The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes

  1. Zeqing Feng
  2. Bo Diao
  3. Rongshuai Wang
  4. Gang Wang
  5. Chenhui Wang
  6. Yingjun Tan
  7. Liang Liu
  8. Changsong Wang
  9. Ying Liu
  10. Yueping Liu
  11. Zilin Yuan
  12. Liang Ren
  13. Yuzhang Wu
  14. Yongwen Chen

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Abstract

While lymphocytopenia is a common characteristic of patients infected by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the mechanisms responsible for this depletion are unclear. Through careful inspection of the spleens and lymph nodes (LNs) from six cases with postmortem examinations, we observed that SARS-CoV-2 could directly infect secondary lymphoid organs to induce cell death. Immunohistochemistry demonstrated ACE2 (angiotensin-converting enzyme 2), the potential receptor of SARS-CoV-2, expresses on tissue-resident CD169 + macrophages in spleens and LNs. Immunofluorescent staining confirmed that viral nucleocaspid protein (NP) can be found in ACE2 + cells, CD169 + macrophages, but not in CD3 + T cells or B220 + B cells in spleens and LNs. SARS-CoV-2 infection induces severe tissue damage including lymph follicle depletion, splenic nodule atrophy, histiocyte hyperplasia and lymphocyte reductions. Moreover, in situ TUNEL staining illustrated that viral infection leads to severe lymphocyte apoptosis, which might be mediated by viral antigens inducing Fas upregulation. Furthermore, SARS-CoV-2 also triggers macrophages to produce IL-6, a proinflammatory cytokine that directly promotes lymphocyte necrosis. Collectively, these results demonstrate that SARS-CoV-2 directly neutralizes human spleens and LNs through infecting tissue-resident CD169 + macrophages.

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  1. ScreenIT

    SciScore for 10.1101/2020.03.27.20045427: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Written informed consent was waived by the Ethics Commission of the designated hospital for emerging infectious diseases
    IRB: Written informed consent was waived by the Ethics Commission of the designated hospital for emerging infectious diseases
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    These antibodies are including anti-SARS-CoV-2 nucleocaspid protein (NP) antibodies (clone ID: 019, 1:100, rabbit IgG; Sino Biological, Beijing)
    anti-SARS-CoV-2 nucleocaspid protein ( NP
    suggested: None
    rabbit IgG
    suggested: None
    anti-IL-6 (sc-130326, 1:100, mouse IgG2b; Santa Cruz) or rabbit-isotype antibody controls (1:100; Dako).
    sc-130326
    suggested: (Santa Cruz Biotechnology Cat# sc-130326, RRID:AB_2127744)
    Immunofluorescence double-staining: For immunofluorescence double-staining, the sections were incubated with primary anti-NP, anti-CD68, anti-CD169, anti-B220, anti-IL-6 antibodies at 4 °C overnight.
    anti-NP
    suggested: None
    anti-CD68
    suggested: None
    anti-CD169
    suggested: None
    anti-B220
    suggested: None
    anti-IL-6
    suggested: None
    After washing with PBS (3 washes, 5 min per wash), the sections were incubated with Alexa Fluor® 555-conjugated goat anti-mouse/rabbit IgG antibodies (Invitrogen, San Diego, CA, USA) or Alexa Fluor® 488-conjugated goat anti-mouse/rabbit IgG1 antibodies (Invitrogen) for an 1 h.
    anti-mouse/rabbit IgG
    suggested: (Biorbyt Cat# orb27530, RRID:AB_10954533)
    anti-mouse/rabbit IgG1
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analysis: Statistical analyses were performed using GraphPad Prism version 8.0 (GraphPad Software, Inc.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (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: 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.

    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.

  2. Version published to 10.1101/2020.03.27.20045427v1 on medRxiv