Searching for coronavirus clues in single cells

Severe cases of COVID-19 are increasingly being tied to inflammation, a complex immune process researchers are trying to decipher by studying the cells involved.

Why it matters: Pinpointing the cells in the body's immune response would help speed the development of treatments and vaccines. It also offers insights into inflammation, which underlies diseases ranging from cancer to arthritis to heart disease.

How it works: Different molecules (cytokines and antibodies, for example) and cells (white blood cells, T cells, macrophages and others) in different pathways control the inflammation response that kicks in when the body is injured or infected.

• But inflammation can also persist due to disease and turn the body's immune system against itself, as in the case of autoimmune conditions like lupus and diabetes, causing damage.

"Inflammation is a double-edged sword," says Yuan Tian, a computational immunologist at Fred Hutchinson Cancer Research Center.

• "It's important to study both sides — what cells are good, what cells are bad — and to go as deep as possible to find the [cell] populations that are really causing a disease and providing protection," he says. "Single-cell technologies are well-suited for this task."
• Most of what's known about the body's defense system comes from studying immune cells in the blood.
• But that doesn't always give the most accurate representation of what's going on in people's tissues, where inflammation takes place, says José Ordovas-Montañes of Boston Children's Hospital and the Broad Institute.

With COVID-19, the immune system seems to go awry in some patients who experience an immune storm that initially fights the virus before turning on the patient's own body.

• Diabetes, a condition characterized by inflammation, is emerging as a risk factor for severe disease.
• And COVID-19 is linked to a rare but severe condition in children called multisystem inflammatory syndrome in which the heart, lungs and other organs become inflamed.

What's happening: Single-cell science tools that have been developed over the last few years can measure the proteins from a cell, its DNA and RNA, whether genes are being expressed, and a cell's location and relationship to other cells. Now those tools are being used to try to understand how SARS-CoV-2, the virus that causes COVID-19, affects the body's immune system.

• Ordovas-Montañes and his colleagues have found cell types in the lungs, nasal passages and intestines that express the receptors for two proteins (ACE2 and TMPRSS2) that help SARS-CoV-2 invade cells. (ACE2 plays a key role in regulating inflammation.)
• The technologies have also been used to identify a type of macrophage that might be the culprit behind inflammation in patients with severe cases of COVID-19. (It's not clear though whether that inflammation was due to preexisting conditions or if it was caused by the disease itself.)

One of the biggest questions about COVID-19 is why it seems to spare some (typically the young), but ravage others (mostly the elderly and those with pre-existing health conditions). There are hints that this, too, comes back to inflammation.

• With COVID-19, it might be that infection in certain cells is handled equally across the ages, but bystander cells could respond differently based on age, says Ordovas-Montañes. Or, he says, it could be that the immune response is the same but organ systems in the young can handle stress better than older patients.

• Ordovas-Montañes and his colleague Alex Shalek of MIT and the Broad Institute are now using single-cell tools to test these hypotheses. They're planning to look at cells directly infected with the virus and those that are bystanders of the infection nearby in the nasal tissue of children with the disease, and compare the immune response to that in older adults with more severe outcomes of the disease.
• Vineet Menachery, an immunologist at the University of Texas Medical Branch, and his colleagues are studying cells from mice infected with coronaviruses to determine how the genome is regulating itself (what are known as epigenetic change) and whether that shifts with age in a way that affects the inflammation response.

The big picture: Understanding how inflammation impacts different cells in different target tissues — whether due to infection, cancer or autoimmune disease — could help to identify the immune memories that can be erased or enhanced to take someone back to a healthy state, Shalek says.

• Pinpointing which cells cause inflammation and piecing it together with how genetics and epigenetics affect the immune process could eventually help to tailor treatments.
• "If we can figure out these profiles, can we predict how you're going to respond based on your epigenetics — in your lung or in your immune cell?" Menachery says. That, he adds, is the long term goal — for COVID-19, bacterial infections and other diseases.