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. 2020 Jul;583(7818):834-838.
doi: 10.1038/s41586-020-2342-5. Epub 2020 May 14.

Pathogenesis and transmission of SARS-CoV-2 in golden hamsters

Sin Fun Sia #  1 , Li-Meng Yan #  1 , Alex W H Chin #  1 , Kevin Fung  2 , Ka-Tim Choy  1 , Alvina Y L Wong  1 , Prathanporn Kaewpreedee  1 , Ranawaka A P M Perera  1 , Leo L M Poon  1 , John M Nicholls  2 , Malik Peiris  1 , Hui-Ling Yen  3
Affiliations

Pathogenesis and transmission of SARS-CoV-2 in golden hamsters

Sin Fun Sia et al. Nature. 2020 Jul.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus with high nucleotide identity to SARS-CoV and to SARS-related coronaviruses that have been detected in horseshoe bats, has spread across the world and had a global effect on healthcare systems and economies1,2. A suitable small animal model is needed to support the development of vaccines and therapies. Here we report the pathogenesis and transmissibility of SARS-CoV-2 in golden (Syrian) hamsters (Mesocricetus auratus). Immunohistochemistry assay demonstrated the presence of viral antigens in nasal mucosa, bronchial epithelial cells and areas of lung consolidation on days 2 and 5 after inoculation with SARS-CoV-2, followed by rapid viral clearance and pneumocyte hyperplasia at 7 days after inoculation. We also found viral antigens in epithelial cells of the duodenum, and detected viral RNA in faeces. Notably, SARS-CoV-2 was transmitted efficiently from inoculated hamsters to naive hamsters by direct contact and via aerosols. Transmission via fomites in soiled cages was not as efficient. Although viral RNA was continuously detected in the nasal washes of inoculated hamsters for 14 days, the communicable period was short and correlated with the detection of infectious virus but not viral RNA. Inoculated and naturally infected hamsters showed apparent weight loss on days 6-7 post-inoculation or post-contact; all hamsters returned to their original weight within 14 days and developed neutralizing antibodies. Our results suggest that features associated with SARS-CoV-2 infection in golden hamsters resemble those found in humans with mild SARS-CoV-2 infections.

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Conflict of interest statement

COMPETING INTERESTS

The authors declare no competing interest.

