Omicron’s Endosomal Route Into Cells May Alter Its Symptom Profile

NEW YORK (Reuters Health) – Unlike previous SARS-CoV-2 variants, Omicron prefers to infect cells via endocytosis, which alters where in the body the virus is most likely to succeed and could explain its milder symptom profile, a new study suggests.

Researchers showed in a series of in vitro experiments that Omicron’s mutations cause it to do poorly at entering cells by fusing with the cell membrane using a mechanism that requires a host enzyme, transmembrane serine protease 2 (TMPRSS2), to first cleave a portion of the viral spike protein.

Instead, Omicron strongly favors endosomal entry, which is independent of TMPRSS2, and the variant proliferates most readily in tissues where TMPRSS2 is scarce, according to the report published in Nature.

Both infection routes – fusion, and transport into the cell via membrane-bound vesicles known as endosomes – require the virus to bind with the host’s ACE-2 receptor, but the fusion mechanism also lets the virus move from cell-to-cell more easily by forming syncytia. Damage from that process has been a hallmark of severe COVID-19 lung disease but is much less common in Omicron infections so far, the authors note.

“It explains why the disease is less severe and causes less pneumonia” with Omicron, said senior study author Dr. Ravindra Gupta, a professor of clinical microbiology and Wellcome Senior Fellow in Clinical Science at the Cambridge Institute of Therapeutic Immunology and Infectious Diseases in the UK.

Since the current work was first released in December as a preprint, other studies have confirmed Omicron’s poor replication in lung cells and have shown that the tissue preferences of this version of the virus are “inverted” as compared with prior variants, Dr. Gupta noted in a phone interview.

Clinical data also seem to confirm some of the in vitro results that suggest Omicron will replicate well in tissues with high levels of ACE-2, low TMPRSS2, and low pH, like nasal epithelial cells, but less well in the throat and lungs.

Dr. Gupta’s team also tested Omicron in gallbladder cells and a colon cancer cell line – both tissues where ACE-2 and TMPRSS2 levels are high and prior variants have thrived – and found Omicron’s replication was impaired in those environments.

There isn’t enough clinical data yet to confirm whether Omicron’s preferred cell-entry mechanism makes it less likely to infect all the tissues favored by prior variants, such as the cornea or the gut, Dr. Gupta noted. “We’re getting anecdotes about more people presenting with bowel symptoms,” he said, but that could be for other reasons. “This tropism (evidence) is very early,” though it could eventually guide understanding of whether people will get long COVID, for example, based on where in the body the infection is focused.

Omicron’s preferences and aversions might also inform treatment options. Most antivirals approved for treating COVID-19 should not be affected by the cell-entry mechanism differences, including Pfizer’s Paxlovid, Merck’s Molnupiravir and Gilead’s Remdesivir, Dr. Gupta said.

However, drugs targeting TMPRSS2, such as camostat mesylate, a pancreatitis drug that has shown some benefit in COVID-19 patients, may be less useful with Omicron.

And in principle, Dr. Gupta said, Omicron could be more sensitive to hydroxychloroquine than previous versions of the virus, because that drug targets the endosomal route. But the high doses that would be needed “are likely to be toxic.”

Dr. Gupta also cautions against relaxing vigilance toward SARS-CoV-2, because the next variant could have very different biology.

He is struck by how greatly Omicron’s evolutionary route to success diverged from that of the previously dominant “variant of concern” (VOC), Delta.

“Delta was kind of going the other way,” notes Dr. Gupta, whose lab has characterized mutations that enhanced Delta’s ability to use TMPRSS2 and thereby increased its infectivity.

The current study found that Omicron has even higher binding affinity for ACE-2 receptors than Delta, but Omicron’s impairment in using TMPRSS2 “shunted” it away from the cell-fusion route and toward the less efficient endosomal route, Dr. Gupta noted. That leaves Omicron more “dependent” on local ACE-2 levels, he said, while Delta’s characteristics left it more dependent on TMPRSS2.

In human nasal-epithelial cell cultures, where endogenous ACE-2 levels are high and TMPRSS2 is low, Delta and Omicron have similar replication rates and viral titers over 24 and 48 hours. But in tissues with high TMPRSS2, Delta outstripped Omicron’s replication, the study found.

Dr. Gupta thinks the next variant of concern won’t come from incremental improvements in a more recent variant, but – like Omicron – will emerge from an “old lineage,” possibly with new surprises in store.

“Important to re-iterate that the next VOC will likely have been evolving from a previous virus over many months and will likely not share these tropism differences,” he wrote on Twitter in early February. “Hence pathogenicity of next VOC likely to be higher, and in context of declining vaccine responses. Time to prepare.”

SOURCE: Nature, online February 1, 2022.

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