Publications by authors named "Jiangning Liu"

48 Publications

SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration.

Signal Transduct Target Ther 2021 09 6;6(1):337. Epub 2021 Sep 6.

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood-brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.
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http://dx.doi.org/10.1038/s41392-021-00719-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419672PMC
September 2021

SARS-CoV-2 leads to myocardial injury in rhesus macaque.

Signal Transduct Target Ther 2021 09 6;6(1):338. Epub 2021 Sep 6.

Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41392-021-00747-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419658PMC
September 2021

Correction: Yang et al. Chebulagic Acid, a Hydrolyzable Tannin, Exhibited Antiviral Activity and against Human Enterovirus 71. 2013, , 9618.

Int J Mol Sci 2021 Aug 6;22(16). Epub 2021 Aug 6.

Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, CAMS & Comparative Medicine Centre, PUMC, Beijing 100021, China.

The authors wish to make the following corrections to this paper [...].
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http://dx.doi.org/10.3390/ijms22168443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395136PMC
August 2021

Correction to: Transmission of H7N9 influenza virus in mice by different infective routes.

Virol J 2021 Jul 6;18(1):140. Epub 2021 Jul 6.

Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical Collage (PUMC); Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, No. 5 Pan Jia Yuan Nan Li, Chaoyang District, Beijing, 100021, China.

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http://dx.doi.org/10.1186/s12985-021-01603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261966PMC
July 2021

Sequential infection with H1N1 and SARS-CoV-2 aggravated COVID-19 pathogenesis in a mammalian model, and co-vaccination as an effective method of prevention of COVID-19 and influenza.

Signal Transduct Target Ther 2021 05 20;6(1):200. Epub 2021 May 20.

Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus, leading to more serious respiratory diseases during this winter. However, the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear. Using a mammalian model, sequential infection was performed in ferrets and in K18-hACE2 mice, with SARS-CoV-2 infection following H1N1. We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19, and enhanced pulmonary damage, but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets. Moreover, mortality was increased in sequentially infected mice compared with single-infection mice. Compared with single-vaccine inoculation, co-inoculation of PiCoVacc (a SARS-CoV-2 vaccine) and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses. Combined immunization effectively protected K18-hACE2 mice against both H1N1 and SARS-CoV-2 infection. Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2, which together notably enhanced pneumonia in ferrets and mice, as well as demonstrated that simultaneous vaccination against H1N1 and SARS-CoV-2 may be an effective prevention strategy for the coming winter.
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http://dx.doi.org/10.1038/s41392-021-00618-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134832PMC
May 2021

Distinct uptake, amplification, and release of SARS-CoV-2 by M1 and M2 alveolar macrophages.

Cell Discov 2021 Apr 13;7(1):24. Epub 2021 Apr 13.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades the alveoli, where abundant alveolar macrophages (AMs) reside. How AMs respond to SARS-CoV-2 invasion remains elusive. Here, we show that classically activated M1 AMs facilitate viral spread; however, alternatively activated M2 AMs limit the spread. M1 AMs utilize cellular softness to efficiently take up SARS-CoV-2. Subsequently, the invaded viruses take over the endo-lysosomal system to escape. M1 AMs have a lower endosomal pH, favoring membrane fusion and allowing the entry of viral RNA from the endosomes into the cytoplasm, where the virus achieves replication and is packaged to be released. In contrast, M2 AMs have a higher endosomal pH but a lower lysosomal pH, thus delivering the virus to lysosomes for degradation. In hACE2 transgenic mouse model, M1 AMs are found to facilitate SARS-CoV-2 infection of the lungs. These findings provide insights into the complex roles of AMs during SARS-CoV-2 infection, along with potential therapeutic targets.
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http://dx.doi.org/10.1038/s41421-021-00258-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043100PMC
April 2021

ACE2 expression is regulated by AhR in SARS-CoV-2-infected macaques.

Cell Mol Immunol 2021 05 1;18(5):1308-1310. Epub 2021 Apr 1.

Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41423-021-00672-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015744PMC
May 2021

SARS-CoV-2 infection aggravates chronic comorbidities of cardiovascular diseases and diabetes in mice.

