SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species
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Abstract
There are no known cures or vaccines for COVID-19, the defining pandemic of this era. Animal models are essential to fast track new interventions and nonhuman primate (NHP) models of other infectious diseases have proven extremely valuable. Here we compare SARS-CoV-2 infection in three species of experimentally infected NHPs (rhesus macaques, baboons, and marmosets). During the first 3 days, macaques developed clinical signatures of viral infection and systemic inflammation, coupled with early evidence of viral replication and mild-to-moderate interstitial and alveolar pneumonitis, as well as extra-pulmonary pathologies. Cone-beam CT scans showed evidence of moderate pneumonia, which progressed over 3 days. Longitudinal studies showed that while both young and old macaques developed early signs of COVID-19, both groups recovered within a two-week period. Recovery was characterized by low-levels of viral persistence in the lung, suggesting mechanisms by which individuals with compromised immune systems may be susceptible to prolonged and progressive COVID-19. The lung compartment contained a complex early inflammatory milieu with an influx of innate and adaptive immune cells, particularly interstitial macrophages, neutrophils and plasmacytoid dendritic cells, and a prominent Type I-interferon response. While macaques developed moderate disease, baboons exhibited prolonged shedding of virus and extensive pathology following infection; and marmosets demonstrated a milder form of infection. These results showcase in critical detail, the robust early cellular immune responses to SARS-CoV-2 infection, which are not sterilizing and likely impact development of antibody responses. Thus, various NHP genera recapitulate heterogeneous progression of COVID-19. Rhesus macaques and baboons develop different, quantifiable disease attributes making them immediately available essential models to test new vaccines and therapies.
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SciScore for 10.1101/2020.06.05.136481: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The animal studies in each of the species were approved by the Animal Care and Use Committee of the Texas Biomedical Research Institute and as an omnibus Biosafety Committee protocol. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Briefly, Cellular phenotypes were studied using antibodies: CD3 (clone SP34-2), CD4 (clone L200), CD3suggested: NoneCD4suggested: None, 37°C for 2 h) or anti-SARS CoV-2 nucleocapsid (N) antibody (Sino Biologicals, USA, 1:100 anti-SARS CoV-2 nucleocapsid ( Nsuggested: None, 37°C for … SciScore for 10.1101/2020.06.05.136481: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The animal studies in each of the species were approved by the Animal Care and Use Committee of the Texas Biomedical Research Institute and as an omnibus Biosafety Committee protocol. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Briefly, Cellular phenotypes were studied using antibodies: CD3 (clone SP34-2), CD4 (clone L200), CD3suggested: NoneCD4suggested: None, 37°C for 2 h) or anti-SARS CoV-2 nucleocapsid (N) antibody (Sino Biologicals, USA, 1:100 anti-SARS CoV-2 nucleocapsid ( Nsuggested: None, 37°C for 2h) and mouse anti-human HLA-DR antibody (Thermo Fisher Scientific, USA, 1:100, 2 h at 37°C). anti-human HLA-DRsuggested: NoneAlexa-Fluor 555 conjugate secondary antibodies (Thermo Fisher Scientific, USA, 1:400, 1 h at 37°C) were used for labelling Spike, Ki67 and HLA-DR, CD68 primary antibodies respectively. HLA-DRsuggested: NoneCD68suggested: NoneExperimental Models: Cell Lines Sentences Resources The stock virus was passaged for a fifth time in Vero E6 cells at a multiplicity of infection (MOI) of approximately 0.001. Vero E6suggested: RRID:CVCL_XD71)Software and Algorithms Sentences Resources Macaques were enrolled from a specific pathogen-free colony maintained at the SNPRC and were tested free from SPF-4 ( SNPRCsuggested: (Southwest National Primate Research Center, RRID:SCR_008292)Samples were then transferred to the sample rack on EpMotion EpMotionsuggested: NoneFor antigenic stimulation cells were cultured overnight with SARS-CoV-2 specific peptide pools of the nucleocapsid (N), membrane (M) and spike (S) proteins (PepTivator SARS-CoV-2 peptide pool, Miltenyi Biotech, USA). SARS-CoV-2suggested: (Active Motif Cat# 91351, RRID:AB_2847848)Statistical analyses: Graphs were prepared and statistical comparisons applied using GraphPad Prism version 8 (La Jolla, CA) GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)2-tailed Student’s t-test, ordinary analysis of variance (ANOVA) or one-way or two-way repeated measure analysis of variance (rmANOVA) with Geisser-Greenhouse correction for sphericity and Tukey’s post hoc correction for multiple-testing (GraphPad Prism 8) was applied wherever applicable and as described in the figure legends. 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 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(s) used on pages 79 and 47. 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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