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 concern1. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)2. 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.
In late December 2019, cases of COVID-19—which is caused by SARS-CoV-2—were identified and reported from Wuhan city (Hubei province, China), where they were linked to a seafood market at which exotic animals were also sold and consumed1,3. The number of confirmed cases has since soared: as of 25 February 2020, almost 78,000 cases and over 2,700 deaths were reported in China4, and imported cases from travellers from mainland China were reported in several other countries. It is critical to establish the pathogenicity and biology of the virus for prevention and treatment of the disease.
Because SARS-CoV-2 is highly homologous with SARS-CoV, human ACE2—which is the entry receptor of SARS-CoV—was also considered to have a high binding ability with the SARS-CoV-2 by molecular biological analysis2,5. We therefore used transgenic hACE2 mice and wild-type mice infected with the HB-01 strain of SARS-CoV-2 to study the pathogenicity of the virus.
Specific-pathogen-free male and female wild-type (n = 15) or hACE2 (n = 19) mice of 6–11 months of age were inoculated intranasally with SARS-CoV-2 strain HB-01 at a dosage of 105 50% tissue culture infectious dose (TCID50) per 50 μl inoculum volume per mouse, after the mice were intraperitoneally anaesthetized using 2.5% avertin; mock-treated hACE2 mice (n = 15) were used as control. Clinical manifestations were recorded from 13 mice (3 HB-01-infected wild-type mice; 3 mock-treated hACE2 mice; and 7 HB-01-infected hACE2 mice). We observed slight bristled fur and weight loss only in the HB-01-infected hACE2 mice—and not the HB-01-infected wild-type mice or mock-treated hACE2 mice—during the 14 days of observation; other clinical symptoms, such as an arched back and decreased response of external stimuli, were not found in any of the mice. Notably, the weight loss of HB-01-infected hACE2 mice was up to 8% at 5 days post-infection (dpi) (Fig. 1a).
Next, we examined viral replication and pathological changes in three mice per group at each time point; the primary organs—including heart, liver, spleen, lung, kidney, brain, intestine and testis—were collected periodically. As shown in Fig. 1b, viral loads were detectable by quantitative PCR with reverse transcription (RT–qPCR) at 1, 3, 5 and 7 dpi in the lungs of HB-01-infected hACE2 mice (but not in those of HB-01-infected wild-type mice; data not shown), and viral RNA copies reached a peak of 106.77 copies per ml at 3 dpi. Viral RNA was also detectable at 1 dpi in the intestine of HB-01-infected hACE2 mice, which was not detected in other tissues along the timeline (Fig. 1b). Although viral loads were detectable in the intestine, no virus in the intestine was isolated at 1 dpi; we therefore speculate that the viral load detected was residual input inoculum from the nasal mucosa transferred to the intestines by swallowing. Consistent with the results showing viral loads in the lung, infectious virus was isolated from the lungs of HB-01-infected hACE2 mice at 1, 3 and 5 dpi; the highest virus titres were detected at 3 dpi (102.44 TCID50 per 100 μl) (Fig. 1c). We isolated infectious virus using Vero E6 cell culture from the lung, and observed SARS-CoV-2 particles using electron microscopy (Fig. 1d). However, the virus was not isolated from the lungs of HB-01-infected wild-type mice or mock-treated hACE2 mice along the detecting timeline (Fig. 1c), which suggests that human ACE2 is essential for SARS-CoV-2 infection and replication in mice. Moreover, we found specific IgG antibodies against the spike (S) protein of SARS-CoV-2 in the sera of HB-01-infected hACE2 mice at 21 dpi (Fig. 1e).