Animal Model Exp Med 2021 03 6;4(1):2-15. Epub 2021 Mar 6.

Key Laboratory of Human Disease Comparative Medicine National Health Commission of China (NHC) Institute of Laboratory Animal Science Peking Union Medicine College Chinese Academy of Medical Sciences Beijing China.

Background: Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID-19. However, how SARS-CoV-2 alters the progression of chronic diseases remain unclear.

Methods: We used adenovirus to deliver h-ACE2 to lung to enable SARS-CoV-2 infection in mice. SARS-CoV-2's impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis.

Results: Pre-existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS-CoV-2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with impaired PI3K/AKT/mTOR signaling.

Conclusion: We established mouse models mimicked the complex pathological symptoms of COVID-19 patients with chronic diseases. Pre-existing diseases could impair the inflammatory responses to SARS-CoV-2 infection, which further aggravated the pre-existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/ame2.12155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954823PMC
March 2021

Susceptibility and Attenuated Transmissibility of SARS-CoV-2 in Domestic Cats.

J Infect Dis 2021 04;223(8):1313-1321

Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Domestic cats, an important companion animal, can be infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This has aroused concern regarding the ability of domestic cats to spread the virus that causes coronavirus disease 2019. We systematically demonstrated the pathogenesis and transmissibility of SARS-CoV-2 in cats. Serial passaging of the virus between cats dramatically attenuated the viral transmissibility, likely owing to variations of the amino acids in the receptor-binding domain sites of angiotensin-converting enzyme 2 between humans and cats. These findings provide insight into the transmissibility of SARS-CoV-2 in cats and information for protecting the health of humans and cats.
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http://dx.doi.org/10.1093/infdis/jiab104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928776PMC
April 2021

SARS-CoV-2 Causes a Systemically Multiple Organs Damages and Dissemination in Hamsters.

Front Microbiol 2020 12;11:618891. Epub 2021 Jan 12.

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread across the world and impacted global healthcare systems. For clinical patients, COVID-19 not only induces pulmonary lesions but also affects extrapulmonary organs. An ideal animal model that mimics COVID-19 in humans in terms of the induced systematic lesions is urgently needed. Here, we report that Syrian hamster is highly permissive to SARS-CoV-2 and exhibit diffuse alveolar damage and induced extrapulmonary multi-organs damage, including spleen, lymph nodes, different segments of alimentary tract, kidney, adrenal gland, ovary, vesicular gland and prostate damage, at 3-7 days post inoculation (dpi), based on qRT-PCR, hybridization and immunohistochemistry detection. Notably, the adrenal gland is a novel target organ, with abundant viral RNA and antigen expression detected, accompanied by focal to diffuse inflammation. Additionally, viral RNA was also detected in the corpus luteum of the ovary, vesicular gland and prostate. Focal lesions in liver, gallbladder, myocardium, and lymph nodes were still present at 18 dpi, suggesting potential damage after disease. Our findings illustrate systemic histological observations and the viral RNA and antigen distribution in infected hamsters during disease and convalescence to recapitulate those observed in humans with COVID-19, providing helpful data to the pathophysiologic characterization of SARS-CoV-2-induced systemic disease and the development of effective treatment strategies.
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http://dx.doi.org/10.3389/fmicb.2020.618891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835519PMC
January 2021

Induction of alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19.

Cell Host Microbe 2021 02 26;29(2):222-235.e4. Epub 2020 Dec 26.

Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China. Electronic address:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2-infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2-infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 was dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain anti-viral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.
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http://dx.doi.org/10.1016/j.chom.2020.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762710PMC
February 2021

Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19.

Cell Res 2020 12 6;30(12):1078-1087. Epub 2020 Nov 6.

Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, 100005, China.

Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-β or IFN-γ upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.
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http://dx.doi.org/10.1038/s41422-020-00435-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646495PMC
December 2020

A glance at the gut microbiota of five experimental animal species through fecal samples.

Sci Rep 2020 10 6;10(1):16628. Epub 2020 Oct 6.

Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing, China.

