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Microbe Mappers Are Tracking Covid-19’s Invisible Traces

DURING THE SECOND week of March, as the World Health Organization declared Covid-19 a global pandemic, a team of latex-gloved scientists from Cornell Weill Medical School fanned out across Penn Station armed with packs of sterile, long-armed swabs and a tripod-mounted instrument for capturing air samples. In New York City, the 100th person had just tested positive for SARS-CoV-2, the coronavirus that causes the deadly new respiratory disease, but the subways remained open and packed with daily commuters. The researchers were there, in one of the most crowded areas of the city, to see if the coronavirus was, too.

Over the years, critics have panned the project as too esoteric and too expensive to be anything more than a splashy publication play. Mason’s original NYC-subway-mapping paper was later corrected after health officials disputed the headline-grabbing findings, which included trace evidence of anthrax and the bugs that cause bubonic plague. But when SARS-CoV-2 began spreading out of China and around the world, MetaSUB’s teams were ready to spring into action.

Normally, they conduct sampling in the summer. But in 17 pilot cities, MetaSUB scientists started swabbing for traces of genetic material from SARS-CoV-2 as early as the first week of February. When subways shut down, they switched to other high-touch surfaces, like ATMs and park benches. So far, they’ve collected 3,600 samples, with 1,000 of those having made it to the Mason lab for analysis. And as more cities within MetaSUB’s network come online, Mason expects data from at least 10,000 samples to flow into the group’s open-access repository.

The goal of all this swabbing and sequencing is twofold: One, to better understand the virus’s transmission dynamics. How long does it stay alive on surfaces? How much of it is in the air? How risky is riding the subway, really? Answers to those kinds of questions can help public health officials make decisions now to protect citizens during the early stages of the pandemic. But the second aim is more long-term: detecting potential hot spots of infection in highly trafficked areas before people start showing up in emergency rooms.

With Covid-19 testing still woefully lagging in the US, even as some states are already starting to relax safety measures, passive disease surveillance may be an important part of the next phase of the pandemic—learning to live with the virus. In addition to subways, scientists have started looking for signs of the virus in other parts of the public infrastructure, including hospitals and wastewater treatment plants. Last month, Ginkgo Bioworks, the largest synthetic biology company in the US, committed $25 million of in-kind work to academic and industry projects focused on combating Covid-19, including free sequencing. At present, the company is sequencing a few hundred patient samples each week to bolster epidemiological investigations in hard-hit areas, but it plans to scale up to 10,000 samples a day to support widespread environmental surveillance in the future.

“The appetite for molecular monitoring has really increased, because people are now seeing what the cost of its absence looks like,” says Mason. That cost is especially high in New York City, where the coronavirus has so far killed more than 12,000 people, including dozens of transit workers.

Outside of MetaSUB, other microbiome researchers are also applying their microbial forensic methods to track how SARS-CoV-2 spreads between people. One of them is Jack Gilbert, who is perhaps best known for spearheading the ambitious Earth Microbiome Project. In pre-pandemic times, he had developed techniques for tracing people’s movements based on their unique microbial signatures. In a 2019 study, Gilbert and his colleagues were able to identify which college students had visited which dorm rooms, based on the trail of germs they left behind. While at the University of Chicago, he led the largest-ever analysis of a hospital’s microbiome, creating detailed maps of microbial exchanges between patients, staff, and surfaces. Now at the University of California San Diego, Gilbert has launched a similar study with a local hospital aimed at understanding how much virus Covid-19 patients are shedding—into the air and onto bedrails, door handles, floors, and the health care workers who take care of them.

Laboratory experiments at the National Institutes of Health have shown that SARS-CoV-2 can survive in aerosols suspended in the air for up to three hours and on some surfaces for days. Other researchers in China and Singapore have been gathering data from inside hospitals, analyzing how environmental conditions, like temperature and humidity, might affect the virus’s ability to stick around. Gilbert wants to add another factor to that equation: the patient’s own microbiome. “Our hypothesis is that unique bacteria present in the respiratory tract of a patient might alter the persistence of the virus in the built environment,” says Gilbert.

The idea has some precedent. Inside the human body, bacterial cells outnumber human cells 10 to one. When a virus invades a human body, it has to interact with the microbial community already in residence. For a long time, doctors have observed that viral respiratory infections can trigger co-infections by pneumonia-causing bacteria in the lungs. This was generally presumed to be a result of the virus knocking back the human immune system, allowing an opportunistic bacteria to start attacking its host. But more recent research has shown that some respiratory viruses, including influenza, can bind directly to several species of bacteria, which makes both the bacteria and the virus better at grabbing on to human cells. In a study published last year, microbiologists at the University of Texas Southwestern Medical Center discovered that binding to bacteria can give some respiratory viruses another advantage—it allows them to stay alive longer in the cold, harsh desert of an otherwise antiseptic hospital room. The virus family they studied, the picornaviruses, which include the virus that causes the common cold, appeared to use the bacteria as a life raft, with the molecular bonds between them stabilizing the virus’s protein shell against heat, light, and even bleach.

