Lethal Infection of Human ACE2-Transgenic Mice Caused by SARS-CoV-2-related Pangolin Coronavirus GX_P2V(short_3UTR)
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Lethal Infection of Human ACE2-Transgenic Mice Caused by SARS-CoV-2-related Pangolin Coronavirus GX_P2V(short_3UTR)
Wei, L.; Liu, S.; Lu, S.; Luo, S.; An, X.; Fan, H.; Chen, W.; Li, E.; Tong, Y.; Song, L.
AbstractSARS-CoV-2-related pangolin coronavirus GX_P2V(short_3UTR) can cause 100% mortality in human ACE2-transgenic mice, potentially attributable to late-stage brain infection. This underscores a spillover risk of GX_P2V into humans and provides a unique model for understanding the pathogenic mechanisms of SARS-CoV-2-related viruses.
5 comments
scicastboard
Dr. Song and co-authors. There appears to be a lot of misinformation in the popular media about this work. Would you please clarify if this virus occurs naturally or was engineered in your lab(s)? Is it circulating in the animal population and whether there is any immediate risk of spillover into the human population in your opinion? Professional comments directly from authors carry more weight than many baseless speculations in popular media and misinfomation in social media. Thank you,
ScienceCast Board
ScienceCast Board
songlihua
Thank ScienceCast Board for this opportunity! I appreciate it. This preprint paper is being misinterpreted on social media. I would like to state several facts:
1. The GX_P2V virus has been published in Nature in 2020 (doi: 10.1038/s41586-020-2169-0). It is not a brand-new virus.
2. The GX_P2V(short_3UTR) mutant was published in Emerging Microbes & Infections in 2022 (doi: 10.1080/22221751.2022.2151383). This cell-adapted mutant is the actual isolate published in the Nature paper. So, the original GX_P2V virus was not isolated. Clearly the original GX_P2V virus in the pangolin sample has severe growth deficiency in Vero cells.
3. The GX_P2V virus is not a human pathogen, although, based on molecular and animal infection experiments, it can infect a broad spectrum of host species, like human, cat, pig, golden hamster, mouse, rat et al. There is no evidence of the original GX_P2V virus circulating in these animals, not even consider this GX_P2V(short-3UTR) mutant. Please refer to publications: EMBO J, doi: 10.15252/embj.2021109962 and J Virol, doi: 10.1128/jvi.01719-22.
4. The GX_P2V(short_3UTR) isolate is highly attenuated in in vitro and in vivo models. In Vero, BGM, and Calu-3 cell lines, the virus induced only mild cytopathic effects, notably failing to produce viral plaques even on the human lung cell line Calu-3. In golden hamster and BALB/c mouse models, the virus can infect the animals' respiratory tracts but did not result in any observable disease symptoms. The attenuated nature of GX_P2V(short_3UTR) was also validated in two distinct human ACE2-transgenic mouse models. Please refer to publications: Emerging Microbes & Infections, doi: 10.1080/22221751.2022.2151383 and J Virol, doi: 10.1128/jvi.01719-22.
The attenuation of GX_P2V(short_3UTR) was also hinted in the Nature paper on the GX_P2V(short_3UTR) isolate (doi: 10.1038/s41586-020-2169-0). In Extended Data Figure 1, after infecting Vero cells for five days, GX_P2V caused noticeable cytopathic effects, but which were limited to cell rounding and mild cytolysis, which starkly contrasted with the severe cytopathic effects reported in SARS-CoV-2.
5. The public has developed a high level of population immunity against GX_P2V due to SARS-CoV-2 immunizations and infections. Collectively, the biological safety risk posed by GX_P2V(short_3UTR) is extremely low. I don’t think there is any immediate risk of spillover into the human population. Please refer to publication: J Med Virol, doi: 10.1002/jmv.29031.
6. Based on previous reports on ACE2 humanized mouse models with SARS-CoV-1 and SARS-CoV-2, there is significant variability in the outcomes of infection in these models, a topic extensively documented in the literature. A single ACE2 humanized mouse model does not constitute a reliable paradigm for evaluating viral pathogenicity. While GX_P2V(short_3UTR) proved lethal in our mouse model, it's important to consider that it did not cause disease upon infecting two other distinct ACE2 humanized mouse strains. The findings reported in this paper do not alter the fundamental nature of GX_P2V(short_3UTR) as being highly attenuated.
7. Several other research groups have repeatedly reported the spillover risk of this virus based on its spike protein binding to human ACE2. Those reports have not caught much attention. In our study, using a unique lethal model, we inadvertently reinforced the perception that this virus has a strong tropism for human brains and causes 100% mortality. We need to revise this in the subsequent revision of the paper and provide additional clarification on the intrinsic attenuated nature of the virus.
8. The GX_P2V(short_3UTR) mutant is a promising live attenuated vaccine against pan-SARS-CoV-2. Partial results can be found in this preprint paper: https://www.researchsquare.com/article/rs-3371123/v1.
songlihua
There have been unfriendly folks trying to misinterpret our work as gain-of-function research. Let me be clear – that is not the case. What we've done is simply tested a passaged virus mutant, nothing more. The ACE2 humanized mice used in our experiments are unique and do not exist in nature. The outcomes from these tests cannot be applicable to humans.
scicastboard
Dr. Song, thank you for this clarification. It's extremely helpful in correcting misinformation.
We have communicated it to reporters and hopefully your points will be correctly communicated to the general public. Regards,
ScienceCast Board
We have communicated it to reporters and hopefully your points will be correctly communicated to the general public. Regards,
ScienceCast Board
songlihua
Thank you for providing this good platform.