Wastewater could unravel COVID mysteries

Studies of wastewater have turned up one of the weirdest observations yet about COVID. Most of the evolution of SARS-CoV-2 is happening within a small fraction of infected people who, for some reason, don't clear the virus for months on end. These persistent infections could be a clue to the way new variants emerge, what causes long COVID and even how the virus got into humans in the first place.

The story of these persistent infections is written in sewage — decipherable from genetic sequences of viral particles, which some people continue to shed long after their initial infection. Scientists can read those sequences with such precision that they can tie different genetic signatures to individual cases.

In one study, virologist Marc Johnson of the University of Missouri Medical School was able to see that for a full year, copious quantities of virus were excreted by a single person who worked at a small company in Wisconsin. "I had never seen viral levels that high," he says. "It was insane."

Such cases are the most likely source of new variants  — delta, omicron and most recently a variant called BA.2.86. Some scientists have suggested that a persistent infection was a key part of the process by which the virus jumped into humans in the first place.

People whose bodies don't clear the virus for months are probably immune-compromised in some way, but scientists aren't sure exactly how. After all, Johnson notes, the Wisconsinite with the yearlong infection was healthy enough to go to work every day. Whether this person was capable of transmitting the virus to others for that entire time isn't clear, but if the consensus is correct that persistent infections gave rise to new variants, then the people with those persistent infections must have transmitted the new variants to others at some point.

Johnson says they were able to trace the source of the virus to wastewater coming from a particular building — a small business of about 30 people. He contacted them and asked all the employees to be tested. Only two thirds of them complied, he recalls, and they were all negative. The persistent virus might have come from one of the people who opted out, or it could have been hiding in places in the body a nasal swab couldn't find — like the GI tract.

Most people do clear the virus, according to current consensus, and not all new variants change the course of the pandemic. Johnson has now found 49 new variants, which he calls "cryptic lineages" because they show up in wastewater but not in human samples. Most such variants won't spread widely. But a few will.

Flu and cold viruses, too, stay in circulation by mutating out of reach of immunity built up in previous seasons, and whether more mutations accumulate in persistent infections remains unknown.Flu can also make radical shifts by exchanging whole viral segments and creating novel combinations, mixing parts of bird, pig and human viruses.

Omicron took scientists by surprise because it had made a bigger leap from previous variants than they thought likely. The most widely accepted explanation is that it evolved within an immune-compromised person, says Johnson. "What made omicron special was the fact that it got out, not the fact that it existed."

Johnson's team found another strange case in Ohio, which came out of wastewater data collected by the Massachusetts-based company Biobot. The virus was showing up in Columbus and in a town of 15,000 people about 40 miles away, suggesting the infected person was traveling back and forth.

Johnson says he tried to use social media to identify the person — but nobody came forward.

Genetic analysis showed that the person probably got infected in late 2020 or early 2021, and was still infected and shedding virus in July 2022.

The signal was persistent for months, says Johnson, then the viral load skyrocketed. For days, that Ohio town showed the highest wastewater levels of the virus during the entire pandemic. The genetic sequences showed the town wasn't having an outbreak — the virus was coming entirely from this one person. Then one day the signal disappeared. Johnson wonders if the person died.

Understanding the nature of such persistent infections might provide clues to the ongoing mystery of COVID's origin. In a new paper in Nature Microbiology, University of North Carolina virologist Ralph Baric and colleagues suggest that an immune-compromised person might have picked up the virus from a pangolin — an animal that's sold in China's illegal wildlife trade. Viruses that infect other animals are usually not well adapted to invade human cells, but such a virus might have acquired the mutations it needed while it was growing in a single individual, given enough time.

Figuring out who is persistently infected would also shed more light on long COVID. "There's got to be some degree of overlap between persistent infection and long COVID," Johnson says. A recent study published in Nature and covered by my colleague Lisa Jarvis suggests that biomarkers of some patients suffering from long COVID show T-cell exhaustion, a sign of persistent infection.

Long COVID afflicted about 6% of U.S. adults last summer. Some people are still debilitated by infections they caught in 2020, suffering problems very similar to chronic fatigue syndrome, which is also badly understood. Some may have undetected persistent infections.

For them, answers — even answers found in the sewer — can't come fast enough.

This guest essay reflects the views of F.D. Flam, a Bloomberg Opinion columnist covering science. She wrote this for Bloomberg Opinion.