Does COVID prefer the gut now? JN.1 is fastest-growing variant to emerge in past two years.

Spiking COVID-19 cases detected in wastewater have prompted some scientists to ask whether JN.1, the strain driving an explosive winter surge, is selectively targeting peoples' intestinal tracts.

The evidence is extremely limited and theoretical, and there's no data suggesting that more people are experiencing severe digestive illnesses from COVID. Yet there's no question that the coronavirus has changed its requirements for entering cells, said Sydney virologist Stuart Turville. This may be consistent with more efficient infection of particular tissues including the gut.

It's just one of the many debates swirling around JN.1. The variant is so highly infectious and immune evasive that some scientists believe it needs its own Greek name to separate it from its highly infectious progenitor, omicron.

"Its mode of entry has diverged significantly from what we saw in 2020," said Turville, whose University of New South Wales lab has been tracking viral entry pathways since the start of the pandemic. "It's presently the peak of this trajectory."

JN.1 is the fastest-growing variant to emerge in the past two years. The World Health Organization designated it a variant of interest Tuesday due to its rapid growth and potential to add to the respiratory virus burden in the Northern Hemisphere. The latest booster formulation should provide good protection against it, according to the organization.

The strain emerged in August from the ultra-mutated BA.2.86, or Pirola variant. While Pirola wasn't especially remarkable, a hallmark mutation that produced JN.1 has resulted in greater transmissibility and immune evasiveness, University of Tokyo scientists reported earlier this month.

Rising quickly

JN.1 is accelerating a year-end COVID wave. In the United States, it accounted for up to 29% of the strains in circulation as of Dec. 8 — and COVID hospitalizations are rising quickly, the Centers for Disease Control and Prevention said last week. It warned that low vaccination rates for COVID and other respiratory bugs could lead to more severe disease and strain on the health system for the rest of winter.

Detections in wastewater have uniformly and exponentially increased in multiple countries, including Austria, Germany, Netherlands, Switzerland and Singapore.

"People are detecting it in wastewater at as high a rate as they were detecting omicron when it first emerged," said Kanta Subbarao, director of the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne, who chairs the agency's technical advisory group on COVID vaccine composition. "But so far, we're not seeing a parallel or concomitant increase in hospitalization. I think we have to watch that space."

More clues

An increase in emergency room visits and other medical-use data will offer clues on the severity of illness JN.1 causes, said Subbarao, who is also a professor of microbiology and immunology at the University of Melbourne's Peter Doherty Institute for Infection and Immunity. "Whether it's become more gut-associated, for instance, we don't know," she said.

The wastewater findings could reflect high circulation in communities, rather than more frequent or more intense gut infections that result in greater or prolonged shedding of the coronavirus in stool.

Diarrhea wasn't more frequently reported by COVID sufferers as of November in the Netherlands, which has tracked symptom data since 2020.

Viral targets

The coronavirus has long shown that it's adept at infecting the gut. The trend away from lower lung infections has been observed since omicron supplanted the delta variant in late 2021.

Turville's research provides a plausible explanation for the change and why JN.1 might prefer the GI tract, said Ryan Hisner, an Indiana school teacher whose self-taught genomic sleuthing has identified important changes in the pandemic virus's evolution.

Still, "it's not clear," Hisner said. "We don't really have any direct evidence."

Inherent changes in the virus are difficult to disentangle from the important role vaccinations and prior infections have played in priming the immune system to recognize and attack the virus before it reaches the lungs, he said.

Even if disease patterns aren't substantially altered by JN.1, the virus is definitely taking a new pathway into cells, according to Turville. While past versions have preferentially latched onto a cleaved version of the ACE-2 cell-surface protein, the new variant represents the coronavirus' strongest predilection yet for an uncleaved version of the cellular doorway.

"I can't see it getting any further than JN.1," Turville said. "JN.1 is so extreme. The key now is to understand how this translates into what tissue niches it now inhabits."