There were no obviously gross pathological or histopathological changes at 1 dpi in any of the mice. Compared with HB-01-infected wild-type mice or mock-treated hACE2 mice (both of which showed homogeneously pink and slightly deflated lung lobes), HB-01-infected hACE2 mice at 3 dpi displayed gross lesions with focal-to-multifocal dark-red discoloration in some of the lung lobes. The lesions progressed into multifocal-to-coalescent scattered dark-reddish-purple areas and focal palpable nodules throughout the lung lobes at 5 dpi (Fig. 2a). The damaged lungs became swollen and enlarged. Microscopically, the lung tissues from HB-01-infected hACE2 mice at 3 dpi displayed moderate interstitial pneumonia, characterized by thickened alveolar septa accompanied by infiltration of inflammatory cells in 70–80% of the lung tissues, and an accumulation of inflammatory cells in partial alveolar cavities (20–30%). Inflammatory cells—including lymphocytes, macrophages and neutrophils—accumulated in the alveolar interstitium and caused thickening of the alveolar walls. At 5 dpi, the lung progressed into coalescing interstitial pneumonia with diffuse lesions, characterized by more-severe thickened alveolar septa accompanied with infiltration of inflammatory cells, and accumulation of inflammatory cells in more alveolar cavities (40–50%). The thickened alveolar septa were filled with macrophages, lymphocytes and neutrophils (Fig. 2a). A small amount of collagen fibre was observed in the thickened alveolar interstitium in the HB-01-infected hACE2 mice by modified Masson’s trichrome stain at 5 dpi (Extended Data Fig. 1a). The bronchiolar epithelial cells showed swelling and degeneration; some of these cells fragmented (Fig. 2a). A few periodic-acid–Schiff-positive-exudation, or denatured and detached, bronchiolar epithelia were occasionally observed in affected bronchioles at 5 dpi (Extended Data Fig. 1b). The alveolar cavities were distended mainly by swollen and degenerative macrophages, lymphocytes and neutrophils (Fig. 2a). To investigate the infiltration of specific inflammatory cells, immunohistochemistry (IHC) was carried out to identify MAC2+ macrophages (Extended Data Fig. 2a), CD3+ T lymphocytes and CD19+ B lymphocytes (Extended Data Fig. 2b). Compared to the lungs of HB-01-infected wild-type mice, more macrophages and T lymphocytes were found in the lungs of HB-01-infected hACE2 mice and their numbers increased along with the prolonged infection time. MAC2+ macrophages were diffusely infiltrated into the alveolar cavities (at 3 dpi) or focally aggregated in the thickened alveolar septa (at 5 dpi) (Extended Data Fig. 2a). CD3+ T lymphocytes were dispersed or (occasionally) aggregated in the alveolar interstitium in HB-01-infected hACE2 mice at 3 and 5 dpi, and some CD19+ B lymphocytes were also observed at 5 dpi (Extended Data Fig. 2b). Perivascular infiltrating inflammatory cells—including lymphocytes, macrophages and neutrophils—were observed multifocally within and adjacent to affected areas of the lungs. In lung lesions, IHC staining of sequential sections revealed that viral antigens were found in macrophages, alveolar epithelia and in bronchial epithelial cells that were degenerative and being desquamated (Fig. 2b). We also observed small amounts of viral antigen in respiratory epithelial cells in areas of the lungs that did not show lesions (data not shown). However, there were no substantial histopathological changes (Extended Data Fig. 3) or viral antigens for SARS-CoV-2 (Extended Data Fig. 4) in the other organs, including myocardium, liver, spleen, kidney, cerebrum, intestine and testis. At 7 dpi, the pneumonia became mild with focal lesion areas (data not shown).
In addition, we demonstrated the colocalization of SARS-CoV-2 S protein (Fig. 3f) and the human ACE2 receptor (Fig. 3g) in alveolar epithelial cells of HB-01-infected hACE2 mice using immunofluorescence, at 3 dpi (Fig. 3h). This phenomenon was not found in mock-treated hACE2 mice (Fig. 3a–d) or HB-01-infected wild-type mice (data not shown), which indicates that SARS-CoV-2—as with SARS-CoV—uses the human ACE2 as a receptor for entry5.
The speed of the geographical spread of COVID-19 has led to the disease being declared a public health emergency of international concern, with cases reported on multiple continents only weeks after the disease was first reported6. Although it has been determined by bioinformatics that the pathogen that causes this epidemic is a novel coronavirus, it is necessary that this is confirmed by animal experiments (following Koch’s postulates)7. Previous clinical studies have confirmed the isolation of the virus from hosts with the disease and cultivation in host cells1. Here we show that, after the experimental infection of hACE2 mice with one of the earliest known isolates of SARS-CoV-2, our mouse model of SARS-CoV-2 infection exhibits viral replication in the lungs characterized by moderate interstitial pneumonia—similar to initial clinical reports of pneumonia caused by SARS-CoV-28. Moreover, we also observed specific antibodies against SARS-CoV-2 and re-isolated the virus from infected mice.
The fatality rate of currently reported cases of COVID-19 is about 2%, which implies that—so far—SARS-CoV-2 does not seem to cause the high fatality rates seen for SARS-CoV (9–11%)9; this suggests that there are differences in pathogenicity between the two viruses. In mice, the pathogenicity of SARS-CoV-2 seems mild compared to SARS-CoV; the latter causes extrapulmonary organ damage (including the brain, kidney, intestine, heart and liver) and, furthermore, neurons are susceptible to infection with SARS-CoV—cerebral vasculitis and haemorrhage were observed in SARS-CoV-infected hACE2 mice10,11. However, only interstitial pneumonia was observed in SARS-CoV-2-infected hACE2 mice, which implies a disparity in pathogenicity between the two coronaviruses.