Experimental animals including the ferret, marmoset, woodchuck, mini pig, and tree shrew have been used in biomedical research. However, their gut microbiota have not been fully investigated. In this study, the gut microbiota of these five experimental animals were analyzed with 16S rRNA sequencing. The phyla Firmicutes, Bacteroidetes, and Fusobacteria were present in the gut microbiota of all the species. Specific phyla were present in different animals: Proteobacteria in the ferret, Tenericutes in the marmoset, and Spirochaetes in the mini pig. Fusobacterium and unidentified Clostridiales were the dominant genera in the ferret, whereas Libanicoccus, Lactobacillus, Porphyromonas, and Peptoclostridium were specific to marmoset, mini pig, woodchuck, and tree shrew, respectively. A clustering analysis showed that the overall distribution of microbial species in the guts of these species mirrored their mammalian phylogeny, and the microbiota of the marmoset and tree shrew showed the closest bray_curtis distances to that of humans. PICRUSt functional prediction separated the woodchuck from the other species, which may reflect its herbivorous diet. In conclusion, both the evolutionary phylogeny and daily diet affect the gut microbiota of these experimental animals, which should not be neglected for their usage in biomedical research.
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http://dx.doi.org/10.1038/s41598-020-73985-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538948PMC
October 2020

Structurally Resolved SARS-CoV-2 Antibody Shows High Efficacy in Severely Infected Hamsters and Provides a Potent Cocktail Pairing Strategy.

Cell 2020 11 14;183(4):1013-1023.e13. Epub 2020 Sep 14.

Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China.

Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" or "down" conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2's epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2's therapeutic potential in treating COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489885PMC
November 2020

Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in rhesus macaques.

Nat Commun 2020 09 2;11(1):4400. Epub 2020 Sep 2.

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmitted through the respiratory route, but potential extra-respiratory routes of SARS-CoV-2 transmission remain uncertain. Here we inoculated five rhesus macaques with 1 × 10 TCID of SARS-CoV-2 conjunctivally (CJ), intratracheally (IT), and intragastrically (IG). Nasal and throat swabs collected from CJ and IT had detectable viral RNA at 1-7 days post-inoculation (dpi). Viral RNA was detected in anal swabs from only the IT group at 1-7 dpi. Viral RNA was undetectable in tested swabs and tissues after intragastric inoculation. The CJ infected animal had a higher viral load in the nasolacrimal system than the IT infected animal but also showed mild interstitial pneumonia, suggesting distinct virus distributions. This study shows that infection via the conjunctival route is possible in non-human primates; further studies are necessary to compare the relative risk and pathogenesis of infection through these different routes in more detail.
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http://dx.doi.org/10.1038/s41467-020-18149-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467924PMC
September 2020

Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2.

Cell 2020 08 6;182(3):713-721.e9. Epub 2020 Jun 6.

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health. The development of a vaccine is urgently needed for the prevention and control of COVID-19. Here, we report the pilot-scale production of an inactivated SARS-CoV-2 vaccine candidate (BBIBP-CorV) that induces high levels of neutralizing antibodies titers in mice, rats, guinea pigs, rabbits, and nonhuman primates (cynomolgus monkeys and rhesus macaques) to provide protection against SARS-CoV-2. Two-dose immunizations using 2 μg/dose of BBIBP-CorV provided highly efficient protection against SARS-CoV-2 intratracheal challenge in rhesus macaques, without detectable antibody-dependent enhancement of infection. In addition, BBIBP-CorV exhibits efficient productivity and good genetic stability for vaccine manufacture. These results support the further evaluation of BBIBP-CorV in a clinical trial.
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http://dx.doi.org/10.1016/j.cell.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275151PMC
August 2020

Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques.

Science 2020 08 2;369(6505):818-823. Epub 2020 Jul 2.

Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. It is unclear whether convalescing patients have a risk of reinfection. We generated a rhesus macaque model of SARS-CoV-2 infection that was characterized by interstitial pneumonia and systemic viral dissemination mainly in the respiratory and gastrointestinal tracts. Rhesus macaques reinfected with the identical SARS-CoV-2 strain during the early recovery phase of the initial SARS-CoV-2 infection did not show detectable viral dissemination, clinical manifestations of viral disease, or histopathological changes. Comparing the humoral and cellular immunity between primary infection and rechallenge revealed notably enhanced neutralizing antibody and immune responses. Our results suggest that primary SARS-CoV-2 exposure protects against subsequent reinfection in rhesus macaques.
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http://dx.doi.org/10.1126/science.abc5343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402625PMC
August 2020

Correction to: The mouse and ferret models for studying the novel avian-origin human influenza A (H7N9) virus.

