The new Netflix doc on the Pangolin wildlife recovery program that saves Pangolins from the illegal trade to China for "traditional" Chinese medicine - it does not mention Covid!!
For example, in Huizhou's Wuqinzhang mountains, the pangolin population has increased from 62 individuals in 2020 to over 100 today China Daily
https://sph.unc.edu/sph-news/continuing-to-learn-about-coronaviruses/
the pangolin virus was found to efficiently use the same receptor [Ace-2 on the Spike] protein from more than 20 species of mammals, including pangolins, humans, mice and hamsters. They also found that the virus grew at similar numbers as SARS-CoV-2, it could naturally be transmitted between hamsters, and it was killed by the existing monoclonal antibodies, antiviral drugs and vaccines that target the original SARS-CoV-2 strain.
As the virus could transmit between non-reservoir hosts, the data argues that a reservoir species is unnecessary and that some SARS-like animal viruses have the intrinsic capabilities to infect and transmit naturally across multiple species without setting up a large reservoir. SARS-CoV-2 also readily transmitted between deer, mink and humans. This intrinsic capability to transmit across species potentially explains how SARS-CoV-2 emerged to cause the COVID-19 pandemic and why researchers have yet to identify this hypothetical reservoir host.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9408936/
We also analyze the host ACE2-interacting residues of the receptor-binding domain of spike glycoprotein in SARS-CoV-2 isolates from bats, and compare it to pangolin SARS-CoV-2 isolates collected from Guangdong province (GD Pangolin-CoV) and Guangxi autonomous regions (GX Pangolin-CoV) of South China. Based on our comparative analysis, we support the view that the Guangdong Pangolins are the intermediate hosts that adapted the SARS-CoV-2 and represented a significant evolutionary link in the path of transmission of SARS-CoV-2 virus. We also discuss the role of intermediate hosts in the origin of Omicron.
https://www.acquaintpublications.com/get/1-5-JCMPHR2024010104%20Galley_Proof-1706172585.pdf
Gupta et al.
[8] conducted a sequence comparative analysis of the host ACE2-
interacting residues of the RBD of spike glycoprotein in SARS-CoV-
2 isolates from bats, which were compared to the respective residues
from pangolin isolated CoVs. These were collected from Guangdong
province and Guangxi autonomous regions of South China. It was
suggested that the Guangdong pangolins might be the intermediate
hosts that adapted to SARS-CoV-2. They would represent a
significant evolutionary link in the path of transmission of SARS-
nterestingly, SARS-CoV-2 neutralizing antibodies were detected in
Thai cave bats and a pangolin at a wildlife checkpoint in Southern
Thailand. Regarding the epicenter of COVID-19 and the origin of the
pandemic strain, Ruan et al. [14] suggested that a more accurate
phrase/definition to establish the origin of COVID-19 would be
‘somewhere, but probably not China.’ It would be based on the
evolutionary genetics of SARS-CoV-2 in the early phase of COVID-
19 and the extensive attempts to find the ‘smoking gun’ in China's
wildlife or the neighboring regions of SE Asia.
https://www.nature.com/articles/s41598-024-51261-x
pangolin's vulnerability to coronavirus infection might be due to their innate gene pseudogenization.
For example, the pseudogenised interferon epsilon (IFNE) is known to be particularly important in epithelial immunity, and we show that interferon-related responses were not upregulated in the infected pangolin skin. We suggest that the pangolin’s innate gene pseudogenisation is indeed likely to be responsible for the animal’s vulnerability to infection.
The pseudogenization of immune system genes in the pangolin genome is believed to be the main contributing factor to high infection susceptibility. These pseudogenes are interferon Epsilon (IFNE), interferon-induced with helicase C domain 1, cyclic GMP-AMP synthase, stimulator of interferon genes, Toll-like receptor 5, and Toll-like receptor 11.
The scientists of the current study have previously analyzed brain and lung samples from a Malayan pangolin and detected a coronavirus infection that was closely related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the most recent coronavirus disease 2019 (COVID-19) pandemic.
In the current study, scientists conducted RNA-Seq analysis of the pangolin skin tissue to understand the transcriptional antiviral response in pangolin skin, particularly in the context of interferon Epsilon (IFNE)-deficiency, which is a unique immune feature of pangolin.
The scientists identified pangolin coronavirus RNA in the skin of Malayan pangolin. This virus is closely related to another pangolin coronavirus MP789, isolated from the Guangdong pangolin. Since both pangolins were kept at the Guangdong Wildlife Rescue Center, the scientists believe both coronaviruses originated from the same source.https://www.news-medical.net/news/20240110/Pangolins-genetic-makeup-linked-to-increased-coronavirus-susceptibility.aspx
This suggests that pangolin coronavirus may suppress endogenous retrovirus gene expression to support viral replication.
