There do seem to be some alternative views on the role of this protein, LRRC15, in the lungs with respect to Sars-CoV-2. See this other paper (Feb 3 2023):
Just to cover the basics, the virus normally accesses cells by binding to ACE2.
> "The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor."
There is a key role played in viral production by furin in ACE2-receptor-binding, which is an 'ubiquitous serine protease' in mammalian cells which plays key roles in processing hormones, growth factors, etc. and which is also exploited by many infectious diseases. This feature of Sars-CoV-2 is of course directly related to the notion that the virus was engineered, because:
> "The presence of a multibasic site (Arg-Arg-Ala-Arg) located at the S1–S2 junction, which is cleaved by furin (Fig. 1), distinguishes SARS-CoV-2 from SARS-CoV and all other known sarbecoviruses whose S protein is not cleaved by furin-like proteases during virus maturation in the infected cell. Cleavage of the S1–S2 boundary is a prerequisite for the cleavage of the S2′ site126, and both cleavage events are essential to initiate the membrane-fusion process."
Accounting for the appearance of this furin cleavage site is a problem for anyone promoting a 'natural origin theory'.
Getting back to this new protein and its potential role, the other paper (first source above) seems to have a different conclusion:
> "Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19."
Their work seems to imply it might not block infection of cells, but instead enhance infection:
> "In order to examine whether LRRC15 might modulate the efficiency of viral entry into ACE2-expressing cells, we employed the naturally susceptible human lung cell line (CaLu-3) that is commonly used as a model for coronavirus infection [47]. We introduced LRRC15 ectopically to these cells to emulate the expression seen in other human lung cell populations we identified in our expression analysis. Compared to unmodified CaLu-3 cells that lack any detectable LRRC15, the expression of LRRC15 modestly enhanced viral infection"
Science is complicated, and popular media reports on recent science are often of very poor quality.
Those are interesting earlier results about LRRC15. The effect of its expression may be dose dependent, with lower levels of LRRC15 promoting infection (or the negative effects of fibrosis) and higher levels inhibiting infection.
It also shows that what happens in cell culture doesn't necessarily translate to in vivo.
> Accounting for the appearance of this furin cleavage site is a problem for anyone promoting a 'natural origin theory'.
I very much think the lab leak origin is quite possible. Whether an engineered virus, or a natural chimeric virus due to bad lab practices (the Wuhan lab collected a large amount of viruses). That said it's not as if other betacoronaviruses don't have furin cleavage sites: https://www.news-medical.net/news/20230209/Assessing-the-zoo...
"The team analyzed 201 Alpha and Beta CoV strains for furin cleavage sites in their spikes. Cleavage sites in spikes were identified from 44 strains, 17 of which have bats as hosts, while 27 have other mammalian hosts. Domestic animals, including dogs, cats, cattle, horses, and rabbits, were also identified as hosts for potentially transmissible CoVs."
> Science is complicated, and popular media reports on recent science are often of very poor quality.
"The University study is one of three independent papers that reveal this specific protein’s interaction with COVID-19."
As I understand it, that lineage of coronaviruses is quite distinct from the sarbecoronavirus lineage and they don't generally infect the same host species in the same geographical regions:
> "For coronaviruses, furin cleavage sites at the interface of the S1 and S2 domain are not unusual, being found widely in betacoronaviruses in the embeco lineage (which are considered to be of rodent origin) as well as in avian-origin gammacoronaviruses and certain feline and canine alphacoronaviruses (with an unknown origin). Furin cleavage sites are also found in certain bat-origin MERS-like merbecovirises, but not—with the exception of SARS-CoV-2—in the sarbecovirus lineage."
For such a specific motif to arise naturally seems to require a scenario like multiple infection of a host species by several different wild-type coronaviruses.
Then there's this feature:
> "So far, a viable natural origin for the SARS-CoV-2 S1–S2 site through recombination or mutation of a bat-origin virus has proved to be elusive. Of note, the S1–S2 cleavage site of SARS-CoV-2 S does not comprise the pattern found in prototypical furin cleavage sites (it is RRxR and not RxK/RR),8
making its origin enigmatic. One feature of the S1–S2 junction for the SARS-CoV-2 spike from the original outbreak is the presence of a leading proline residue, which might have promoted furin cleavage."
