Publications by authors named "Linlin Bao"

88 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

The Ablation of Envelope Protein Glycosylation Enhances the Neurovirulence of ZIKV and Cell Apoptosis in Newborn Mice.

J Immunol Res 2021 16;2021:5317662. Epub 2021 Jul 16.

Comparative Medicine Center, Peking Union Medical College (PUMC) and, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS), Beijing 100021, China.

Zika virus (ZIKV) has attracted the wide global attention due to its causal link to microcephaly. In this study, two amino acid (aa) mutation (E143K and R3394K) were identified at the fourth generation (named ZKC2P4) during the serial passage of ZIKV-Asian lineage ZKC2/2016 strain in the newborn mouse brain, while another seven aa deletions in envelope (E) protein were detected in ZKC2P6. ZKC2P6 is a novel nonglycosylated E protein Asian ZIKV we first identified and provides the first direct supporting evidence that glycosylation motif could be lost during the passage in neonatal mice. To study the impact of E protein glycosylation ablation, we compared the pathogenicity of ZKC2P6 with that of ZKC2P4. The results showed that the loss of E protein glycosylation accelerated the disease progression, as evidenced by an earlier weight loss and death, a thinner cerebral cortex, and more serious tissue lesions and inflammation/necrosis. Furthermore, ZKC2P6 exhibited a greater ability to replicate and caused severer cell apoptosis than that of ZKC2P4. Therefore, the ablation of E glycosylation generally enhances the neurovirulence of ZIKV and cell apoptosis in newborn mice.
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http://dx.doi.org/10.1155/2021/5317662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302398PMC
July 2021

Ficolin A exacerbates severe H1N1 influenza virus infection-induced acute lung immunopathological injury via excessive complement activation.

Cell Mol Immunol 2021 Sep 23;18(9):2278-2280. Epub 2021 Jul 23.

Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.

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http://dx.doi.org/10.1038/s41423-021-00737-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298942PMC
September 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

Repurposing CFDA-approved drug carrimycin as an antiviral agent against human coronaviruses, including the currently pandemic SARS-CoV-2.

Acta Pharm Sin B 2021 Mar 11. Epub 2021 Mar 11.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing 100050, China.

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a CFDA-approved macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.
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http://dx.doi.org/10.1016/j.apsb.2021.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946546PMC
March 2021

Insight into the performance and microbial community profiles of magnetite-amended anaerobic digestion: Varying promotion effects at increased loads.

Bioresour Technol 2021 Jun 4;329:124928. Epub 2021 Mar 4.

Fujian Provincial Research Center of Industrial Wastewater Biochemical Treatment (Huaqiao University), Xiamen 361021, China; Department of Environmental Science and Engineering, Huaqiao University, Xiamen 361021, China.

In current study, the enhancement effect of magnetite on anaerobic digestion was evaluated at increased organic loading rate (OLR) from 1.6 to 25.6 kg COD·m·d. The supplement of magnetite enhanced the methane yield by 7-483% accompanied with faster VFAs conversion. Microbial analysis suggested the varied enhancing effect achieved at different OLRs was attributed to different syntrophic interactions triggered by magnetite. More specially, an electroactive syntropy was established between Trichococcus with Methanobacterium at OLR lower than 6.4 kg COD·m·d, while with the OLR increase, more acid fermentative bacteria (Propionimicrobium, Syner-01) were enriched and further enhanced methanogenesis in a syntrophic way with Methanosaeta. Overall, the incorporation of magnetite was a promising approach to achieve efficient anaerobic digestion, OLR was also critical factor affecting the methanogenesis and should be carefully regulated in future application.
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http://dx.doi.org/10.1016/j.biortech.2021.124928DOI Listing
June 2021

Size-distribution-based assessment of human inhalation and dermal exposure to airborne parent, oxygenated and chlorinated PAHs during a regional heavy haze episode.

Environ Pollut 2020 Aug 24;263(Pt A):114661. Epub 2020 Apr 24.

State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, PR China. Electronic address:

The adverse health effects of haze and particle-bound contaminants in China have recently caused increasing concern, and particle size plays a significant role in affecting human exposure to haze-correlated pollutants. To this background, size-segregated particulate samples (nine size fractions (<0.4, 0.4-0.7, 0.7-1.1, 1.1-2.1, 2.1-3.3, 3.3-4.7, 4.7-5.8, 5.8-9.0 and > 9.0 μm) were collected in three scale-gradient cities in northern China and analysed for a series of parent, oxygenated and chlorinated polycyclic aromatic hydrocarbons (PAHs, O-PAHs and Cl-PAHs). The total geometric mean concentrations of PAHs and O-PAHs for Beijing, Zhengzhou and Xinxiang were 98.1 and 27.2, 77.9 and 77.5, 41.0 and 30.7 ng m, respectively, which were 50-200 times higher than those for Cl-PAHs (0.5, 0.7 and 0.4 ng m). Though unimodal size-distribution patterns were found for all these contaminants for these three cities, PAHs represented distinctly higher concentration levels around the peak fraction (0.7-2.1 μm) than O-PAHs and Cl-PAHs. With 4-6 ring PAHs as dominant components in all samples, the percentage proportion of 2-3 ring PAHs (ranging from 1% to 26%) generally increased with particle size increasing, implying the sources of these compounds varied little among the 9 size fractions in all three cities. The International Commission on Radiological Protection (ICRP) model and permeability coefficient method were synchronously applied to the size-segregated data for inhalation and dermal exposure assessment to intensively estimate the human exposure doses to airborne PAHs. Further, the incremental lifetime cancer risk (ILCR) was calculated and it's found that ILCR from inhalation was higher than that from dermal uptake for children and adults in Beijing and Zhengzhou, while the ILCR for Xinxiang presented a contrary pattern, revealing dermal uptake to be an equally significant exposure pathway to airborne PAHs compared to inhalation.
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http://dx.doi.org/10.1016/j.envpol.2020.114661DOI Listing
August 2020

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

Sensitivity of SARS-CoV-2 to different temperatures.

Animal Model Exp Med 2020 Dec 29;3(4):316-318. Epub 2020 Dec 29.

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.

This study was designed to investigate the sensitivity of SARS-CoV-2 to different temperatures, to provide basic data and a scientific basis for the control of COVID-19 epidemic. The virus was dispersed in 1 mL basal DMEM medium at a final concentration of 10 TCID/mL and then incubated at 4, 22, 30, 35, 37, 38, 39 and 40°C for up to 5 days. The infectivity of residual virus was titrated using the Vero E6 cell line. The results showed that the virus remained viable for 5 days at 4°C, and for 1 day only at 22 and 30°C. We found that the infectivity of the virus was completely lost after less than 12 hours at 37, 38 and 39°C, while at 40°C, the inactivation time of the virus was rapidly reduced to 6 hours. We show that SARS-CoV-2 is sensitive to heat, is more stable at lower temperatures than higher temperature, remains viable for longer at lower temperatures, and loses viability rapidly at higher temperatures.
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http://dx.doi.org/10.1002/ame2.12141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824962PMC
December 2020

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

Publisher Correction: A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2021 Feb;590(7844):E23

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.

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http://dx.doi.org/10.1038/s41586-020-03108-4DOI Listing
February 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

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

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2020 10 29;586(7830):572-577. Epub 2020 Jul 29.

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.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.
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http://dx.doi.org/10.1038/s41586-020-2599-8DOI Listing
October 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

Randomized trial of electrodynamic microneedling combined with 5% minoxidil topical solution for treating androgenetic alopecia in Chinese males and molecular mechanistic study of the involvement of the Wnt/β-catenin signaling pathway.

J Dermatolog Treat 2020 Jun 1:1-11. Epub 2020 Jun 1.

Department of Dermatology, The First Affiliated Hospital of China Medical University, Shenyang, China.

Treatment of androgenetic alopecia (AGA) with concurrent electrodynamic microneedling and 5% minoxidil may further stimulate hair growth. To evaluate the efficacy of microneedling combined with 5% minoxidil in Chinese male AGA patients and to explore the underlying mechanisms. Seventy-one male volunteers with AGA completed the entire trial and follow-up. The first group ( = 23) received only 5% minoxidil twice daily for 24 weeks; the second group ( = 23) received only microneedle therapy every 3 weeks for eight treatments; and the third group ( = 25) received the combination treatment for a total of 24 weeks. Changes in hair density and diameter were evaluated before and after treatment every 3 weeks, and patients were followed up at 6 months after the final treatment. In the combination group, a PCR array was used to detect the expression of molecules in the Wnt/β-catenin pathway within the hair loss sites on top of the head before and after treatment and within the scalp tissues from non-hair loss sites on top of the head. The tissues were obtained by punches in the most severe area of hair loss on top of the head and in the adjacent normal hair area without hair loss. Real-time quantitative PCR and western blotting were used to further examine changes in the differentially expressed molecules identified by PCR array (FZD3) and in molecules in the Wnt/β-catenin signaling pathway closely related to hair growth (β-catenin and LEF-1). Compared to single minoxidil or single microneedle treatment, the combination therapy showed superior therapeutic effects clinically, with further upregulation of FZD3, β-catenin, and LEF-1 expression levels at both mRNA and protein levels in the treated areas. Microneedling combined with 5% minoxidil can improve AGA, and the underlying mechanism may involve activation of the Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1080/09546634.2020.1770162DOI Listing
June 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
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