A variant of the coronavirus once helped the global pork industry. Could we be protected? | Science

Long before COVID-19 became a household word—in 1946To be specific, veterinary researchers at Purdue University reported that something invading the innards of young pigs caused diarrhea, vomiting and weight loss, ultimately killing most of them. Scientists didn’t know the cause of the disease, which devastated US pig farms, but they could trigger the disease by feeding crushed pieces of diseased pig intestines to healthy piglets. This pig farmer’s nightmare, over time, turned out to be a coronavirus, which was named transmissible gastroenteritis virus (TGEV).

To date, TGEV has never harmed a human, and its relationship to SARS-CoV-2, the driver of COVID-19, is remote. But after spreading around the world during the 1970s, TGEV took a strange turn: the disease it caused all but disappeared when an even more transmissible, but less harmful variant of TGEV essentially immunized pigs against the original virus. “The best coronavirus vaccine was made by nature,” says Stanley Perlman, a veteran coronavirus researcher at the University of Iowa.

The fate of TGEV was unveiled years ago, but some researchers have recently questioned whether the latest concerning SARS-CoV-2 variant, Omicron, could produce a similar twist in the ongoing human pandemic. Omicron causes far too many serious illnesses and deaths to celebrate as a savior – last week it recorded a higher daily death toll in the United States than the Delta variant at its peak. But some suspect it will also be a “natural vaccine” against more pathogenic strains.

Unlike COVID-19 vaccines, veterinary vaccines developed for TGEV had little impact and could not reverse the massive losses suffered by the livestock industry. But in the late 1970s, European farmers experienced the most unexpected relief: the disease caused by the virus began to fade and, over time, disappeared. “We didn’t quite understand what was going on,” says Maurice Pensaert, professor emeritus at Ghent University, who was then one of the few scientists in the world studying TGEV.

One oddity was that litters continued to test positive for TGEV on standard antibody tests. “There was no diarrhea at all, but the percentage of pigs with antibodies against TGEV was very high,” recalls Pensaert, whose fascination with the virus dates back to the 1960s when he went to graduate school. on the TGEV at Purdue University.

It appeared to Pensaert and his colleagues that perhaps another related virus was triggering the production of antibodies, protecting the little pigs. In 1984, they report the confirmation of this novel hypothesis, a new variant of TGEV. Just as Omicron has a different “tropism” than the original SARS-CoV-2 and other variants – it targets the upper airway bronchi rather than the lungs – the TGEV variant attacked different tissues from its parent. Although TGEV preferred cells from the gastrointestinal tract, the mutant preferred trachea, bronchi, and lungs. Pensaert and his colleagues therefore named it porcine respiratory coronavirus (PRCV). “We never imagined that PRCV would emerge,” says Linda Saif, a veteran coronavirologist at The Ohio State University, Wooster, who developed TGEV vaccines in the 1970s as part of her master’s and doctorate. theses.

Work on porcine coronaviruses progressed slowly in the 1980s because research funding was scarce. “Coronaviruses weren’t important in humans, so nobody paid attention to this enteric virus or this respiratory strain in pigs,” Saif says.

PRCV surfaces in the United States in 1989, again protecting newborn piglets from TGEV. But its genetic sequence differed from that of the European cousin. “It wasn’t like it appeared in Europe and then traveled to the United States and started infecting pigs,” Saif says. “It rose independently.”

Like Omicron compared to previous variants, PRCV spreads much more easily than its predecessor. He started showing up on farms with what Saif calls “high security herds,” kept several miles away from other herds. “That’s how transmissible this coronavirus was by the respiratory route,” she says.

In another parallel to COVID-19, the pig story has its own speculation about the origins of a pandemic virus traced back to a lab. Pensaert wonders if PRCV in Europe evolved from a potential TGEV vaccine that he and his colleagues in Ghent made by repeatedly passing the original virus through cell culture to weaken or attenuate its pathogenicity. . The virus still alive in the vaccine was clearly different from PRCV, but it could have mutated further, perhaps in vaccinated animals or during commercial production of the vaccine, to create the variant. “It’s hard to say, but I’ve asked myself this question many times,” he says.

