Scientists at the La Jolla Institute for Immunology (LJI) have found direct evidence that exposure to common cold coronaviruses can train T cells to fight SARS-CoV-2. Indeed, a common cold partially protected mice from lung damage during SARS-CoV-2 infection before exposure to the coronavirus.
New research published recently Nature communication, provides an important first look at how “cross-reactive” T cells—those that can fight multiple viruses from the same family—develop in an animal model. “We are learning how these immune cells develop and function,” said LJI research instructor Annie Elong Ngono, Ph.D., co-leader of the study.
The Shrestha Laboratory is now working to develop novel vaccines purposefully designed to harness these powerful T cells. These vaccines will protect against SARS-CoV-2 and provide immunity against several other coronaviruses with pandemic potential.
“Our research will help scientists design and develop ‘pan-coronavirus’ vaccines that generate broad, cross-protective responses.”
LGI Professor Sujan Shrestha, Ph.D., senior study leader and member of the LGI Center for Vaccine Innovation
How powerful are T cells?
T cells tend to specialize. They learn to find specific molecular targets called epitopes that belong to specific pathogens. “Cross-reactive” T cells are important to human health because they differ-; but closely related-; Pathogens such as coronaviruses recognize epitope targets on different family members. This viral family includes serious pathogens such as the common cold coronavirus and SARS-CoV-2.
The COVID-19 pandemic has put cross-reactive T cells in the spotlight. In early 2020, LJI professors Shane Crotty, Ph.D., and Alessandro Sette, Dr.Biol.Sci., discovered that many people—;who had never been exposed to SARS-CoV-2—;already had T cells. which identified the new coronavirus. How did these T cells know what to look for?
SARS-CoV-2 only appeared in 2019, but many people were infected with the common cold coronavirus long before that. LGI scientists have shown that cross-reactive T cells can recognize targets from both viruses. In follow-up studies, researchers even found an association between cross-reactive T cells and a lower risk of developing severe COVID-19.
If T cells can learn to target both viruses simultaneously, perhaps scientists can design a vaccine against many types of coronaviruses, including the new SARS-CoV-2 variant. That was the hope-; But there was still much to learn.
“To design better vaccines we need to know how these protective T cells develop and how long the window of protection lasts,” said LJI postdoctoral fellow Rubens Alves, PhD, who served as first author of the new study.
Best Labs is working to answer those questions. Members of the lab specialize in developing humanized mouse models, which allow them to study infectious diseases and human-relevant immune cell responses in a controlled environment.
Cross-reactive T cells for rescue
For the new study, the researchers used mouse strains that can produce the exact same type of T cells found in humans. The researchers infected these mice with one of the most prevalent common cold coronaviruses known as OC43. Both SARS-CoV-2 and OC43 are betacoronaviruses.
The scientists found that mice infected with OC43 produced CD4+ “helper” T cells and CD8+ “killer” T cells that cross-reacted with SARS-CoV-2. These cells target the same epitopes as T cells collected from humans with SARS-CoV-2 exposure.
Next, the researchers developed a model of sequential infection by following SARS-CoV-2 with OC43 infection in these humanized mice. They tested whether cross-reactive T cells actually helped protect mice from severe COVID-19.
Cross-reactive CD4+ “helper” T cells actually helped prevent the virus from invading the respiratory system. Mice with prior OC43 exposure showed lower levels of SARS-CoV-2 infection in their airways and were less likely to develop pneumonia and lung damage. Cross-reactive T cells really helped prevent severe disease.
“Our lab’s expertise in mouse models has allowed us to go deeper into what the human studies have suggested,” said Elong Ngono.
Next steps in vaccine design
SARS-CoV-2 is not the first coronavirus to cause a serious outbreak. SARS, which caused a deadly outbreak in 2003, was also a coronavirus. So is MERS. This new study is an important step in understanding how T cells can simultaneously learn to recognize and cross-react to many coronaviruses — including the emerging SARS-CoV-2 variant and other family members with pandemic potential.
Going forward, the team wants to investigate how exposure to other types of common cold coronaviruses affects T cells. Will cross-reactive T cells still develop? Will they seek the same shared epitope or different targets?
“We now have mouse models to study different human infection scenarios, such as the typical situation when a person has been infected multiple times with different common cold coronaviruses before encountering SARS-CoV-2,” said Shrestha. “We even now have a model to characterize different SARS-CoV-2 vaccine-induced human T cell responses and determine the contribution of these T cells to vaccine-induced protection.”
Shrestha said the institute is well equipped to move forward with this epidemic prevention research. He credits LJI with ensuring that LJI scientists have critical training and facilities for infectious disease research. Shrestha also emphasized that philanthropic support made it possible for the institute to build a biosafety level 3 laboratory for it-; and many other-; Critical research.