Scientists Uncover Biological Signatures of the Worst Covid-19 Cases

Although the delineations aren’t always clear-cut, the immune system’s responses to pathogens can be roughly grouped into three categories: type 1, which is directed against viruses and certain bacteria that infiltrate our cells; type 2, which fights parasites like worms that don’t invade cells; and type 3, which goes after fungi and bacteria that can survive outside of cells. Each branch uses different cytokines to rouse different subsets of molecular fighters.

People with moderate cases of Covid-19 take what seems like the most sensible approach, concentrating on type 1 responses, Dr. Iwasaki’s team found. Patients struggling to recover, on the other hand, seem to be pouring an unusual number of resources into type 2 and type 3 responses, which is kind of “wacky,” Dr. Iwasaki said. “As far as we know, there is no parasite involved.”

It’s almost as if the immune system is struggling to “pick a lane,” Dr. Wherry said.

This disorientation also seems to extend into the realm of B cells and T cells — two types of immune fighters that usually need to stay in conversation to coordinate their attacks. Certain types of T cells, for instance, are crucial for coaxing B cells into manufacturing disease-fighting antibodies.

Last month, Dr. Wherry and his colleagues published a paper in Science finding that, in many patients with severe Covid-19, the virus had somehow driven a wedge between these two close-knit cellular communities. It’s too soon to tell for sure, but perhaps something about the coronavirus is preventing B and T cells from “talking to each other,” he said.

These studies suggest that treating bad cases of Covid-19 might require an immunological reset — drugs that could, in theory, restore the balance in the body and resurrect lines of communication between bamboozled cells. Such therapies could even be focused on specific subsets of patients whose bodies are responding bizarrely to the virus, Dr. Blish said: “the ones who have deranged cytokines from the beginning.”

But that’s easier said than done. “The challenge here is trying to blunt the response, without completely suppressing it, and getting the right types of responses,” Dr. August said. “It’s hard to fine-tune that.”

Timing is also crucial. Dose a patient too early with a drug that tempers immune signaling, and they may not respond strongly enough; give it too late, and the worst of the damage may have already been done. The same goes for treatments intended to shore up the initial immune response against the coronavirus, like interferon-based therapies, Dr. Blish said. These could stamp out the pathogen if given shortly after infection — or run roughshod over the body if administered after too long of a delay.

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