Our results demonstrate the pathogenicity of SARS-CoV-2 in mice, which—together with previous clinical studies1—completely satisfies Koch’s postulates7 and confirms that SARS-CoV-2 is the pathogen responsible for COVID-19. Our mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of this disease.Note added in proof: In the version of this paper that was originally published online, Fig. 2a contained a duplication. In the version of the figure that was originally published, tissue sections from a WT + HB-01 sample were shown instead of tissue sections from ACE2 + mock. The originally published figure can be found here as Supplementary Fig. 1.
No statistical methods were used to predetermine sample size. The experiments were not randomized and investigators were not blinded to allocation during experiments and outcome assessment.
Mouse studies were performed in an animal biosafety level 3 (ABSL3) facility using HEPA-filtered isolators. All procedures in this study involving mice were reviewed and approved by the Institutional Animal Care and Use Committee of the Institute of Laboratory Animal Science, Peking Union Medical College (BLL20001). All of the experiments complied with all relevant ethical regulations.
Viruses and cells
The SARS-CoV-2 strain HB-01 was provided by W. Tan1. The complete genome for this SARS-CoV-2 has been submitted to GISAID (identifier: BetaCoV/Wuhan/IVDC-HB-01/2020|EPI_ISL_402119), and deposited in the China National Microbiological Data Center (accession number NMDC10013001 and genome accession number MDC60013002-01). Seed SARS-CoV-2 stocks and virus isolation studies were performed in Vero cells, which are maintained in Dulbecco’s modified Eagle’s medium (DMEM) (Invitrogen) supplemented with 10% fetal bovine serum (FBS), 100 IU/ml penicillin, and 100 μg/ml streptomycin, and incubated at 37 °C, 5% CO2. For infected mice, lung homogenates were used for virus titration tests using endpoint titration in Vero E6 cells. Virus titres of the supernatant were determined using a standard TCID50 assay.
For the mouse experiments, specific-pathogen-free, 6–11-month-old male and female hACE2 mice were obtained from the Institute of Laboratory Animal Science, Peking Union Medical College. Transgenic mice were generated by microinjection of the mouse Ace2 promoter driving the human ACE2 coding sequence into the pronuclei of fertilized ova from ICR mice, and then human ACE2 integrated was identified by PCR as previous described10; the human ACE2 mainly expressed in the lungs, heart, kidneys and intestines of transgenic mice. After being intraperitoneally anaesthetized by 2.5% avertin with 0.02 ml/g body weight, the hACE2 or wild-type (ICR) mice were inoculated intranasally with SARS-CoV-2 stock virus at a dosage of 105 TCID50, and hACE2 mice intranasally inoculated with an equal volume of PBS were used as a mock-infection control. The infected mice were continuously observed to record body weight, clinical symptoms, responses to external stimuli and death. Mice were dissected at 1, 3, 5 and 7 dpi to collect different tissues to screen virus replication and histopathological changes.
Preparation of homogenate supernatant
Tissues homogenates (1 g/ml) were prepared by homogenizing perfused tissues using an electric homogenizer for 2 min 30 s in DMEM. The homogenates were centrifuged at 3,000 rpm for 10 min at 4 °C. The supernatant was collected and stored at −80 °C for viral titre and viral load detection.
RNA extraction and RT–qPCR
Total RNA was extracted from tissues homogenates of organs using the RNeasy Mini Kit (Qiagen), and reverse transcription was performed using the PrimerScript RT Reagent Kit (TaKaRa) following the manufacturers’ instructions. RT–qPCR reactions were performed using the PowerUp SYBG Green Master Mix Kit (Applied Biosystems), in which samples were processed in duplicate using the following cycling protocol: 50 °C for 2 min, 95 °C for 2 min, followed by 40 cycles at 95 °C for 15 s and 60 °C for 30 s, and then 95 °C for 15 s, 60 °C for 1 min, 95 °C for 45 s. The primer sequences used for RT–qPCR are targeted against the envelope (E) gene of SARS-CoV-2 and are as follows: forward: 5′-TCGTTTCGGAAGAGACAGGT-3′, reverse: 5′-GCGCAGTAAGGATGGCTAGT-3′. The PCR products were verified by sequencing using the dideoxy method on an ABI 3730 DNA sequencer (Applied Biosystems). During the sequencing process, amplification was performed using specific primers. The sequences for this process are available upon request to the corresponding author. The sequencing reads obtained were linked using DNAMAN, and the results were compared using the Megalign module in the DNAStar software package. The SYBR green real-time PCR standard curve was generated by serial tenfold dilutions of recombinant plasmid with a known copy number (from 1.47 × 109 to 1.47 × 101 copies per μl). These dilutions were tested and used as quantification standards to construct the standard curve by plotting the plasmid copy number against the corresponding threshold cycle values (Ct). Results were expressed as log10-transformed numbers of genome equivalent copies per ml of sample.