Virol J 2020 06 24;17(1):83. Epub 2020 Jun 24.

Institute of Laboratory Animal Sciences, Chinese Academy of Medical, Sciences (CAMS) & Comparative Medicine Center, Peking Union Medical, Collage (PUMC), Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Beijing, China.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12985-020-01356-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315497PMC
June 2020

Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 via Close Contact and Respiratory Droplets Among Human Angiotensin-Converting Enzyme 2 Mice.

J Infect Dis 2020 07;222(4):551-555

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

We simulated 3 transmission modes, including close-contact, respiratory droplets and aerosol routes, in the laboratory. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be highly transmitted among naive human angiotensin-converting enzyme 2 (hACE2) mice via close contact because 7 of 13 naive hACE2 mice were SARS-CoV-2 antibody seropositive 14 days after being introduced into the same cage with 3 infected-hACE2 mice. For respiratory droplets, SARS-CoV-2 antibodies from 3 of 10 naive hACE2 mice showed seropositivity 14 days after introduction into the same cage with 3 infected-hACE2 mice, separated by grids. In addition, hACE2 mice cannot be experimentally infected via aerosol inoculation until continued up to 25 minutes with high viral concentrations.
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http://dx.doi.org/10.1093/infdis/jiaa281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313959PMC
July 2020

Immunogenicity of a DNA vaccine candidate for COVID-19.

Nat Commun 2020 05 20;11(1):2601. Epub 2020 May 20.

Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA, 19104, USA.

The coronavirus family member, SARS-CoV-2 has been identified as the causal agent for the pandemic viral pneumonia disease, COVID-19. At this time, no vaccine is available to control further dissemination of the disease. We have previously engineered a synthetic DNA vaccine targeting the MERS coronavirus Spike (S) protein, the major surface antigen of coronaviruses, which is currently in clinical study. Here we build on this prior experience to generate a synthetic DNA-based vaccine candidate targeting SARS-CoV-2 S protein. The engineered construct, INO-4800, results in robust expression of the S protein in vitro. Following immunization of mice and guinea pigs with INO-4800 we measure antigen-specific T cell responses, functional antibodies which neutralize the SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and biodistribution of SARS-CoV-2 targeting antibodies to the lungs. This preliminary dataset identifies INO-4800 as a potential COVID-19 vaccine candidate, supporting further translational study.
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http://dx.doi.org/10.1038/s41467-020-16505-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239918PMC
May 2020

Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients' B Cells.

Cell 2020 07 18;182(1):73-84.e16. Epub 2020 May 18.

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China. Electronic address:

The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here, we report the rapid identification of SARS-CoV-2-neutralizing antibodies by high-throughput single-cell RNA and VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1 clonotypes, 14 potent neutralizing antibodies were identified, with the most potent one, BD-368-2, exhibiting an IC of 1.2 and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, respectively. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Additionally, the 3.8 Å cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody's epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2-neutralizing antibodies could be directly selected based on similarities of their predicted CDR3 structures to those of SARS-CoV-neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B cell sequencing in response to pandemic infectious diseases.
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http://dx.doi.org/10.1016/j.cell.2020.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231725PMC
July 2020

Therapeutic efficacy of Pudilan Xiaoyan Oral Liquid (PDL) for COVID-19 in vitro and in vivo.

Signal Transduct Target Ther 2020 05 8;5(1):66. Epub 2020 May 8.

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41392-020-0176-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205908PMC
May 2020

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.

Nature 2020 07 7;583(7818):830-833. Epub 2020 May 7.

Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has become a public health emergency of international concern. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV). Here we infected transgenic mice that express human ACE2 (hereafter, hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss as well as virus replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of considerable numbers of macrophages and lymphocytes into the alveolar interstitium, and the accumulation of macrophages in alveolar cavities. We observed viral antigens in bronchial epithelial cells, macrophages and alveolar epithelia. These phenomena were not found in wild-type mice infected with SARS-CoV-2. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of COVID-19.
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http://dx.doi.org/10.1038/s41586-020-2312-yDOI Listing
July 2020

Development of an inactivated vaccine candidate for SARS-CoV-2.

Science 2020 07 6;369(6499):77-81. Epub 2020 May 6.

Division of Respiratory Virus Vaccines, National Institute for Food and Drug Control, Beijing, China.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. Because of the novelty of the virus, there are currently no SARS-CoV-2-specific treatments or vaccines available. Therefore, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here, we developed a pilot-scale production of PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats, and nonhuman primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains. Three immunizations using two different doses, 3 or 6 micrograms per dose, provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support the clinical development and testing of PiCoVacc for use in humans.
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http://dx.doi.org/10.1126/science.abc1932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202686PMC
July 2020

Immunization with a fusion protein vaccine candidate generated from truncated peptides of human enterovirus 71 protects mice from lethal enterovirus 71 infections.

Virol J 2020 04 22;17(1):58. Epub 2020 Apr 22.

NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, CAMS&PUMC, Beijing, 100021, People's Republic of China.

Background: Prophylactic vaccines are critical in preventing hand, foot, and mouth disease (HFMD) primarily caused by human enterovirus 71 (EV71) infection. Children aged less than 5 years are especially susceptible to EV71 infections. In addition to the development of vaccines containing the inactivated virus, those containing virus-like particles (VLPs) with repeated antigens also constitute an effective preventive strategy for EV71 infections, with safety and productivity advantages. We previously developed a fusion protein composed with truncated peptides of the EV71 capsid protein, which assembled into spherical particles. This study aimed to assess the immunoprotective effects of this fusion protein as a vaccine candidate in a mouse model of EV71 infection.

Methods: To evaluate the protective effect of fusion protein vaccine candidate, neonatal mice born by immunized female mice, as well as normal neonatal mice immunized twice were infected with EV71 virus. Whereafter, the survival rates, clinical scores and viral loads were measured.

Results: The high dosage and booster immunization helped induce specific serum antibodies with high neutralization titers, which were transferred to neonatal mice, thereby facilitating effective resistance towards EV71 infection. An active immune response was also observed in neonatal mice which generated following immunization.

Conclusions: The present results suggest that this fusion protein is a suitable vaccine candidate in treating EV71 infections.
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http://dx.doi.org/10.1186/s12985-020-01328-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178760PMC
April 2020

Age-related rhesus macaque models of COVID-19.

Animal Model Exp Med 2020 Mar 30;3(1):93-97. Epub 2020 Mar 30.

MHC Key Laboratory of Biosafety National Institute for Viral Disease Control and Prevention China CDC Beijing China.

Background: Since December 2019, an outbreak of the Corona Virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) in Wuhan, China, has become a public health emergency of international concern. The high fatality of aged cases caused by SARS-CoV-2 was a need to explore the possible age-related phenomena with non-human primate models.

Methods: Three 3-5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS-CoV-2, and then analyzed by clinical signs, viral replication, chest X-ray, histopathological changes and immune response.

Results: Viral replication of nasopharyngeal swabs, anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS-CoV-2 challenge. Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema, notably, old monkeys exhibited diffuse severe interstitial pneumonia. Viral antigens were detected mainly in alveolar epithelial cells and macrophages.

Conclusion: SARS-CoV-2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys. Rhesus macaque models infected with SARS-CoV-2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/ame2.12108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167234PMC
March 2020

Fabrication of Highly Dispersed Cu-Based Oxides as Desirable NH-SCR Catalysts via Employing CNTs To Decorate the CuAl-Layered Double Hydroxides.

ACS Appl Mater Interfaces 2019 Sep 27;11(36):32917-32927. Epub 2019 Aug 27.

College of Chemistry and Chemical Engineering , Taiyuan University of Technology , Taiyuan 030024 , PR China.

