How do bats live with so many viruses? New bat stem cells hint at an answer

2023-02-21

Compared with other mammals, bats are notorious for hosting more viruses that are dangerous to people but not themselves. It’s an oddity that’s drawn renewed attention since COVID-19 broke out in humans—many scientists suspect the coronavirus SARS-CoV-2 leaped from bats into people, directly or via an intermediate host. Seeking to create large quantities of bat tissue to help study why the flying animals are so virus-friendly, a research team now reports it has transformed adult bat cells into versatile stem cells that can be coaxed to form many kinds of tissue.

The advance, described today in Cell, thrills many bat scientists. “If the work in this paper can be (easily) reproduced in other groups with different bat species, the impact will be huge!” says Linfa Wang, a bat coronavirus researcher at the Duke-NUS Medical School in Singapore. And early studies of the bat stem cells have already suggested the animals may not only tolerate viruses, but actually let them remain active, possibly because doing so has some advantage for the hosts.

The new work traces back to the spring of 2020. As the COVID-19 pandemic started, Thomas Zwaka, a stem cell researcher at the Icahn School of Medicine at Mount Sinai, became fascinated by the question of why bats carry so many viruses that can cause human disease. But researchers studying this question have been hampered by the fact that getting bat samples to study in the lab is difficult. “Even with a breeding colony [like our team has], it is still a challenge to get sufficient bat cells reliably and reproducibly for certain types of research,” Wang says.

To sidestep that problem, Zwaka wanted to create bat stem cells that could be kept in the lab and be differentiated, as needed, into specific kinds of tissue. Some researchers had claimed years before to have done this, but the work had never been reproduced.

But with much of the world shut down by COVID-19, Zwaka first had to figure out how to get some bat tissue delivered to his laboratory. Javier Juste, an evolutionary biologist at the Spanish National Research Council, eventually agreed to send Zwaka some samples from a colony of greater horseshoe bats he was studying in Seville. To have fresh tissue that could survive the long flight, Juste prepared the bat samples at the airport in Madrid just before they were loaded on one of the few planes still crossing the Atlantic Ocean. In his New York City lab, Zwaka then tried to use a strategy developed in 2006 by Japanese researcher Shinya Yamanaka to force adult mammalian cells back into an earlier, stem cell–like state. But the recipe for creating these induced pluripotent stem (iPS) cells did not work on the bat samples.

After months of tweaking the formula, however, Zwaka and his colleagues finally found a combination of factors that worked. Several tests, including differentiating the transformed bat cells into multiple types of cells, suggested they were indeed pluripotent cells. The researchers then repeated the procedure with cells from a different bat species, the greater mouse-eared bat, with similar results. “The two bats are evolutionarily very distant,” Zwaka says. “So this told us that our protocol probably works with many different bats.”

In studying these cells, Zwaka’s team noticed something interesting. Certain viruses can insert versions of their genes into the genomes of human or mouse cells, and these viral sequences sometimes reawaken in cells that are in a pluripotent state. And when Zwaka and colleagues looked for remnants of these viral sequences in the bat iPS cells, they found numerous active versions—as well as some proteins that these sequences produce.

“It’s just striking how many of these virus sequences there are,” says Zwaka, who proposes that bats don’t restrain these active sequences because their replication may act as a defense strategy against other viruses or as a kind of self-vaccination.

That remains speculation for now, other bat researchers caution. Scientists have proposed before that viruses and bats have a symbiotic relationship, Wang says, but it is hard to prove.

Indeed, Kevin Olival, a bat researcher at the EcoHealth Alliance, a nonprofit research group based in New York City, says the data in the new Cell paper are too limited to conclude that bat stem cells are special in how they handle the integrated, or endogenous, viral sequences. But he thinks the new stem cell technique could help conduct similar sequence-hunting studies in a wide range of other mammals, “and see if bats really are above average in this sense.”

Bat scientists, meanwhile, are enthusiastic about finally having a recipe for creating bat iPS cells. “We are already discussing in my team how to make use of these pluripotent cells,” says Vincent Munster, a virologist at the U.S. National Institute of Allergy and Infectious Diseases. “This is a terrific paper,” adds Jacob Hanna, a stem cell researcher at the Weizmann Institute of Science. “Undoubtedly this is going to become a widely used platform.”

Science, 21 February 2023
; https://science.org