on the DoE report re. COVID origins: “The scientific literature contains essentially nothing but original research articles that support a natural origin of this virus pandemic” . Our comparative genomic analysis suggests that SARS-CoV-2 may have originated in the recombination of a virus similar to pangolin-CoV with one similar to RaTG13. Pangolin-CoV was detected in 17 out of the 25 Malayan pangolins that we analysed. Malayan pangolin (Manis javanica) captured by the Guangxi customs agency, termed MpCoV-GX, in terms of receptor usage, cell tropism, and pathogenicity in wild-type BALB/c mice, human angiotensin-converting enzyme 2 (ACE2)-transgenic mice, and human ACE2 knock-in mice. We found that MpCoV-GX can utilize ACE2 from humans ...Our results indicate that the higher levels of expression of ACE2 observed in the lungs of mice relative to humans may reflect the fact that the mouse promoter drives expression of ACE2 in populous airway club cells while the human promoter drives expression in alveolar type 2 (AT2) cells. It's from the Pangolin!
on the DoE report re. COVID origins: “The scientific literature contains essentially nothing but original research articles that support a natural origin of this virus pandemic”
Here we show that a coronavirus, which we name pangolin-CoV, isolated from a Malayan pangolin has 100%, 98.6%, 97.8% and 90.7% amino acid identity with SARS-CoV-2 in the E, M, N and S proteins, respectively. In particular, the receptor-binding domain of the S protein of pangolin-CoV is almost identical to that of SARS-CoV-2, with one difference in a noncritical amino acid. Our comparative genomic analysis suggests that SARS-CoV-2 may have originated in the recombination of a virus similar to pangolin-CoV with one similar to RaTG13. Pangolin-CoV was detected in 17 out of the 25 Malayan pangolins that we analysed.
https://www.nature.com/articles/s41586-020-2313-x
NEW YORK – Scientists in China have discovered a new MERS-like bat coronavirus (CoV) in illegally smuggled Malayan pangolins that can infect and replicate in human cells, suggesting it may jump to humans someday and cause disease
We sequenced the viromes of 161 pangolins that were smuggled into China and assembled 28 vertebrate-associated viruses, 21 of which have not been previously reported in vertebrates....Notably, a coronavirus related to HKU4-CoV, which was originally found in bats, was identified.
Pangolin-CoV-HKU4-P251T was located at the root of bat HKU4 coronavirus clade (Fig. 4a and Extended Data Fig. 3g). Considering that Tylonycteris-bat-CoV-HKU4 possesses a spike (S) protein capable of utilizing the MERS-CoV receptor human dipeptidyl-peptidase-4 (hDPP4)37, we assessed the receptor binding domain (RBD) similarity of MERS-CoV-related coronaviruses. Both pangolin-CoV-HKU4-P251T and Tylonycteris-bat-CoV-HKU4 shared 4 of 10 key residues in the RBD of MERS-CoV38 (Extended Data Fig. 6a). Although pangolin-CoV-HKU4-P251T was distantly related to MERS-CoV for most of the genome, their relationship was much closer in the RBD region (Extended Data Fig. 6b). In terms of hosts, pangolin DPP4 showed higher aa similarity with human DPP4 (89.0%–89.3%) than bat DPP4 (82.4%–83.2%), suggesting a risk for a more probable spillover event of pangolin-CoV-HKU4-P251T through the utilization of human DPP4. Another bat-associated virus, a novel species of the genus Shanbavirus of family Piconaviridae, was first recognized in pangolins.
https://www.nature.com/articles/s41564-022-01181-1
To date, intermediate hosts of SARS-CoV-2 remain obscure and controversial. Several studies have shown that SARS-CoV-2-related pangolin coronavirus (Pangolin-CoV) has a high sequence similarity to SARS-CoV-2 and might be the initial source of SARS-CoV-2; however, the biological characteristics of Pangolin-CoV are still largely unknown. In this study, we evaluated the pathogenicity and transmissibility of Pangolin-CoV in Syrian golden hamsters Mesocricetus auratus (Linnaeus, 1758) and compared it with SARS-CoV-2. Pangolin-CoV could effectively infect hamsters, showed similar tissue tropism to SARS-CoV-2 and replicated efficiently in the respiratory system and brain. The infected hamsters had no weight loss but had obvious viral shedding and lung pathological injury.
https://www.sciencedirect.com/science/article/pii/S2589004222006216
Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity
for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.
https://www.cell.com/cell/pdf/S0092-8674(23)00049-1.pdf
As the most trafficked game mammals, pangolins may play an important role
in the ecology of CoVs as suggested by the identification of
two CoV lineages phylogenetically related to SARS-CoV-2
from smuggled Malayan pangolins (Manis javanica) in Guang-
dong and Guangxi, China. 11,12 Importantly, these two viruses,
termed Pangolin-CoV-GD and -GX, were isolated and demon-
strated to efficiently use human ACE2 as a receptor and replicate
in human cells, suggesting a high risk of zoonotic transmission
to humans.12...