Figures

Extended Data Figure 1.
Extended Data Figure 1.. Sequence alignment of ACE2 proteins (1–420) from human, macaca, hamster, and mouse.
Amino acid residues of human ACE2 that are experientially shown to interact with the receptor binding domain (RBD) of SARS-CoV-2 are denoted by *. Amino acid residues that are important for the interaction between human ACE2 and RBD of SARS-CoV are highlighted in red boxes.
Extended Data Figure 2.
Extended Data Figure 2.. Haemotoxylin and eosin (H&E) staining and immunohistochemistry on SARS-CoV-2 challenged hamster tissues.
a, Hyperplasia of the pneumocytes detected on 7 dpi. b, Detection of CD3 positive cells (using rabbit anti-human CD3 polyclonal antibody) in the lungs on 5 dpi. c, Detection of SARS-CoV-2 N protein (red staining, using monoclonal antibody 4D11) and olfactory neurons (brown staining, using monoclonal antibody TuJ1) from the nasal turbinate on 5 dpi. d, Detection of olfactory neurons (using monoclonal antibody TuJ1) from the nasal turbinate of a mock infected hamster (N=1). e, Nasal epithelial cells from the nasal turbinate of a mock infected hamster (N=1) showed negative staining for TuJ1. f, Detection of olfactory neurons from nasal turbinate on 2 dpi. g, Detection of olfactory neurons from nasal turbinate on 7 dpi. h. Detection of olfactory neurons from nasal turbinate on 14 dpi. i, H&E staining of the brain tissue on 5 dpi. j, H&E staining of the heart on 5 dpi. k, H&E staining of the liver on 5 dpi. l, H&E staining of the kidney on 5 dpi. Hamsters were intra-nasally inoculated with PBS (mock infection, N=1) or with 8 × 104 TCID50 of SARS-CoV-2 (N=9) and the tissues were collected on 2 (N=3), 5 (N=3), 7 (N=3) dpi. H&E and immunohistochemistry with tissues from three animals showed similar results and the representative results were shown.
Extended Data Figure 3.
Extended Data Figure 3.. Experimental layout for the aerosol transmission experiment in hamsters.
To evaluate SARS-CoV-2 transmissibility via aerosols, one naïve hamster was exposed to one inoculated donor hamster in two adjacent stainless steel wired cages on 1 dpi for 8 hours. DietGel®76A (ClearH2O®) was provided to the hamsters during the 8-hour exposure. Exposure was done by holding the animals inside individually ventilated cages (IsoCage N, Techniplast) with 70 air changes per hour. Experiments were repeated with three pairs of donors: aerosol contact at 1:1 ratio. After exposure, the animals were single-housed in separate cages and were continued monitored for 14 days.
Figure 1.
Figure 1.. Viral load and histopathological changes in golden Syrian hamsters intranasally challenged with SARS-CoV-2.
a, Infectious viral load (log10TCID50/mL) and viral RNA (log10 RNA copies/mL) detected in the lungs of SARS-CoV-2 challenged hamsters (N=3) on 2, 5, 7 dpi. b, Infectious viral load and viral RNA detected in the kidney of SARS-CoV-2 challenged hamsters (N=3) on 2, 5, 7 dpi. Individual data points and mean±SD were shown; the detection limit (1.789 log10 TCID50/ mL) was shown with the dotted line. c, Haemotoxylin and eosin (H&E) staining of the lungs of SARS-CoV-2 challenged hamsters on 2 dpi. d, Detection of SARS-CoV-2 N protein at bronchial epithelial cells (indicated by an arrow) by immunohistochemistry on 2 dpi. e, H&E staining of the lungs on 5 dpi. f, Detection of N protein in pneumocytes with lung consolidation (indicated by an arrow) on 5 dpi. g, H&E staining of the lungs on 7 dpi. h, The lack of detection of N protein in the lungs on 7 dpi. i, H&E staining of nasal turbinate of challenged hamsters on 2 dpi. j, Detection of N protein in nasal epithelial cells (arrow on the right) and cells morphologically resembling olfactory neurons (arrow on the left) on 2 dpi. k, H&E staining of duodenum of challenged hamsters on 2 dpi. l, Detection of N protein in the duodenum epithelial cells on 2 dpi. The experiment was performed once with 9 hamsters challenged with 8 × 104 TCID50 of SARS-CoV-2, and tissues were collected from 3 animals for histopathology examination and immunohistochemistry at each time point. H&E staining and immunohistochemistry performed using tissues from three animals showed comparable results, and the representative images were shown.
Figure 2.
Figure 2.. Transmission of SARS-CoV-2 in golden Syrian hamsters by direct contact.
a, Infectious viral load (log10TCID50/mL, shown in bars) and viral RNA copy numbers (log10 RNA copies/mL, shown in color-matched dots) detected in the nasal washes of donor hamsters (N=3) inoculated with 8 × 104 TCID50 of SARS-CoV-2. b, Body weight changes (% weight change compared to day 0) of hamsters inoculated with SARS-CoV-2 (N=9, including 3 donors and 9 challenged animals described in Fig. 1); individual data points and mean±SD were shown. c, Transmission of SARS-CoV-2 to naïve hamsters (N=3) that were each co-housed with one inoculated donor on 1 dpi; infectious viral load and viral RNA copy numbers detected in the nasal washes of contact hamsters were shown. d, Body weight changes (% weight change compared to the day of exposure) of contact hamsters (N=3) infected with SARS-CoV-2. e, Transmission of SARS-CoV-2 to naïve hamsters (N=3) that were each co-housed with one donor on 6 dpi; infectious viral load and viral RNA copy numbers detected in the nasal washes of contact hamsters were shown. f, Body weight changes of contact hamsters (N=3). Direct contact transmission experiments with co-housed donors with naïve contacts on 1 dpi and 6 dpi, respectively, were each performed once with three repeats.
Figure 3.
Figure 3.. Transmission of SARS-CoV-2 in golden Syrian hamsters via aerosols and fomites.
a, Infectious viral load (log10TCID50/mL, shown in bars) and viral RNA copy numbers (log10 RNA copies/mL, shown in color-matched dots) detected in the nasal washes of donor hamsters (N=3) inoculated with 8 × 104 TCID50 of SARS-CoV-2. b, Infectious virus and viral RNA detected in the fecal samples of donor hamsters (N=3). c, Body weight changes of donor hamsters (N=3); individual data points and mean±SD were shown. d, Aerosol transmission of SARS-CoV-2 to naïve hamsters (N=3) exposed to donors for 8 hours on 1 dpi; Infectious virus and viral RNA detected in the nasal washes of aerosol contact hamsters were shown. e, Infectious virus and viral RNA detected in the fecal samples of aerosol contact hamsters (N=3). f, Body weight changes (% weight change compared to the day of exposure) of aerosol contact hamsters (N=3). g, Fomite transmission of SARS-CoV-2 to naïve hamsters (N=3) that were single-housed in donors’ soiled cages for 48 hours; Infectious virus and viral RNA detected in the nasal washes of fomite contact hamsters were shown. h, Infectious virus and viral RNA detected in the fecal samples of fomite contact hamsters (N=3). i, Body weight changes (% weight change compared to the day of exposure) of fomite contact hamsters (N=3). Aerosol transmission and fomite transmission experiments were each performed once with three repeats.
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