Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States

Martines, Roosecelis B; Ritter, Jana M.; Matkovic, Eduard; Gary, Joy; Bollweg, Brigid C.; Bullock, Hannah; Goldsmith, Cynthia S.; Silva‐Flannery, Luciana; Seixas, Josilene Nascimento; Reagan‐Steiner, Sarah; Uyeki, Timothy M.; Denison, Amy M.; Bhatnagar, Julu; Shieh, Wun‐Ju; Zaki, Sherif R.

doi:10.3201/eid2609.202095

Cited by 351 publications

(488 citation statements)

References 44 publications

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“…The impact of a species difference (between ferrets and hamsters) in pulmonary pathogenicity at the inoculation dose used in these species is unclear. SARS-CoV-2 is detected in the lungs of the majority of human fatal cases (18)(19)(20)] and ISARIC clinical investigations 21 SARS-CoV-2 RNA was also measured in our study in the intestinal tract of ferrets and hamsters, although at a lower level than in the upper respiratory tract. As in most human cases (22), no infectious virus was isolated from intestinal samples, while viral RNA was detected.…”

Section: Discussionsupporting

confidence: 56%

Hamster and ferret experimental infection with intranasal low dose of a single strain of SARS-CoV-2

Monchâtre-Leroy

Lesellier²,

Wasniewski

et al. 2020

Preprint

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Understanding the pathogenesis of the SARS-CoV-2 infection is key to develop preventive and therapeutic strategies against COVID-19, in the case of severe illness but also when the disease is mild. The use of appropriate experimental animal models remains central in the in-vivo exploration of the physiopathology of infection and antiviral strategies. This study describes SARS-CoV-2 intra-nasal infection in ferrets and hamsters with low doses of low-passage SARS-CoV-2 clinical French isolate UCN19, describing infection levels, excretion, immune responses and pathological patterns in both animal species. Individual infection with 103 pfu SARS-CoV-2 induced a more severe disease in hamsters than in ferrets. Viral RNA was detected in the lungs of hamsters but not of ferrets and in the brain (olfactive and/or spinal bulbs) of both species. Overall, the clinical disease remained mild, with serological responses detected from 7 days and 10 days post inoculation in hamsters and ferrets respectively. Virus became undetectable and pathology resolved within 14 days. The kinetics and levels of infection can be used in ferrets and hamsters as experimental models for understanding the pathogenicity of SARS-CoV-2, and testing the protective effect of drugs.

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Section: Discussionsupporting

confidence: 56%

Hamster and ferret experimental infection with intranasal low dose of a single strain of SARS-CoV-2

Monchâtre-Leroy

Lesellier²,

Wasniewski

et al. 2020

Preprint

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“…Similarly, these reports describe general ndings and the presence of MKs is not further commented. In the remaining autopsy studies, including a review article there are no references to MKs [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]41]. Various reasons could explain this absence.…”

Section: Discussionmentioning

confidence: 99%

Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage. An autopsy study with clinical correlation and review of the literature.

Valdivia-Mazeyra

Salas

Nieves-Alonso

et al. 2020

Preprint

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Megakaryocytes are normally present in the lung where they play a role in platelet homeostasis. The latter are well known to participate in the pathogenesis of lung damage, particularly in acute lung injury. Although megakaryocytes are usually not mentioned as a characteristic histopathologic finding associated to acute pulmonary injury, a few studies point out that their number is increased in the lungs of patients with diffuse alveolar damage. In this autopsy study we have observed a relevant number of pulmonary megakaryocytes in COVID-19 patients dying with acute respiratory distress syndrome. We have studied pulmonary tissue samples of 18 patients most of which died after prolonged disease and use of mechanical ventilation. Most samples showed fibroproliferative or fibrotic diffuse alveolar damage and an increased number of megakaryocytes. In six, thrombi of the pulmonary microcirculation were seen. We compare our findings with previous published autopsy reports, mainly focusing on the description of megakaryocytes. Our patients showed abnormal coagulation parameters with high levels of fibrinogen, D-dimers and variable thrombocytopenia. Since the lung is considered an active site of megakariopoiesis, a prothrombotic status leading to platelet activation, aggregation and consumption may trigger a compensatory pulmonary response. An increased number of pulmonary megakaryocytes suggests and supports a relation with the thrombotic events so often seen in COVID-19. Regardless of its etiology, future studies of patients dying with acute pulmonary injury should include pulmonary megakaryocytes as a histologic variable of interest.

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“…While conventional immunohistochemistry studies have been used to assess the presence or absence of SARS-CoV-2 antigen in human and animal tissues [29–33,42,46,47], none of them were able to provide a greater spatial context of the infection site. By combining TOC with LSFM, we acquired large intact volumes of SARS-CoV-2-infected respiratory tissues from ferrets (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…Within the respiratory tract, detection of viral antigen and RNA suggested a preferential replication of SARS-CoV-2 in the upper respiratory tract (URT) of ferrets [29–31], whereas viral antigen was detected in both the URT und lower respiratory tract (LRT) of Syrian hamsters [32,33]. In humans and non-human primates (NHPs), viral antigen detection indicates virus replication in both the URT and LRT [42,46,47].…”

Section: Introductionmentioning

confidence: 99%

3D reconstruction of SARS-CoV-2 infection in ferrets emphasizes focal infection pattern in the upper respiratory tract

Zaeck

Scheibner

Sehl

et al. 2020

Preprint

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The visualization of viral pathogens in infected tissues is an invaluable tool to understand spatial virus distribution, localization, and cell tropism in vivo. Commonly, virus-infected tissues are analyzed using conventional immunohistochemistry in paraffin-embedded thin sections. Here, we demonstrate the utility of volumetric three-dimensional (3D) immunofluorescence imaging using tissue optical clearing and light sheet microscopy to investigate host-pathogen interactions of pandemic SARS-CoV-2 in ferrets at a mesoscopic scale. The superior spatial context of large, intact samples (> 150 mm3) allowed detailed quantification of interrelated parameters like focus-to-focus distance or SARS-CoV-2-infected area, facilitating an in-depth description of SARS-CoV-2 infection foci. Accordingly, we could confirm a preferential infection of the ferret upper respiratory tract by SARS-CoV-2 and emphasize a distinct focal infection pattern in nasal turbinates. Conclusively, we present a proof-of-concept study for investigating critically important respiratory pathogens in their spatial tissue morphology and demonstrate the first specific 3D visualization of SARS-CoV-2 infection.

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Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States

Cited by 351 publications

References 44 publications

Hamster and ferret experimental infection with intranasal low dose of a single strain of SARS-CoV-2

Hamster and ferret experimental infection with intranasal low dose of a single strain of SARS-CoV-2

Increased number of pulmonary megakaryocytes in COVID-19 patients with diffuse alveolar damage. An autopsy study with clinical correlation and review of the literature.

3D reconstruction of SARS-CoV-2 infection in ferrets emphasizes focal infection pattern in the upper respiratory tract

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