Saif thought the same about the attenuated TGEV vaccines used in the United States, but sequencing experiments revealed that the PRCV there had more in common with natural TGEV than the vaccine strains. (There is no clear explanation for how Omicron came into existence, which has also fueled some speculation that the variant originated in laboratory mice infected with SARS-CoV-2 or other research.)

Sequencing of TGEV and PRCV, however, revealed a surprising difference. In the surface protein gene, spike, PRCV had a deletion of more than 600 nucleotides. “It was a surprise for everyone,” says Saif. Stranger still, the deletion did not affect the spike receptor-binding domain, the small part of the protein whose shape plays a key role in attaching to a host cell and infecting it.

Research into PRCV and TGEV – which only began to receive serious funding after the emergence of a deadly human coronavirus disease, severe acute respiratory syndrome, in 2002 – finally showed the sequence codes lacking PRCV for the tip region which binds to sialic acids, sugars that decorate cells. The hypothesis, Saif says, is that this domain allows the tip of TGEV to bind to intestinal mucins, gel-forming proteins rich in sialic acids that make up the sticky goop between some cells. (They are best known for being an ingredient in snot.) Once attached to the tip, the sialic acids “prevent the virus from being washed away [of the intestines] before it can latch onto the cell receptor,” Saif explains. The absence of this sialic acid binding site is “the likely reason why PRCV can no longer infect the gut.”

When PRCV appeared, “suddenly we had a mild respiratory infection, we developed generalized herd immunity, and this virus was able to outcompete some of the other strains,” Saif says. As PRCV spread, large pig farms coincidentally stepped up measures to protect animals from all pathogens, so it is difficult to fully attribute the disappearance of TGEV to this natural vaccine. But she thinks the new variant played a role.

“Everyone hopes that will be the case with Omicron,” she adds. Omicron may also interact with mucins differently than previous variants, which could explain why it prefers to park in the upper airways rather than deep in the lungs, causing milder disease.

The Omicron-PRCV parallels break down in one extremely important way: the SARS-CoV-2 variant still causes many cases of severe disease in people who have not been vaccinated or lack immunity to natural infection . Both Saif and Pensaert point out that we also don’t know if infection with Omicron protects people against other variants that more easily cause serious illness.

Yet a later plot point in the pig saga suggests another way Omicron could help humans in the future. Some fear that Omicron and Delta could swap genetic material to produce a “recombinant” with the worst traits of the two: Omicron’s high transmissibility and Delta’s severity. But there is a contrasting and optimistic scenario proposed by TGEV and PRCV: they eventually recombined in a new US-dominant variant that spreads more easily than TGEV, does not cause severe disease in piglets, and can still thwart severe cases caused by TGEV, Saif says. If Omicron immunizes people safely and similarly recombines with and tames a more pathogenic variant of SARS-CoV-2, that would be “the best-case scenario,” she says.

The pig story has a big asterisk next to that fairy tale ending. In 2010, another coronavirus from the same branch of the coronavirus family tree began to devastate the little piggies. Called porcine epidemic diarrhea virus (PEDV), it had circulated among pigs for decades without causing serious illness, but a highly virulent strain emerged in China. The variant found its way to the United States in 2013, possibly introduced via imported pig feed, suggests Saif.

PEDV vaccines hit the market to fight this deadly strain, but there is little real data to show they work. And recently, the PEDV/TGEV recombinants have started circulating. If this Three Little Swine Virus saga has any morals that apply to humans, Omicron or later, even milder variants could help curb the COVID-19 pandemic — for now. But they might not protect us from the next big, bad coronavirus to find a way to reach our doorstep.

Clarification, February 4, 10 a.m.: This story has been updated to note that the TGEV PRCV variant and the latest recombinant can cause mild disease in pigs, although symptoms are usually not as severe as those caused by the original virus. We also clarified that PEDV belongs to the same branch of the coronavirus family tree, but not to the same lineage. Linda Saif’s affiliation has also been corrected.

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