Longitudinal omics in Syrian hamsters integrated with human data unravel complexity of moderate immune responses to SARS-CoV-2
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Abstract
In COVID-19, the immune response largely determines disease severity and is key to therapeutic strategies. Cellular mechanisms contributing to inflammatory lung injury and tissue repair in SARS-CoV-2 infection, particularly endothelial cell involvement, remain ill-defined. We performed detailed spatiotemporal analyses of cellular and molecular processes in SARS-CoV-2 infected Syrian hamsters. Comparison of hamster single-cell sequencing and proteomics with data sets from COVID-19 patients demonstrated inter-species concordance of cellular and molecular host-pathogen interactions. In depth vascular and pulmonary compartment analyses (i) supported the hypothesis that monocyte-derived macrophages dominate inflammation, (ii) revealed endothelial inflammation status and T-cell attraction, and (iii) showed that CD4+ and CD8+ cytotoxic T-cell responses precede viral elimination. Using the Syrian hamster model of self-limited moderate COVID-19, we defined the specific roles of endothelial and epithelial cells, among other myeloid and non-myeloid lung cell subtypes, for determining the disease course.
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SciScore for 10.1101/2020.12.18.423524: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Virus stocks were propagated under BSL-3 conditions in Vero E6 cells (ATCC CRL-1586) in minimal essential medium (MEM; PAN Biotech, Aidenbach, Germany) supplemented with 10 % fetal bovine serum (PAN Biotech), 100 IU/mL penicillin G and 100 g/mL streptomycin (Carl Roth, Karlsruhe, Germany). Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Adjusted P values were calculated by DEseq2 using Benjamini-Hochberg corrections of Wald test P values. DEseq2suggested: (DESeq2, RRID:SCR_015687)Statistical Analyses of clinical data Graph-Pad Prism v8 (GraphPad Software Inc. GraphPadsu…SciScore for 10.1101/2020.12.18.423524: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Virus stocks were propagated under BSL-3 conditions in Vero E6 cells (ATCC CRL-1586) in minimal essential medium (MEM; PAN Biotech, Aidenbach, Germany) supplemented with 10 % fetal bovine serum (PAN Biotech), 100 IU/mL penicillin G and 100 g/mL streptomycin (Carl Roth, Karlsruhe, Germany). Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Adjusted P values were calculated by DEseq2 using Benjamini-Hochberg corrections of Wald test P values. DEseq2suggested: (DESeq2, RRID:SCR_015687)Statistical Analyses of clinical data Graph-Pad Prism v8 (GraphPad Software Inc. GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)The Ensemble annotation was extended by mapping ENSEMBL gene ids without annotated gene names to entrez identifiers and to the homolog associated gene names using biomaRt (Durinck et al., 2009). ENSEMBLsuggested: (Ensembl, RRID:SCR_002344)Analysis of bulk RNA-sequencing data Reads were aligned to the genome using hisat2 (Kim et al., 2019) and quantified using quasR (Gaidatzis et al., 2015). hisat2suggested: (HISAT2, RRID:SCR_015530)quasRsuggested: (QUASR, RRID:SCR_006820)Integration with mouse data was performed using matching gene names between mouse and hamster, while gene names in the human data were converted to mouse using biomaRt. biomaRtsuggested: (biomaRt, RRID:SCR_019214)Results from OddPub: Thank you for sharing your code and data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has several limitations, including limited disease spectrum by restriction to moderate disease, lack of detailed B cell response analysis beyond 14 dpi, and need for improvement of gene annotation in the current version hamster genomes. Furthermore, it does not recapitulate the various covariates and preexisting conditions that can affect disease outcome. Clearly, we are only at the beginning of matching the course of disease in hamsters and humans in greater detail. Nevertheless, we already provide clear evidence that Syrian hamsters recapitulate the course of moderate human SARS-CoV-2 infection. Hamsters displayed nearly prototypic antiviral immune responses starting with rapid, yet self-restricted neutrophilic response, along with a fast and strong monocytic innate immune response following activation after virus uptake, augmenting local anti-viral responses and pro- inflammatory CC chemokine production recruiting a potent type 1 T cell response that probably contributed to elimination of pulmonary residing virus via cytotoxic effector mechanisms. Neutralizing antibodies of IgM type aided in preventing viral spread and fostered cellular virus uptake. Viral infection and inflammatory response in and by lung epithelium is not predominant. Upon successful elimination of virus, alveolar epithelial repair mechanisms started, along with endothelial suppression of fibrotic programs, thus enabling pulmonary regeneration in convalesced hamsters. Hence, Syrian hamsters rep...
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: We did not find any issues relating to colormaps.
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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