Study significance
The study detects replicating coronavirus in the skin of Malayan pangolin and provides transcriptomic landscapes of the host immune response to coronavirus infection. The study also finds that the pathways downstream of the lost immune system genes are not upregulated in response to the infection. This highlights that the pseudogenization of key immune system-related genes can significantly modulate pangolin's antiviral responses and make them susceptible to coronavirus infection.
So they studied a Pangolin seized by Chinese customs - from Malaysia....
Overall, China is a significant consumer market for pangolins, with an estimated demand of up to 200,000 individuals per year. Between 2007 and 2016, 209 pangolin seizures were recorded in China, including 2405 live pangolins, 11,419 dead pangolins, and 34,946 kg of scales. Malaysia, Indonesia, and Viet Nam were identified as major source countries for whole pangolins in those seizures.
Despite the trade restrictions, more than a million pangolins (including Asian and African species) have been poached and illegally traded ...
https://www.nature.com/articles/s41421-023-00557-9
d the global illicit trade of pangolins increases the risks of spillover of pangolin viruses to humans. During the search for the natural host of SARS-CoV-2, we and another group independently identified SARS-CoV-2-related pangolin coronaviruses (pCoVs) in trafficked Malayan pangolins12,13. Compared with bCoVs, some pCoVs showed high binding affinity to ACE2, the receptor of SARS-CoV-214, and functional assays with pseudovirus confirmed that pCoVs are capable of entering a panel of human cells2,15. Importantly, bioinformatic analysis suggested that the entire receptor binding domain (RBD) of SARS-CoV-2 was introduced through recombination with pCoVs, representing a critical step in the evolution of SARS-CoV-2 to acquire the capability to infect humans16,17. However, human infections with pCoVs have not yet been documented, and the potential risk of spillover of pCoVs to humans remains incompletely investigated.
Pangolin - the Missing Link between Bats and Humans for Covid
All Eight Species of Pangolins are threatened or endangered....
though animals may be the original natural host for these viruses, the drivers of a spillover are all too human.
Domesticated species, primates and bats were identified as having more zoonotic viruses than other species. Among threatened wildlife species, those with population reductions owing to exploitation and loss of habitat shared more viruses with humans. Exploitation of wildlife through hunting and trade facilitates close contact between wildlife and humans, and our findings provide further evidence that exploitation, as well as anthropogenic activities that have caused losses in wildlife habitat quality, have increased opportunities for animal–human interactions and facilitated zoonotic disease transmission.
https://royalsocietypublishing.org/doi/10.1098/rspb.2019.2736
Pangolins belong to the order Pholidota, also known as scaly anteaters, while the order Pilosa includes sloths and anteaters.
Pangolin as intermediate host... via bats to humans
• Pangolin-CoV is the second closest relative of SARS-CoV-2 behind RaTG13• Five key amino acids in the RBD are consistent between Pangolin-CoV and SARS-CoV-2• Only SARS-CoV-2 contains a potential cleavage site for furin proteases
https://www.sciencedirect.com/science/article/pii/S0960982220303602
Five key amino acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and SARS-CoV-2, but four amino acid mutations are present in RaTG13. Both Pangolin-CoV and RaTG13 lost the putative furin recognition sequence motif at S1/S2 cleavage site that can be observed in the SARS-CoV-2. Conclusively, this study suggests that pangolin species are a natural reservoir of SARS-CoV-2-like CoVs.
SARS-CoV, which is the coronavirus that caused the severe acute respiratory syndrome (SARS) pandemic in 2003, is a close relative of SARS-CoV-2. It was also found to have been transmitted from bats to an intermediate host – the masked palm civet – which subsequently infected humans. Similarly, MERS-CoV, the coronavirus that caused Middle East respiratory syndrome (MERS) in 2012, jumped from bats to another intermediate host, the dromedary camel, before infecting humans.