Gilbert suspects the same could be true for SARS-CoV-2. “It could be that if you happen to have the wrong bug at the time you get infected, that makes you a super-spreader,” says Gilbert. “Super-spreaders,” people who can infect not one or two but potentially dozens of others, can have an outsize impact on how fast new outbreaks take off. But the mechanisms behind super-spreading remain poorly understood. Gilbert hopes to be able to offer some clues sometime next month, when his team finishes analyzing the thousand or so samples they’ve collected so far. The data could help doctors rapidly identify which people are more likely to be super-spreaders, so those people can take additional precautions.

Other research projects will take much longer to begin providing insight. Gilbert’s UCSD colleague and Earth Microbiome Project cofounder, Rob Knight, recently launched a series of longitudinal studies with Southern California hospitals exploring whether the other bugs that live in people’s lungs are associated with different Covid-19 outcomes. The goal is to eventually develop biomarkers that can predict a person’s susceptibility to more severe forms of the disease. While age and preexisting conditions are the biggest risk factors for Covid-19, the mysterious illness has also inexplicably killed many young, previously healthy people. Studies are already ongoing to see if people’s genetics play a role. Why not the microbiome?

Mason’s lab has also teamed up with New York Presbyterian Hospital to analyze the nasal swabs of thousands of suspected and confirmed Covid-19 patients and sequence everything inside their noses. So far, the group has sequenced viral genomes from 155 patients. When they plugged the sequences into Nextstrain—an open-source database that uses genetic data as ink to paint vast evolutionary maps of viruses—146 of them clustered neatly together. The closest genetic relative to the version of the virus that was inside more than 90 percent of those patients was a virus found inside a Covid-19 patient in Belgium. That told Mason that, consistent with research made public earlier this month, travelers from Europe had likely seeded New York’s coronavirus outbreak. But after the virus arrived in the city it mutated, and it was that version that quickly spread through the population. “New York City appears to have a unique strain of SARS-CoV-2,” says Mason. His team detailed its findings in a study that is awaiting peer review, posted to a preprint server last week.

However, he cautions, that doesn’t on its own offer an explanation for why the city got hit so hard. In the Bronx, which has the highest Covid-19 fatality rates in the country, Mason says they see the same strain circulating as in Manhattan, where his lab is. “Once you cross the East River, death rates double. But that has nothing to do with the strain of the virus and everything to do with socioeconomic disparities.”

Still, his group is now conducting additional analyses of samples collected from inside the hospital rooms of sequenced patients to see if the mutations acquired by the novel New York City strain might have enhanced the coronavirus’s ability to jump between people. In other words, that’s a competing hypothesis for what makes a super-spreader: The x factor might be mutations in each local strain, rather than the virus’s ability to hitch a ride on bacteria already inside a Covid-19 victim’s lungs.

And as for the subways? Mason’s team has found plenty of genetic material from humans, the flu virus, and some bacteria, but so far, no sign of SARS-CoV-2. That’s good news, he says, and probably reflects the enhanced cleaning and disinfection the Metropolitan Transit Authority enacted in mid-March. As MTA starts making plans for how it will reopen the subway once state officials relax stay-at-home orders, Mason hopes his swabbers can help the agency respond more nimbly to head off potential new outbreaks. Regular environmental sampling could flag surfaces that need more thorough cleaning and aid the city’s forthcoming army of contact tracers. It could also allow city officials to partition public spaces into zones that are safe for people to enter and ones that have a high risk of infection, rather than just keeping everything shut down.

“Without any environmental surveillance infrastructure we’re still going to be blind to the risks around us,” says Mason, who’s been sharing his team’s data with the MTA and city council members. “We have the molecular tools to map these risks. Why wouldn’t we do it if we can?”

To be sure, information from environmental sequencing is better than no information at all. But there are limits to what it can reveal. Finding viral RNA on surfaces doesn’t necessarily mean people can get sick from touching them. The length of the RNA molecule provides clues about whether the virus is whole, intact, and capable of contagion. But to know for sure requires taking the sample back to the lab and seeing if it can infect cells in petri dishes. That’s just as true for subway cars as it is for hospital rooms.

Doctors at the University of Nebraska Medical Center were among the first in the US to care for Covid-19 patients, after some Americans evacuated from Wuhan were flown there in early February. UNMC researchers rigorously swabbed and sampled air from the biocontainment units that housed those patients. They discovered that the virus was everywhere—coughed into the air, settling on surfaces, and splashed out of toilets. But of the more than 160 samples taken from the isolation units, none of them successfully infected cell lines.

So even if SARS-CoV-2 starts showing up in subways again (which it will, inevitably, once people start riding them), that’s not necessarily a reason to send a city back into lockdown. The MTA is reportedly pursuing plans to make riders maintain 6 feet of social distance aboard trains and buses. But if the thought of going back to work aboard a rolling petri dish fills you with dread, remember the basics: Wear a mask, don’t touch your face (no matter how much you want to!), and wash your hands often.

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