Milder COVID-19 Symptoms Tied to Prior Run-Ins With Other (Common Cold) Coronaviruses

Killer T cells from patients with mild cases of COVID-19 show evidence of recent encounters with other coronaviruses.

In COVID-19 patients whose symptoms were mild, Stanford researchers found they were more likely than sicker patients to have signs of previous infection from similar, less virulent coronaviruses.

A study by researchers at the Stanford University School of Medicine suggests that people with COVID-19 may experience milder symptoms if certain cells of their immune system “remember” past encounters with seasonal coronaviruses — the ones that cause about a quarter of the colds children get.

These immune cells are better equipped to mobilize quickly against SARS-CoV-2, the coronavirus responsible for COVID-19, if they’ve already met its gentler cousins, the scientists concluded.

The findings may help explain why some people, especially children, seem much more resilient than others to infection by SARS-CoV-2, the coronavirus that causes COVID-19. They may also make it possible to predict which people are likely to develop the most severe symptoms of COVID-19.

The immune cells in question, called killer T cells, roam the blood and lymph, park in tissues and perform stop-and-frisk operations on resident cells. The study, published online July 1 in Science Immunology, found that killer T cells from the sickest COVID-19 patients showed fewer signs of previous run-ins with cold-causing coronaviruses.

Discussions about immunity to COVID-19 often revolve around antibodies – proteins that can attach to a virus before it can infect a vulnerable cell. But antibodies are easily fooled, said Mark Davis, PhD, a professor of microbiology and immunology; director of Stanford’s Institute for Immunity, Transplantation and Infection; and a Howard Hughes Medical Institute investigator. Davis is the study’s senior author.

“Patogens evolve rapidly and ‘learn’ to hide their critical properties from our antibodies,” said Davis, who is also the Burt and Marion Avery Family Professor. But T cells recognize pathogens in a different way, and they’re hard to fool.

Our cells all provide real-time reports on their inner state of affairs by routinely sawing some samples of every protein they’ve made lately into small pieces called peptides and displaying those peptides on their surface for inspection by T cells. .

Memory T cells

When a killer T cell’s receptor detects a peptide on the cell surface that doesn’t belong there, such as a protein produced by an invading microorganism, the T cell declares war. It multiplies ferociously and its numerous progeny — whose receptors all target the same peptide sequence — scramble to destroy any cell carrying these telltale peptide indications of that cell’s invasion by a pathogenic microbe.

Some of the myriad daughter cells of the original killer T cell settle down and remain above the fray. These “memory T cells” exhibit increased sensitivity and exceptional longevity. They often remain in the blood and lymph for decades, ready to spring into action if they ever cross paths with the peptide that triggered the wave of T-cell expansion that spawned them. That willingness can save precious time when suppressing a previously encountered virus or close cousin.
As the pandemic progressed, Davis mused: “Many people get very sick or die from COVID-19, while others walk around not knowing they have it. Why?”

To find out, the study’s lead author, postdoctoral fellow Vamsee Mallajosyula, PhD, first confirmed that some parts of the SARS-CoV-2 sequence are in fact identical to analogous parts of one or more of the four widespread coronavirus strains. that cause colds. He then assembled a panel of 24 different peptide sequences that were either unique to proteins made by SARS-CoV-2 or that were also found on similar proteins made by one or more (or even all) seasonal strains.

The researchers analyzed blood samples taken from healthy donors before the COVID-19 pandemic began, meaning they had never encountered SARS-CoV-2 — although many were believed to have been exposed to cold-causing strains of coronavirus. The scientists determined the number of T cells targeting each peptide represented in the panel.

They found that the killer T cells from unexposed individuals targeting SARS-CoV-2 peptides shared with other coronaviruses were more likely to proliferate than killer T cells targeting peptides found only on SARS-CoV-2. The T cells targeting those shared peptide sequences had likely encountered some milder strain of coronavirus before — and had multiplied in response, Davis said.

Many of these killer T cells were in “memory” mode, he added.

“Memory cells are by far the most active in defense against infectious diseases,” Davis said. “They are what you want to have to fight a recurrent pathogen. They are intended to generate vaccines.”

Killer T cells whose receptors target peptide sequences unique to SARS-CoV-2 must proliferate over several days to pick up speed after exposure to the virus, Davis said. “That lost time can mean the difference between not even noticing that you have a disease and dying from it,” he said.

Less severe COVID-19

To test this hypothesis, Davis and his colleagues turned to blood samples from COVID-19 patients. They found that COVID-19 patients with milder symptoms did indeed have many killer memory T cells targeting peptides that SARS-CoV-2 shared with other coronavirus strains. The numbers of expanded killer T cells from sick patients mainly belonged to the T cells that typically target peptides unique to SARS-CoV-2 and thus likely had started all over again in their response to the virus.

“It may be that patients with severe COVID-19 were not, at least not recently, infected by milder strains of coronavirus, so they didn’t retain effective memory killer T cells,” Davis said.

Davis noted that cold-causing seasonal coronavirus strains are widespread among children, who rarely develop severe COVID-19, although they are just as likely to become infected as adults.

“Sniffing and sneezing are a hallmark of childcare,” he said, “and coronavirus-induced colds are a big part of the reason. As many as 80% of children in the United States are exposed within the first few years of life. .”

Reference: “CD8+ T cells specific for conserved coronavirus epitopes correlate with milder disease in COVID-19 patients” by Vamsee Mallajosyula, Conner Ganjavi, Saborni Chakraborty, Alana M. McSween, Ana Jimena Pavlovitch-Bedzyk, Julie Wilhelmy, Allison Nau, Monali Manohar, Kari C. Nadeau and Mark M. Davis, Jul 1, 2021, Science Immunology.
DOI: 10.1126/sciimmunol.abg5669

Davis and Mallajosyula have filed patents for the technology used in this study through Stanford’s Office of Technology Licensing.

Davis is a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Stanford Maternal and Child Health Research Institute, the Stanford Cancer Institute, and the Stanford Wu Tsai Neurosciences Institute.

Other Stanford study co-authors include former undergraduate student Conner Ganjavi; postdoctoral researcher Saborni Chakraborty, PhD; former life science research professionals Alana McSween and Allison Nau; graduate student Ana Jimena Pavlovitch-Bedzyk; life science research professional Julie Wilhelmy; Monali Manohar, PhD, laboratory director and research scientist at the Sean N. Parker Center for Asthma and Allergy Research; and Kari Nadeau, MD, PhD, professor of pediatrics and director of the Sean N. Parker Center.

The work was funded by the National Institutes of Health (grants AI057229 and U01 AI140498); Stanford’s Institute of Immunity, Transplantation, and Infection; the Howard Hughes Medical Institute; the Bill and Melinda Gates Foundation; the Sean N. Parker Center and the Sunshine Foundation.

Stanford’s Department of Microbiology and Immunology also supported the work.