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      Salivary glands are a target for SARS‐CoV‐2: a source for saliva contamination

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          Abstract

          The ability of the new coronavirus SARS‐CoV‐2 to spread and contaminate is one of the determinants of the COVID‐19 pandemic status. SARS‐CoV‐2 has been detected in saliva consistently, with similar sensitivity to that observed in nasopharyngeal swabs. We conducted ultrasound‐guided postmortem biopsies in COVID‐19 fatal cases. Samples of salivary glands (SGs; parotid, submandibular, and minor) were obtained. We analyzed samples using RT‐qPCR, immunohistochemistry, electron microscopy, and histopathological analysis to identify SARS‐CoV‐2 and elucidate qualitative and quantitative viral profiles in salivary glands. The study included 13 female and 11 male patients, with a mean age of 53.12 years (range 8–83 years). RT‐qPCR for SARS‐CoV‐2 was positive in 30 SG samples from 18 patients (60% of total SG samples and 75% of all cases). Ultrastructural analyses showed spherical 70–100 nm viral particles, consistent in size and shape with the Coronaviridae family, in the ductal lining cell cytoplasm, acinar cells, and ductal lumen of SGs. There was also degeneration of organelles in infected cells and the presence of a cluster of nucleocapsids, which suggests viral replication in SG cells. Qualitative histopathological analysis showed morphologic alterations in the duct lining epithelium characterized by cytoplasmic and nuclear vacuolization, as well as nuclear pleomorphism. Acinar cells showed degenerative changes of the zymogen granules and enlarged nuclei. Ductal epithelium and serous acinar cells showed intense expression of ACE2 and TMPRSS receptors. An anti‐SARS‐CoV‐2 antibody was positive in 8 (53%) of the 15 tested cases in duct lining epithelial cells and acinar cells of major SGs. Only two minor salivary glands were positive for SARS‐CoV‐2 by immunohistochemistry. Salivary glands are a reservoir for SARS‐CoV‐2 and provide a pathophysiological background for studies that indicate the use of saliva as a diagnostic method for COVID‐19 and highlight this biological fluid's role in spreading the disease. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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          Is Open Access

          Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

          Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.
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            A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury

            During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world 1,2,3 . A new coronavirus (SARS-CoV) was identified as the SARS pathogen 4,5,6,7 , which triggered severe pneumonia and acute, often lethal, lung failure 8 . Moreover, among infected individuals influenza such as the Spanish flu 9,10 and the emergence of new respiratory disease viruses 11,12 have caused high lethality resulting from acute lung failure 13 . In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor 14 . The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses. Supplementary information The online version of this article (doi:10.1038/nm1267) contains supplementary material, which is available to authorized users.
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              Multiorgan and Renal Tropism of SARS-CoV-2

