Prediction of Non-canonical Routes for SARS-CoV-2 Infection in Human Placenta Cells

  1. Flávia Bessi Constantino
  2. Sarah Santiloni Cury
  3. Celia Regina Nogueira
  4. Robson Francisco Carvalho
  5. Luis Antonio Justulin

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Abstract

The SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The data available about COVID-19 during pregnancy have demonstrated placental infection; however, the mechanisms associated with intrauterine transmission of SARS-CoV-2 is still debated. Intriguingly, while canonical SARS-CoV-2 cell entry mediators are expressed at low levels in placental cells, the receptors for viruses that cause congenital infections such as the cytomegalovirus and Zika virus are highly expressed in these cells. Here we analyzed the transcriptional profile (microarray and single-cell RNA-Seq) of proteins potentially interacting with coronaviruses to identify non- canonical mediators of SARS-CoV-2 infection and replication in the placenta. Despite low levels of the canonical cell entry mediators ACE2 and TMPRSS2 , we show that cells of the syncytiotrophoblast, villous cytotrophoblast, and extravillous trophoblast co-express high levels of the potential non-canonical cell-entry mediators DPP4 and CTSL . We also found changes in the expression of DAAM1 and PAICS genes during pregnancy, which are translated into proteins also predicted to interact with coronaviruses proteins. These results provide new insight into the interaction between SARS-CoV-2 and host proteins that may act as non-canonical routes for SARS-CoV-2 infection and replication in the placenta cells.

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  1. Version published to 10.3389/fmolb.2021.614728
  2. Version published to 10.1101/2020.06.12.148411v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2020.06.12.148411: (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

    Software and Algorithms
    SentencesResources
    Differential expression analysis of the placenta during pregnancy trimesters: We reanalyzed microarray data from villous trophoblast tissues of first (45-59 days, n = 4), second trimester (109-115 days, n = 4), and third trimesters (n = 4) available in Gene Expression Omnibus (GEO), under the accession number GSE9984 (36).
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    Enrichment analysis: We used the Metascape tool (https://metascape.org) (37) to perform functional enrichment analysis of the genes lists generated in the clustering and differential expression analyses.
    Metascape
    suggested: (Metascape, RRID:SCR_016620)
    Tissue-specific gene networks of potential virus-host placenta interactome: The HumanBase webtool (https://hb.flatironinstitute.org) (39) was used to generate the tissue-specific gene network of placental genes coding for proteins that potentially interact with SARS-CoV-2 based on P-HIPSTER or that we identified as either associated with COVID-19 or that we hypothesized may be associated with the disease, based on the literature (Supplementary Table 8).
    HumanBase
    suggested: (HumanBase, RRID:SCR_016145)
    Data representation and analysis: Morpheus (https://software.broadinstitute.org/morpheus/) was used to generate the heatmaps and to perform the clustering analyses.
    https://software.broadinstitute.org/morpheus/
    suggested: (Morpheus by Broad Institute, RRID:SCR_017386)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Although our in-silico analyses are a starting point, they have limitations. We reanalyzed published placenta datasets with a limited number of samples (microarray = 12 individuals, and scRNA-seq = 5 individuals) and, consequently, validations in a large cohort of samples must be performed. The predicted interactions presented here should also be experimentally validated in infected cells or placenta to circumvent these limitations. Moreover, the analyses of single-cell data should be conducted for the entire period of gestation, considering that we only evaluated single-cell data from the first trimester of pregnancy. The detection of SARS-CoV-2 in the placenta needs to be performed in a large cohort of pregnant women with COVID-19, including asymptomatics. Considering that vertical transmission of SARS-CoV-2 is still debated, the follow-up of newborns from mothers with COVID-19 during pregnancy should be necessary since, if it occurs even in the non-asymptomatic, the long-term consequences are mostly unknown. In conclusion, despite low-levels of ACE2 and TMPRSS2, our analyses demonstrate that villous trophoblast cells express high levels of potential non-canonical cell-entry mediators DDP4 and CTSL. We also found changes in the expression of the DAAM1 and PAICS genes coding for proteins predicted to interact with SARS-CoV proteins during pregnancy. These results provide new insight into the interaction between SARS-CoV-2 and the host proteins and indicate that coronaviruses...

    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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  4. Version published to 10.1101/2020.06.12.148411v1 on bioRxiv