COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system
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Abstract
While recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Yet, olfactory and taste dysfunction are rather common in COVID-19, especially in pauci-symptomatic patients which constitutes the most frequent clinical manifestation of the infection. We conducted a virologic, molecular, and cellular study of the olfactory system from COVID-19 patients presenting acute loss of smell, and report evidence that the olfactory epithelium represents a highly significant infection site where multiple cell types, including olfactory sensory neurons, support cells and immune cells, are infected. Viral replication in the olfactory epithelium is associated with local inflammation. Furthermore, we show that SARS-CoV-2 induces acute anosmia and ageusia in golden Syrian hamsters, both lasting as long as the virus remains in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling in COVID-19 patients presenting with persistent loss of smell reveals the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. Viral persistence in the olfactory epithelium therefore provides a potential mechanism for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management and future therapeutic strategies.
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SciScore for 10.1101/2020.11.18.388819: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable SARS-CoV-2 model in hamsters: Male and female Syrian hamsters (Mesocricetus auratus) of 5-6 weeks of age (average weight 60-80 grams) were purchased from Janvier Laboratories and handled under specific pathogen-free conditions. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Sections were then blocked in PBS supplemented with 10% goat serum, 4% fetal calf serum and 0.4% Triton X-100 for 2h at room temperature, followed by overnight incubation at 4°C with primary antibodies: rat anti-CD11b (1/100, 550282, … SciScore for 10.1101/2020.11.18.388819: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable SARS-CoV-2 model in hamsters: Male and female Syrian hamsters (Mesocricetus auratus) of 5-6 weeks of age (average weight 60-80 grams) were purchased from Janvier Laboratories and handled under specific pathogen-free conditions. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Sections were then blocked in PBS supplemented with 10% goat serum, 4% fetal calf serum and 0.4% Triton X-100 for 2h at room temperature, followed by overnight incubation at 4°C with primary antibodies: rat anti-CD11b (1/100, 550282, BD-Biosciences) anti-CD11bsuggested: (BD Biosciences Cat# 550282, RRID:AB_393577)After rinsing, slides were incubated with the appropriate secondary antibodies (1/500: goat anti-rat Alexa Fluor 546, A11081; goat anti-rabbit Alexa Fluor 488, A11034; goat anti-mouse IgG2a Alexa Fluor 546, A21133; goat anti-chicken Alexa Fluor 647, A32933, Invitrogen) for 2 hours at room temperature. anti-ratsuggested: (Molecular Probes Cat# A-11081, RRID:AB_141738)anti-rabbitsuggested: (Thermo Fisher Scientific Cat# A-11034, RRID:AB_2576217)anti-mouse IgG2asuggested: (Innovative Research Cat# A21133, RRID:AB_1500823)anti-chickensuggested: (Thermo Fisher Scientific Cat# A32933, RRID:AB_2762845)A32933suggested: NoneExperimental Models: Cell Lines Sentences Resources Viral stocks were titrated on Vero-E6 cells by classical plaque assay using semisolid overlays (Avicel, RC581-NFDR080I, DuPont)(46). Vero-E6suggested: NoneSoftware and Algorithms Sentences Resources 6 (StataCorp LLC, Texas, USA) and Prism software (GraphPad, version 8, San Diego, USA), with p < 0.05 considered significant. StataCorpsuggested: (Stata, RRID:SCR_012763)Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 27 and 31. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2020.11.18.388819: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement This interventional study received the approval from the ethical committee “Comité de Protection Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable SARS-CoV-2 model in hamsters Male and female Syrian hamsters (Mesocricetus auratus) of 5-6 weeks of age (average weight 60-80 grams) were purchased from Janvier Laboratories and handled under specific pathogen-free conditions. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Sections were then blocked in PBS supplemented with 10% goat serum, 4% fetal calf serum and 0.4% Triton X-100 for 2h at room temperature, followed by overnight … SciScore for 10.1101/2020.11.18.388819: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement This interventional study received the approval from the ethical committee “Comité de Protection Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable SARS-CoV-2 model in hamsters Male and female Syrian hamsters (Mesocricetus auratus) of 5-6 weeks of age (average weight 60-80 grams) were purchased from Janvier Laboratories and handled under specific pathogen-free conditions. