 18 coronavirus patients and 68 healthy individuals with no exposure to the virus. T-helper cells are critical for the development and maintenance of protective antibody responses in humans. Scientists believe these cells may play an important role in the immune response to SARS-CoV-2.
After isolating immune cells from the blood of each patient, the authors stimulated these cells in petri dishes with small, synthetic fragments of the SARS-CoV-2 “spike protein.” This is the viral component that forms characteristic, crown-like protrusions on its surface.
Specifically, the researchers designed two pools of these protein fragments, or peptides, each spanning a different section of the spike protein. One peptide pool designated “S-I” contained fragments from the part of the protein involved in viral entry into human cells. Researchers note that this section of the protein represents a major target of human antibodies that are able to block SARS-CoV-2. The other peptide pool, dubbed “S-II,” contains fragments derived from the part of the spike protein that is similar to spike proteins from common cold human coronaviruses.
Using a technique called flow cytometry, the researchers determined whether the T-helper cells in the cultures reacted to the virus fragments. Flow cytometry uses a laser beam to detect and measure physical and chemical characteristics of cells.
How prior exposure to ‘common cold’ coronaviruses may help
The study shows that T-helper cells from COVID-19 patients react strongly to both peptide pools, with 67% of patients reacting to S-I, and 85% reacting to S-II.
“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,” explains one of the study’s three lead authors, Claudia Giesecke-Thiel, in a statement. “The fact that not all patients with COVID-19 showed this T-helper cell response to viral fragments is probably due to fact that T cells cannot be activated outside the human body during an acute or particularly severe phase of an illness.”
The team was surprised to find that T-helper cells from the blood of healthy individuals who were never exposed to SARS-CoV-2 can also react to the two peptide pools. The majority of this response is geared to the S-II peptide pool, with 35% of these individuals exhibiting reactivity.
“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,” explains Giesecke-Thiel. “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 show that T-helper cells from the blood of healthy participants are also activated by the spike protein of the common cold coronaviruses. This phenomenon of immune cells being able to respond to two different viruses is known as cross-reactivity.
“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,” explains co-lead author Leif Erik Sander. “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.”
Follow-up research in progress
The research team plans to look more closely at the significance of this cross-reactivity between SARS-CoV-2 and other human coronaviruses. A new experiment, dubbed the Charité Corona Cross Study, is already underway.
For the new study, scientists will follow COVID-19 risk populations, including child daycare staff, pediatric practice staff, and care home residents, over several months. Researchers will test for SARS-CoV-2 positivity in these populations over time. They will also perform comprehensive immunological workups to characterize the reactivity of antibodies and T cells against the virus.
The authors are also collecting blood samples from at least 1,000 recovered COVID-19 patients. They plan to examine how a range of immunological factors correlate with symptoms. The findings could help predict the clinical course of COVID-19 in people with and without previous coronavirus infection.
“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,” explains the study’s third co-lead author, Andreas Thiel. “If we assume that these cold viruses are capable of conferring a certain level of immunity against SARS-CoV-2, 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. This group of people will therefore be a particular focus of the ‘Charité Corona Cross Study’.”
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