The specific IgG against SARS-CoV-2 from HB-01-infected hACE2 and wild-type mice was determined by ELISA. Ninety-six-well plates were coated with the Spike 1 (S1) protein of SARS-CoV-2 (0.1 μg/100 μl, Sino Biological, 40591-V08H), the tested sera were diluted at 1:100 and added to each well, and 3 multiple wells were set for each sample, and then incubated at 37 °C for 30 min, followed by goat anti-mouse secondary antibodies conjugated with HRP (ZB-2305, zhongshan,1:10,000 dilution), and incubated at room temperature for 30 min. The reaction was developed by TMB substrate and the optical densities at 450 nm were determined (Metertech960 enzyme marker with 450 nm wavelength).
Laboratory preparation of the antibody of SARS-CoV-2 S1 protein
Mice were immunized with purified SARS-CoV-2 S1 protein (Sino biological) and splenocytes of hyper-immunized mice were fused with myeloma cells. Positive clones were selected by ELISA using SARS-CoV-2 S1 protein (Extended Data Fig. 5). The cell supernatant of 7D2 clone, which binds to the SARS-CoV-2 S1 protein, was collected for immunofluorescence analysis.
Autopsies were performed in an animal biosafety level 3 (ABSL3) laboratory. Major organs were grossly examined and then fixed in 10% buffered formalin solution, and paraffin sections (3–4 μm in thickness) were prepared routinely. Haematoxylin and eosin, periodic acid–Schiff and modified Masson’s trichrome stains were used to identify histopathological changes in all of the organs. The histopathology of the lung tissue was observed by light microscopy.
The organs were fixed in 10% buffered formalin solution, and paraffin sections (3–4 μm in thickness) were prepared routinely. Sections were treated with an antigen retrieval kit (Boster, AR0022) for 1 min at 37 °C and quenched for endogenous peroxidases in 3% H2O2 in methanol for 10 min. After blocking in 1% normal goat serum, the sections were incubated with 7D2 monoclonal antibody (laboratory preparation) at 4 °C overnight, followed by HRP-labelled goat anti-mouse IgG secondary antibody (Beijing ZSGB Biotechnology, ZDR-5307). Alternatively, the sections were stained with rat IgG2a antibody (Abcam, ab18450, RTK2758), MAC2 antibody (Cedarlane Laboratories, CL8942AP), CD3 antibody (Dako, A0452) or CD19 antibody (Cell Signaling Technology, 3574) at 4 °C overnight. Subsequently, the sections were incubated with goat anti-rat IgG secondary antibody (HRP) (Beijing ZSGB Biotechnology, PV9004) or goat anti-rabbit IgG secondary antibody (HRP) (Beijing ZSGB Biotechnology, PV9001) for 60 min, and visualized by 3,30-diaminobenzidine tetrahydrochloride (DAB). The slices were counterstained with haematoxylin, dehydrated and mounted on a slide and viewed under an Olympus microscope. The sections from HB-01-infected wild-type mice, mock-treated hACE2 mice or HB-01-infected hACE2 mice were directly incubated with HRP-labelled goat anti-rat/mouse/rabbit IgG and used as the negative control for MAC2, CD19, CD3 or viral antigen staining. Rat IgG2a antibody was used as isotype control for MAC2 staining. For the expression of viral antigen, the sections from HB-01-infected wild-type mice or mock-treated hACE2 mice incubated with anti-S protein antibody was also used as a negative control.
For analysis of the colocalization of viruses and the human ACE2 receptor, the lung tissue sections were washed twice with PBS, fixed by Immunol staining fix solution (P0098, Beyotime Biotechnology), blocked for 1 h at room temperature by Immunol staining blocking buffer (P0102, Beyotime Biotechnology) and then incubated overnight at 4 °C with the appropriate primary and secondary antibodies. The nuclei were stained with DAPI. Anti-S protein antibody (mouse monoclonal 7D2, laboratory preparation, 1:200) and anti-hACE2 antibody (rabbit polyclonal, ab15348, Abcam, 1:200) were used as the primary antibodies. The sections were washed with PBS and incubated with secondary antibodies conjugated with FITC (goat anti-mouse, ZF-0312, Beijing ZSGB Biotechnology, 1:200) and TRITC (goat anti rabbit, ZF-0317, Beijing ZSGB Biotechnology, 1:200), dried at room temperature and observed via fluorescence microscopy. The sections from mock-treated or HB-01-infected hACE2 mice were directly incubated with FITC-conjugated goat anti-mouse IgG or TRITC-conjugated goat anti-rabbit IgG and used as the negative control. For the expression of human ACE2, the sections from wild-type mice stained with anti-ACE2 antibody were used as the negative control, and the stable cell line expressing human ACE2 was used as the positive control. For the viral antigen, the sections from mock-treated hACE2 mice incubated with anti-S protein antibody were used as the negative control.