Sarbecoronaviruses are a subset of betacoronaviruses. And I seriously doubt we have a comprehensive sequence database of all sarbecoronaviruses. If furin cleavage sites are present in about 21% of alpha- and betacoronaviruses I would expect they would also be present in a minority of most lineages within these clades. "Furin cleavage sites are also found in certain bat-origin MERS-like merbecovirises"
> For such a specific motif to arise naturally seems to require a scenario like multiple infection of a host species by several different wild-type coronaviruses.
Two would be enough. And we know that happens already (ala XBB, deltacron, etcetera).
> > "So far, a viable natural origin for the SARS-CoV-2 S1–S2 site through recombination or mutation of a bat-origin virus has proved to be elusive. Of note, the S1–S2 cleavage site of SARS-CoV-2 S does not comprise the pattern found in prototypical furin cleavage sites (it is RRxR and not RxK/RR),8 making its origin enigmatic. One feature of the S1–S2 junction for the SARS-CoV-2 spike from the original outbreak is the presence of a leading proline residue, which might have promoted furin cleavage."
This is interesting, indeed. I wonder why an engineered site wouldn't use the prototypical cleavage motif, instead using one that might need (if I'm reading the quote correctly) a leading proline residue in order to promote cleavage?
I suppose if people were inserting furin cleavage sites specifically into the Sars-CoV-2 precursor sequence, then they might generate a series of variants to see which one worked best when it came to results of infectivity tests in human cell lines?
Regarding bat lineages and host viruses, this 2019 paper seems to indicate that the other betacoronavirus lineage with the furin site, the Merbecovirus, has a different bat host range from the Sarbecovirus lineage that gave rise to Sars-CoV-2:
"Compared to Sarbecovirus and Nobecovirus, the bat hosts that harbor viruses from the Merbecovirus sub-genus are more diverse. This is in line with the presence of more CoV species belonging to Merbecovirus."
(I generally trust papers on this evolutionary origin stuff published before the pandemic a bit more than those published after, as there might be less conflicts-of-interest issues).
> I suppose if people were inserting furin cleavage sites specifically into the Sars-CoV-2 precursor sequence, then they might generate a series of variants to see which one worked best when it came to results of infectivity tests in human cell lines?
This makes sense.
I think here's the most relevant quote from that article: "So far, no betaCoVs from the sub-genus Merbecovirus have been detected in bats of suborder Yinpterochiroptera."
While the paper does mention one member of Yangochiroptera (Chaerephon plicatus) that has been discovered infected with sarbecoviruses, it looks like there's little room for infectious overlap of merbecoviruses and sarbecoviruses (which predominantly infect Yinpterochiropterans, at least as detected as of the paper publication).
So if the SARS-CoV-2 progenitor did get its furin cleavage site from a co-infection with a merbecovirus, this would have been a really rare event indeed. At least if the co-infection happened in a bat species, and not in another animal or a human who deals with bats.
https://journals.plos.org/plosbiology/article?id=10.1371/jou...
Just to cover the basics, the virus normally accesses cells by binding to ACE2.
> "The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor."
There is a key role played in viral production by furin in ACE2-receptor-binding, which is an 'ubiquitous serine protease' in mammalian cells which plays key roles in processing hormones, growth factors, etc. and which is also exploited by many infectious diseases. This feature of Sars-CoV-2 is of course directly related to the notion that the virus was engineered, because:
> "The presence of a multibasic site (Arg-Arg-Ala-Arg) located at the S1–S2 junction, which is cleaved by furin (Fig. 1), distinguishes SARS-CoV-2 from SARS-CoV and all other known sarbecoviruses whose S protein is not cleaved by furin-like proteases during virus maturation in the infected cell. Cleavage of the S1–S2 boundary is a prerequisite for the cleavage of the S2′ site126, and both cleavage events are essential to initiate the membrane-fusion process."
https://www.nature.com/articles/s41580-021-00418-x
Accounting for the appearance of this furin cleavage site is a problem for anyone promoting a 'natural origin theory'.
Getting back to this new protein and its potential role, the other paper (first source above) seems to have a different conclusion:
> "Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19."
Their work seems to imply it might not block infection of cells, but instead enhance infection:
> "In order to examine whether LRRC15 might modulate the efficiency of viral entry into ACE2-expressing cells, we employed the naturally susceptible human lung cell line (CaLu-3) that is commonly used as a model for coronavirus infection [47]. We introduced LRRC15 ectopically to these cells to emulate the expression seen in other human lung cell populations we identified in our expression analysis. Compared to unmodified CaLu-3 cells that lack any detectable LRRC15, the expression of LRRC15 modestly enhanced viral infection"
Science is complicated, and popular media reports on recent science are often of very poor quality.