              To the Editor: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects cells in the respiratory tract, 1,2 but its direct affinity for organs other than the lungs remains poorly defined. Here, we present data from an autopsy series of 27 patients (see the clinical data in Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) that show that SARS-CoV-2 can be detected in multiple organs, including the lungs, pharynx, heart, liver, brain, and kidneys. We first quantified the SARS-CoV-2 viral load in autopsy tissue samples obtained from 22 patients who had died from Covid-19. Seventeen patients (77%) had more than two coexisting conditions (Figure 1A), and a greater number of coexisting conditions was associated with SARS-CoV-2 tropism for the kidneys (Table S2), even in patients without a history of chronic kidney disease (Table S3). The highest levels of SARS-CoV-2 copies per cell were detected in the respiratory tract, and lower levels were detected the kidneys, liver, heart, brain, and blood (Figure 1B). These findings indicate a broad organotropism of SARS-CoV-2. Since the kidneys are among the most common targets of SARS-CoV-2, we performed in silico analysis of publicly available data sets of single-cell RNA sequencing. This analysis revealed that RNA for angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin L (CTSL) — RNA of genes that are considered to facilitate SARS-CoV-2 infection 3 — is enriched in multiple kidney-cell types from fetal development through adulthood (Fig. S1). This enrichment may facilitate SARS-CoV-2–associated kidney injury, as previously suggested. 4 We also quantified the SARS-CoV-2 viral load in precisely defined kidney compartments obtained with the use of tissue microdissection from 6 patients who underwent autopsy (1 patient who was included in the previously mentioned 22 patients as an internal negative control, plus 5 additional patients). Three of these 6 patients had a detectable SARS-CoV-2 viral load in all kidney compartments examined, with preferential targeting of glomerular cells (Fig. S2). We also detected viral RNA and protein with high spatial resolution using in situ hybridization and indirect immunofluorescence with confocal microscopy (Figure 1C). Data on additional controls are provided in Figures S3 and S4. On the basis of these findings, renal tropism is a potential explanation of commonly reported new clinical signs of kidney injury in patients with Covid-19, 5 even in patients with SARS-CoV-2 infection who are not critically ill. Our results indicate that SARS-CoV-2 has an organotropism beyond the respiratory tract, including the kidneys, liver, heart, and brain, and we speculate that organotropism influences the course of Covid-19 disease and, possibly, aggravates preexisting conditions.
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                Author and article information

                Contributors
                burns@usp.br
                Journal
                J Pathol
                J Pathol
                10.1002/(ISSN)1096-9896
                PATH
                The Journal of Pathology
                John Wiley & Sons, Ltd (Chichester, UK )
                0022-3417
                1096-9896
                21 May 2021
                July 2021
                : 254
                : 3 ( doiID: 10.1002/path.v254.3 )
                : 239-243
                Affiliations
                [ 1 ] Department of Pathology, School of Medicine University of São Paulo São Paulo Brazil
                [ 2 ] Adolfo Lutz Institute Division of Pathology São Paulo Brazil
                [ 3 ] Department of Otorhinolaryngology, School of Medicine University of São Paulo São Paulo Brazil
                [ 4 ] Department of Stomatology, School of Dentistry University of São Paulo São Paulo Brazil
                [ 5 ] Department of Periodontics and Oral Medicine, School of Dentistry University of Michigan Ann Arbor MI USA
                [ 6 ] Department of Gastroenterology, School of Medicine University of São Paulo São Paulo Brazil
                [ 7 ] Institute of Tropical Medicine, School of Medicine University of São Paulo São Paulo Brazil
                [ 8 ] São Paulo Autopsy Service University of São Paulo São Paulo Brazil
                Author notes
                [*] [* ] Correspondence to: LFF da Silva, Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, sala 1155 – Cerqueira Cesar, São Paulo – SP, 01246‐903, Brazil.

                E‐mail: burns@ 123456usp.br

                Author information
                https://orcid.org/0000-0002-9073-9989
                https://orcid.org/0000-0001-6659-7186
                https://orcid.org/0000-0002-1842-9521
                https://orcid.org/0000-0002-0181-6357
                Article
                PATH5679
                10.1002/path.5679
                8250228
                33834497
                2d7660e0-e12b-4707-9be4-c0815ca77732
                © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 12 March 2021
                : 14 October 2020
                : 06 April 2021
                Page count
                Figures: 2, Tables: 0, Pages: 5, Words: 3154
                Funding
                Funded by: Bill and Melinda Gates Foundation , open-funder-registry 10.13039/100000865;
                Award ID: 10.13039/100000865
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico , open-funder-registry 10.13039/501100003593;
                Award ID: 401825/2020‐5
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo , open-funder-registry 10.13039/501100001807;
                Award ID: 10.13039/501100001807
                Categories
                Brief Report
                Brief Report
                Custom metadata
                2.0
                July 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:02.07.2021

                Pathology
                covid‐19,autopsy,infection control,salivary gland,rt‐pcr, sars‐cov‐2,saliva
                Pathology
                covid‐19, autopsy, infection control, salivary gland, rt‐pcr, sars‐cov‐2, saliva

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