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Sections were then blocked in PBS supplemented with 10% goat serum, 4% fetal calf serum and 0.4% Triton X-100 for 2h at room temperature, followed by overnight incubation at 4°C with primary antibodies: rat anti-CD11b (1/100, 550282, BD-Biosciences), rabbit anti-SARS- CoV nucleoprotein (1/500, provided by Dr Nicolas Escriou, Institut Pasteur, Paris), anti-CD11bsuggested: (BD Biosciences Cat# 550282, RRID:AB_393577)anti-SARS- CoV nucleoproteinsuggested: NoneAfter rinsing, slides were incubated with the appropriate secondary antibodies (1/500: goat anti-rat Alexa Fluor 546, A11081; goat anti-rabbit Alexa Fluor 488, A11034; goat anti-mouse IgG2a Alexa Fluor 546, A21133; goat anti-chicken Alexa Fluor 647, A32933, Invitrogen) for 2 hours at room temperature. anti-ratsuggested: (Molecular Probes Cat# A-11081, RRID:AB_141738)anti-rabbitsuggested: (Thermo Fisher Scientific Cat# A-11034, RRID:AB_2576217)anti-mouse IgG2asuggested: (Innovative Research Cat# A21133, RRID:AB_1500823)anti-chickensuggested: (Thermo Fisher Scientific Cat# A32933, RRID:AB_2762845)A32933suggested: NoneExperimental Models: Cell Lines Sentences Resources Viral stocks were titrated on Vero-E6 cells by classical plaque assay using semisolid overlays (Avicel, RC581-NFDR080I, DuPont)(46). Vero-E6suggested: NoneSoftware and Algorithms Sentences Resources Four days before testing, Hamsters received chocolate cereals (Coco pops, Kellogg’s) that they ate within one hour. Cocosuggested: (CoCo, RRID:SCR_010947)(StataCorp LLC, Texas, USA) and Prism software (GraphPad, version 8, San Diego, USA), with p < 0.05 considered significant. StataCorpsuggested: (Stata, RRID:SCR_012763)Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04366934 Recruiting Study of the Pathogenesis of Olfactory Disorders in COVID-19 Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap used on pages 27, 31, 31, 31, 31 and 31. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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SciScore for 10.1101/2020.11.18.388819: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement This interventional study received the approval from the ethical committee “Comité de Protection Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable SARS-CoV-2 model in hamsters Male and female Syrian hamsters (Mesocricetus auratus) of 5-6 weeks of age (average weight 60-80 grams) were purchased from Janvier Laboratories and handled under specific pathogen-free conditions. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Sections were then blocked in PBS supplemented with 10% goat serum, 4% fetal calf serum and 0.4% Triton X-100 for 2h at room temperature, followed by overnight … SciScore for 10.1101/2020.11.18.388819: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement This interventional study received the approval from the ethical committee “Comité de Protection Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable SARS-CoV-2 model in hamsters Male and female Syrian hamsters (Mesocricetus auratus) of 5-6 weeks of age (average weight 60-80 grams) were purchased from Janvier Laboratories and handled under specific pathogen-free conditions. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Sections were then blocked in PBS supplemented with 10% goat serum, 4% fetal calf serum and 0.4% Triton X-100 for 2h at room temperature, followed by overnight incubation at 4°C with primary antibodies: rat anti-CD11b (1/100, 550282, BD-Biosciences), rabbit anti-SARS- CoV nucleoprotein (1/500, provided by Dr Nicolas Escriou, Institut Pasteur, Paris), anti-CD11bsuggested: (BD Biosciences Cat# 550282, RRID:AB_393577)anti-SARS- CoV nucleoproteinsuggested: NoneAfter rinsing, slides were incubated with the appropriate secondary antibodies (1/500: goat anti-rat Alexa Fluor 546, A11081; goat anti-rabbit Alexa Fluor 488, A11034; goat anti-mouse IgG2a Alexa Fluor 546, A21133; goat anti-chicken Alexa Fluor 647, A32933, Invitrogen) for 2 hours at room temperature. anti-ratsuggested: (Molecular Probes Cat# A-11081, RRID:AB_141738)anti-rabbitsuggested: (Thermo Fisher Scientific Cat# A-11034, RRID:AB_2576217)anti-mouse IgG2asuggested: (Innovative Research Cat# A21133, RRID:AB_1500823)anti-chickensuggested: (Thermo Fisher Scientific Cat# A32933, RRID:AB_2762845)A32933suggested: NoneExperimental Models: Cell Lines Sentences Resources Viral stocks were titrated on Vero-E6 cells by classical plaque assay using semisolid overlays (Avicel, RC581-NFDR080I, DuPont)(46). Vero-E6suggested: NoneSoftware and Algorithms Sentences Resources Four days before testing, Hamsters received chocolate cereals (Coco pops, Kellogg’s) that they ate within one hour. Cocosuggested: (CoCo, RRID:SCR_010947)(StataCorp LLC, Texas, USA) and Prism software (GraphPad, version 8, San Diego, USA), with p < 0.05 considered significant. StataCorpsuggested: (Stata, RRID:SCR_012763)Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04366934 Recruiting Study of the Pathogenesis of Olfactory Disorders in COVID-19 Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: Please consider improving the rainbow (“jet”) colormap used on pages 27, 31, 31, 31, 31 and 31. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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