Transmission electron microscopy
Supernatant from Vero E6 cell cultures that showed cytopathic effects was collected, inactivated with 2% paraformaldehyde for at least 2 h, and ultracentrifuged to sediment virus particles. The enriched supernatant was negatively stained on film-coated grids for examination. The negative stained grids were observed under transmission electron microscopy.
All data were analysed with GraphPad Prism 8.0 software. Statistically significant differences were determined using unpaired t-tests, Student’s t-tests, Welch’s t-tests or Mann–Whitney U-tests, as applicable and according to test requirements. A two-sided P value < 0.05 was considered statistically significant. *P < 0.05, **P < 0.01, ***P < 0.001. No statistical methods were used to predetermine sample size. The experiments were not randomized and the investigators were not blinded to allocation during experiments and outcome assessment.
Further information on research design is available in the Nature Research Reporting Summary linked to this paper.
All raw data are available from the corresponding authors on reasonable request. Source data are provided with this paper.
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We thank G. F. Gao for his advice and coordination on this work; H. Deng, X. Yang and L. Zhang for providing the hACE2 mice as a gift; and G. Wong for helping us to proofread the manuscript. This work was supported by National Research and Development Project of China (2020YFC0841100), Fundamental Research Funds for CAMS of China (2020HY320001), National Key Research and Development Project of China (2016YFD0500304), CAMS initiative for Innovative Medicine of China (2016-I2M-2-006) and National Mega projects of China for Major Infectious Diseases (2017ZX10304402, 2018ZX10301403).
The authors declare no competing interests.
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Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
a, Modified Masson’s trichrome stain of the lung. Compared to the HB-01-infected wild-type mice, increased collagen fibres (blue-stained fibres) in the thickened alveolar interstitium were observed in the HB-01-infected hACE2 mice at 3 and 5 dpi. Blue frames in the top-right corners are magnifications of the region in the corresponding blue box. b, Periodic acid–Schiff (PAS) stain of the respiratory epithelium in bronchioles. A small amount of mucus accumulated on the surface of bronchial epithelial cells. Red frames in the top-right corners are magnifications of the region in the corresponding red box. Scale bars, 40 μm. Data in a, b are representative of three independent experiments.
Extended Data Fig. 2 IHC was carried out to identify MAC2+ macrophages, CD3+ T lymphocytes and CD19+ B lymphocytes.
a, Diffuse infiltration of macrophages (red arrow) in the expanded alveolar septa in HB-01-infected hACE2 mice at 3 and 5 dpi. b, Many T lymphocytes (red arrow) infiltrated the thickened alveolar septa in the first row of b at 5 dpi in the HB-01-infected hACE2 mice. A few B lymphocytes (red arrow) were observed in the HB-01-infected hACE2 mice. Scale bars, 40 μm. Data in a, b are representative of three independent experiments.
Extended Data Fig. 3 Histopathological observations of the organs in HB-01-infected wild-type and hACE2 mice.
There were no substantial histopathological changes in the organs (including myocardium, liver, spleen, kidney, cerebrum, intestine and testis) in HB-01-infected hACE2 mice compared with HB-01-infected wild-type mice. Scale bars, 100 μm. Data are representative of three independent experiments.
There were no SARS-CoV-2 antigens in the organs (including myocardium, liver, spleen, kidney, cerebrum, intestine and testis). Scale bars, 50 μm. Data are representative of three independent experiments.
The plate coated with 0.2 μg SARS-CoV-2 S1 protein was incubated with 7D2 antibody as primary antibody (1:200), and detected using HRP-conjugated goat anti-mouse secondary antibody. The titre of antibody was determined using ELISA. Data are mean ± s.d. Significant differences are indicated with asterisks (n = 3, two-tailed unpaired Student’s t-test, **P = 0.0011).
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Bao, L., Deng, W., Huang, B. et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature 583, 830–833 (2020). https://doi.org/10.1038/s41586-020-2312-y
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