The Malayan or Javan pangolin (Manis javanica) was suspected of being this intermediate host based on, 1) its ACE2 receptor sequence, 2) the presence of Sarbecoviruses related to SARS-CoV-2 (Liu et al., 2019; Liu et al., 2020a; Andersen et al., 2020; Han, 2020) in animals smuggled from the Indomalayian region, and 3) the presence of pangolins in wet markets in China where they are considered a delicacy and a component of traditional pharmacopeia. Several studies, based on metagenomics, have concluded on a diversity of the pangolin's virome, the close relationship of the ACE2-binding region of the viral spike named “Receptor Binding Domain” (RBD) to that of SARS-CoV-2 and the in silico model prediction of recombinants between pangolins and R. affinis bats Sarbecoviruses (Liu et al., 2019; Lam et al., 2020; Zhang et al., 2020; Lau et al., 2020; Wahba et al., 2020; Wong et al., 2020).. However, this is purely an in silico modeling and bats and pangolins from which Sarbecoviruses have been described are found in very distant regions and display very different biology and ecology, making such a recombination event very questionable. Furthermore, a recent in depth genomic analysis demonstrated that there was no recombination in SARS-CoV-2 and that it has circulating at least in bats for several decades (Boni et al., 2020). Furthermore, the drawback with metagenomic analyses is that there is no evidence that the different parts come from the same virus and the observed recombinants might result from artifactual assembly mosaics. The SARS-CoV-2 S1 spike protein binds the human ACE2 cell surface molecules (Yan et al., 2020; Zhao et al., 2020a, Zhao et al., 2020b; Wang and Cheng, 2020).
https://www.sciencedirect.com/science/article/pii/S1567134820303245
urthermore, the COVID-19 epidemic did not start in December 2019 in the Huanan Seafood Wholesale Market (HSWM) where pangolins were supposed to be sold but earlier and outside HSWM (Frutos et al., 2020). Another conclusion is that very closely related Sarbecoviruses circulate in different hosts worldwide raising the question of the dynamic of zoonotic emergence and the role played by wildlife. Two hypothetic models of zoonotic emergence can be envisioned, the well-known spillover model and an alternative model we propose to name the circulation model. The spillover model theorizes that zoonotic emergence starts as a consequence of a zoonotic pressure (Plowright et al., 2017). In this model, the virus is developing into an epizootic stage in an animal population, reaching the threshold needed for interspecies transmission and following contact with humans, develop within the human populations. Socio-economic factors and demographic dynamic trigger the epidemic or pandemic expansion of the disease (Plowright et al., 2017; Frutos et al., 2020). According to the spillover model, the disease already exists as an epizootic and, thus, identifying the animal reservoir is essential to stop viral spread. However, when considering the last three main coronavirus epidemics, i.e. SARS, MERS and COVID-19, several requirements for the spillover model are not fulfilled. First of all, no epizootic necessary to reach the level of zoonotic pressure required for the spillover was ever recorded for either SARS, MERS or COVID-19. Palm civets and dromedaries were identified as intermediate hosts carrying viruses similar to SARS and MERS, respectively (Song et al., 2005; Azhar et al., 2014; Briese et al., 2014). However, they were identified by sampling in the absence of epizootics. Infected masked palm civets were found in markets in Guangdong and Hong Kong (Song et al., 2005). Infected dromedaries were found in the Arabian Peninsula and in Africa (Briese et al., 2014: Müller et al., 2014). Noteworthy, camels used in the Arabian Peninsula are imported from Africa (Younan et al., 2016) and no MERS outbreak or related epizootic were ever reported in Africa. Until now, no animal intermediate was formally identified in the COVID-19 pandemic. Currently, only hypotheses exclusively based on in silico models and predictions have been put forward. Two closely related bat CoVs were identified but both from samples collected before the outbreak and outside Hubei, i.e. Yunnan (Zhou et al., 2020a; Zhou et al., 2o20b). The proposed circulation model for zoonotic emergence complies with the observations done until now. In this model there is no requirement for zoonotic pressure or epizootic episode prior to the emergence of a human disease. No epizootics were reported in civets or camels for SARS or MERS, respectively. Furthermore, there is no animal reservoirs displaying a disproportionate risk of triggering a zoonosis and potentially zoonotic viruses are evenly spread in all animal taxa (Mollentze and Streicker, 2020). Searching for a culprit in the wild is not realistic (Mollentze and Streicker, 2020). According to the circulation model there is a broad circulation of viruses in different species, including humans, upon contact but with no epidemic to follow. This fits with the observation that humans have been a lot more exposed to various viruses than expected and without any related epidemic (Pike et al., 2010). Out of 60 viruses involved in zoonoses, 59 are RNA viruses (Brook and Dobson, 2015). Several RNA viruses, among which the Coronaviruses, including SARS-CoV and SARS-CoV-2, were shown to undergo a quasispecies evolutionary process (Zhang et al., 2007; Tang et al., 2009; Plowright et al., 2017; Song et al., 2005). This process postulates that there is no specific preadaptation of the virus to the host but instead a post-exposure, host-driven selection of viruses displaying the best propensity to evade immune surveillance and replicate. Contact, low affinity receptor interaction and lack of molecular interference during replication are enough to establish productive infection after what the virus will follow in-host selection. This is compatible with the high diversity observed in the spike proteins of Coronaviruses (Andersen et al., 2020) which is under positive selection, i.e. host driven (Zhang e al, 2007; Tang et al., 2009; Briese et al., 2014; Tang et al., 2006; Xu et al., 2004). In line with this model, the RBD from SARS-CoV-2 is not fully optimized for human ACE2 (Andersen et al., 2020). According to the circulation model, what really prepares the ground for the epidemic is simply an accidental event, i.e. a mutation, recombination or reassortment in the virus genome. The virus is already present in an animal population close to humans or even in humans, and this mutation makes it more invasive and/or pathogenic. This was very recently reported in SARS-CoV-2 (Korber et al., 2020) and beyond coronaviruses has been observed in influenza, chikungunya or Zika viruses (Webster et al., 1982: Tsetsarkin and Weaver, 2011; Yuan et al., 2017).