In this study, three kinds of CuAl-LDO/CNT (LDO, layered double oxide) catalysts were prepared by the assembly of CNTs and CuAl-LDH (LDH, layered double hydroxides) as well as subsequently structural topological transformation. The effects of the assembly method on the surface structure property and the DeNO performance of the prepared samples were systematically investigated. It was found that three CuAl-LDO/CNT catalysts showed preferable NH-SCR catalytic performance compared with CuAl-LDO where the catalyst CuAl-LDO/CNTs(I) exhibited optimum NO conversion (>80%) and N selectivity (>90%) within 180-300 °C. Such fine catalytic performance can be attributed to the proper surface acidity and redox ability of the catalyst, which might be correlated with the high dispersion of Cu-based active centers caused by the induced nucleation and effective separation action of LDH by carbon nanotubes. In addition, the outstanding HO and SO resistance of the CuAl-LDO/CNTs(I) catalyst was also obtained because of the synergistic effect between CuAl-LDO and CNTs, which could greatly promote the activation and decomposition of ammonium sulfate at lower temperatures.
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http://dx.doi.org/10.1021/acsami.9b08699DOI Listing
September 2019

GS-9620 inhibits enterovirus 71 replication mainly through the NF-κB and PI3K-AKT signaling pathways.

Antiviral Res 2018 05 6;153:39-48. Epub 2018 Feb 6.

Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC) & Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Key Laboratory of Human Disease Comparative Medicine Ministry of Health, Beijing, PR China. Electronic address:

Human enterovirus 71 (EV71) is the second most common cause of hand, foot, and mouth disease (HFMD), which can occur as a severe epidemic especially among children under 5-years old. New and improved treatment strategies to control EV71 infection are therefore urgently required. The heterocyclic compound GS-9620, a potent and selective agonist of Toll-like receptor 7 (TLR7), has been reported to activate plasmacytoid dendritic cells (pDCs), and suppress HBV as well as HIV replication. In this study, we indicated that GS-9620 also could inhibit EV71 replication in the mouse model of EV71 infection. With three-days treatment after EV71 infection, the levels of proinflammatory cytokines/chemokines, like IFN-α, IFN-γ and MCP-1, were sharply reduced in serum compared to those without treatment. Furthermore, GS-9620 activated TLR7 in the limb muscle cells, which stimulated the NF-κB and PI3K/AKT signaling pathways. When NF-κB or PI3K/AKT inhibitors were used, the antiviral effect of the GS-9620 was impacted. Overall, our data implied GS-9620 probably activates NF-κB and PI3K/AKT signaling pathways to clear the virus.
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http://dx.doi.org/10.1016/j.antiviral.2018.02.002DOI Listing
May 2018

Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates.

ACS Infect Dis 2016 05 11;2(5):361-76. Epub 2016 Apr 11.

Tsinghua-Peking Center for Life Sciences & School of Pharmaceutical Sciences, Tsinghua University , Haidian District, Beijing 100084, People's Republic of China.

Severe acute respiratory syndrome (SARS) is caused by a coronavirus (SARS-CoV) and has the potential to threaten global public health and socioeconomic stability. Evidence of antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro and in non-human primates clouds the prospects for a safe vaccine. Using antibodies from SARS patients, we identified and characterized SARS-CoV B-cell peptide epitopes with disparate functions. In rhesus macaques, the spike glycoprotein peptides S471-503, S604-625, and S1164-1191 elicited antibodies that efficiently prevented infection in non-human primates. In contrast, peptide S597-603 induced antibodies that enhanced infection both in vitro and in non-human primates by using an epitope sequence-dependent (ESD) mechanism. This peptide exhibited a high level of serological reactivity (64%), which resulted from the additive responses of two tandem epitopes (S597-603 and S604-625) and a long-term human B-cell memory response with antisera from convalescent SARS patients. Thus, peptide-based vaccines against SARS-CoV could be engineered to avoid ADE via elimination of the S597-603 epitope. We provide herein an alternative strategy to prepare a safe and effective vaccine for ADE of viral infection by identifying and eliminating epitope sequence-dependent enhancement of viral infection.
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http://dx.doi.org/10.1021/acsinfecdis.6b00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075522PMC
May 2016
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