This study showed that pangolins carry pre-emergent MERS-like CoVs that are related to bats but are capable of direct infection and show enhanced infectivity to humans compared with the bat viruses, indicating the important role of pangolins in CoV emergence in humans.
https://www.cell.com/cell/pdf/S0092-8674(23)00009-0.pdf
The acquisition of an FCS at the S1/S2
junction of SARS-CoV-2 (so far unique in
the sarbecovirus family) was a key deter-
minant of its pandemic emergence, and
its deletion impairs respiratory transmis-
sion in animal models. 9 FCS are more
common in the merbecovirus family
including in MERS-CoV itself, 10 but in
the HKU4 group thus far sequenced, no
such FCS exists. However, the substitu-
tion of a KQQR motif at the S1/S2 junction
in the bat HKU4 to the RQQR found in
MjHKU4r-CoV-1 results in the generation
of a minimal consensus FCS (RXXR)
(Figure 1A). The authors show that
although weak in comparison to MERS-
CoV, MjHKU4r-CoV-1 Spike is processed
by furin. The FCS enhances viral pseudo-
type entry into human cells by 2–3 orders
of magnitude compared to bat HKU4.
This study raises several important questions (Figure 1B). First, how commonly are
pangolins exposed to bat coronaviruses? Four seized animals were positive for viral RNA, but a further seven had antibody responses consistent with infection. Second, as mainly solitary animals, where were the pangolins infected—in the wild or after their capture, and did MjHKU4r-CoV-1 come directly from bats or via another species?
And last, have human handlers been exposed, and if so, is there any evidence
of infection or illness?
Recent studies of live game sales in China have revealed evidence of extensive
cross-species transmission of mammalian viruses, including bat coronaviruses, to
animals on sale in markets.11 Bat merbecoviruses and sarbecoviruses have wide
species tropism defined by receptor usage, raising the question of whether acquisition of expanded protease activation tips the balance between a low risk of infection and the potential for respiratory transmission in humans or other species, which would require further in vivo transmission studies in model animals using MjHKU4r-CoV-1 with the FCS reverted to KQQR.
Recent demonstration of bat merbecoviruses with the ability to use the sarbecovi-
rus mammalian entry receptor, ACE2, further expands the potential of these vi-
ruses to emerge in humans.12 With smuggled pangolins now shown to harbor two
groups of pandemic-potential coronaviruses, this study highlights how the illegal
wildlife trade is a key risk area for emerging viruses that requires improved international surveillance and regulation as a priority.
https://journals.asm.org/doi/full/10.1128/jvi.01719-22
To date, two SARSr-CoV-2 strains have been isolated from pangolins seized in Guangxi and Guangdong by the customs agency of China, respectively. However, it remains unclear whether these viruses cause disease in animal models and whether they pose a transmission risk to humans. In this study, we investigated the biological features of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin (Manis javanica) captured by the Guangxi customs agency, termed MpCoV-GX, in terms of receptor usage, cell tropism, and pathogenicity in wild-type BALB/c mice, human angiotensin-converting enzyme 2 (ACE2)-transgenic mice, and human ACE2 knock-in mice. We found that MpCoV-GX can utilize ACE2 from humans, pangolins, civets, bats, pigs, and mice for cell entry and infect cell lines derived from humans, monkeys, bats, minks, and pigs.
IMPORTANCE:
In this work, we investigated the biological features and pathogenicity of a SARSr-CoV-2 strain isolated from a smuggled Malayan pangolin, named MpCoV-GX. We found that MpCoV-GX can utilize ACE2 from 7 species for cell entry and infect cell lines derived from a variety of mammalian species. MpCoV-GX can infect mice expressing human ACE2 without causing severe disease. These findings suggest the potential of cross-species transmission of MpCoV-GX, and highlight the need of further surveillance of SARSr-CoV-2 in pangolins and other potential animal hosts.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011168
Our results indicate that the higher levels of expression of ACE2 observed in the lungs of mice relative to humans may reflect the fact that the mouse promoter drives expression of ACE2 in populous airway club cells while the human promoter drives expression in alveolar type 2 (AT2) cells.... Differences in the structure of ACE2 between mouse and man prevent the virus from infecting cells lining the airways of the mouse, limiting the usefulness of wildtype mice as a model system for studying COVID-19.
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