A major positive effect of the circulation model is that the focus is put on these human activities and not on wildlife. We must reconsider the way we interact with Nature. Pangolins, bats and other animals are not responsible for the epidemics or pandemics affecting humans. Blaming wildlife for zoonotic emergence may result in useless and highly damaging culling, mass slaughter and loss of biodiversity.
For both viruses and animal cells to function, genetic sequences (RNA or DNA) must be translated into proteins, which then carry out many tasks of the virus and the cell. These proteins exist as linked chains of single amino acids; each amino acid in a protein is encoded by a group of three nucleotides, also known as a codon, in the genetic sequence.
Since there are 64 possible different codons but only 20 amino acids, several codons can correspond to the same amino acid; different organisms will have different preference for which codon is used for a given amino acid. The early study hypothesized that for the coronavirus to effectively grow inside an animal cell, the codon usage preferences of the coronavirus should match that of the host cell.
The researchers compared the codon usage in the SARS-CoV-2 virus against that of the cells in eight animals at the Wuhan Huanan Seafood Wholesale Market. That study found that the snakes share the most similar codon usage pattern to SARS-CoV-2, thereby declaring that snakes were the most likely intermediate hosts.
However, their central hypothesis that coronaviruses and their animal hosts share similar codon usage was never verified. Our team at the University of Michigan scrutinized this hypothesis, and performed a more systematic analysis that we published in a recent follow-up study. We compared the codon usages of three coronaviruses (SARS-CoV-2, SARS-CoV and MERS-CoV) to those of more than 10,000 different kinds of animals.
To our surprise, we found that the codon usage of a coronavirus is not determined by its hosts. For example, the codon usage of SARS-CoV and MERS-CoV is much closer to frogs and snakes than to their real animal hosts (civets and camels, respectively). This shows that it is not possible to use only codon usage in animals’ cells to infer the hosts of coronaviruses, suggesting that the early claim of snake-borne transmission of SARS-CoV-2 is likely to be incorrect.
Importantly, MERS-422 and the pangolin SARS-like coronavirus are being used to demonstrate the performance and breadth of broadly protective vaccines that protect against zoonotic, epidemic and pandemic SARS and MERS-related viruses that threaten human populations.
A coronavirus can use more than one kind of animal to infect humans: For example, while civets are best known for transmitting SARS, other animals such as raccoon dogs and ferret badgers are also able to carry SARS. Similarly, cats and ferrets can also be infected by SARS-CoV-2; it is still unknown whether humans can get infected by the coronavirus residing within these animals.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7106181/
SARS originated from southern China and rapidly transmitted to more than 30 countries in early 2003. In just 6 months, there were more than 8000 infected individuals, with over 700 deaths worldwide.1 The other infection resulting in equally deadly consequences was caused by a highly pathogenic avian influenza A (H5N1) virus. It was first described in a mini-outbreak in Hong Kong in late 1997.
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SARS-CoV may behave like H5N1 influenza virus and act as a potent inducer of proinflammatory cytokines. There is evidence to show that H5N1 influenza may upregulate the production of various cytokines such as tumour necrosis factor-α.16 Such a cytokine storm may be partly responsible for such severe multiorgan involvement in adult patients. Longitudinal studies in children infected with SARS-CoV, however, have not revealed any significant elevation of proinflammatory cytokines such as interleukin-6 and tumour necrosis factor-α.
A larger longitudinal study has also been performed in adult patients, the results showing a significant elevation of the neutrophil chemokines interleukin-8, monocyte chemoattractant protein-1 and T-helper cell chemokine interferon-γ-inducible protein-10.17 This process may lead to a recruitment and accumulation of macrophages and neutrophils, causing inflammatory damage to the lung parenchyma and other tissues or organs.
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