Neural epidermal growth factor-like 1 protein variant increases survival and modulates the inflammatory and immune responses in human ACE-2 transgenic mice infected with SARS-CoV-2

  1. Roopa Biswas
  2. Shannon Eaker
  3. Dharmendra Kumar Soni
  4. Swagata Kar
  5. Denae LoBato
  6. Cymbeline Culiat

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Abstract

Coronavirus disease 2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is a worsening global pandemic. COVID-19 has caused at least 1.7 million deaths worldwide and over 300,000 in the United States. Recently, two promising vaccines are being administered in several countries. However, there remains an urgent need for a therapeutic treatment for COVID-19 patients with severe respiratory damage that can lead to intensive care, prolonged hospitalization, or mortality. Moreover, an increasing population of patients manifest lingering disabling symptoms (called Long Haulers). Here, we tested the efficacy of a recombinant neural epidermal growth factor like 1 protein variant (NELL1-NV1) in a COVID-19 mouse model, transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor (tg-mice hACE2) infected with SARS-CoV-2. The administration of NELL1-NV1 to SARS-CoV-2-infected tg-mice hACE2 significantly improved clinical health score and increased survival. Analyses of bronchoalveolar (BAL) fluid demonstrated decreased levels of several cytokines and chemokines (IFN-γ, IL-10, IL-12 p70, CXCL-10/IP-10, MIG and Rantes), in NV1-treated treated mice compared to controls. Cytokines including IL-1α, IL-9, IL-6, LIX/CXCL5, KC/CXCL1, MIP-2/CXCL2, MIP-1α/CCL3, and G-CSF, critical to immune responses such as neutrophil recruitment, viral clearance and vascularization, were increased compared to controls. Our data suggest the potential of NELL1-NV1-based therapy to mitigate the cytokine storm, modulate the abnormal immune response and repair respiratory tissue damage in COVID-19 patients.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.08.430254: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: The experiments with live virus challenge were carried out at BIOQUAL Inc. (Rockville, MD, USA) biosafety level 3 (BSL-3) facilities in compliance with local, state, and federal regulations under IACUC protocol #20-083.
    Randomizationnot detected.
    BlindingRepresentative tissue specimens were examined from treatment groups (PBS N=3; NV1 treatment at 1.25 mg/kg BW dose, N=5; NV1 treatment at 2.5 mg/kg BW, N=4) by a board certified veterinary anatomic pathologist blinded to treatment group.
    Power Analysisnot detected.
    Sex as a biological variable). tg-mice hACE2 (8-10-weeks-old; N=15, 8 females, 7 males) were anesthetized with ketamine/xylazine and infected via intranasal injection with 2.8 × 103 pfu of SARS-CoV-2.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    A plaque-forming assay was conducted in confluent layers of Vero E6 cells to determine the concentration of live virions, measured as plaque-forming units (pfu)
    Vero E6
    suggested: RRID:CVCL_XD71)
    Experimental Models: Organisms/Strains
    SentencesResources
    Mouse model for COVID-19: The tg-mice hACE2 (strain 034860 B6.Cg-TG(K18-ACE2) 2Primn/J) were obtained from Jackson Laboratory (Bar Harbor, ME, USA).
    tg-mice hACE2
    suggested: None
    B6.Cg-TG(K18-ACE2 ) 2Primn/J
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical Analysis: Analyses of percent change in body weight, Kaplan-Meir survival, and change in cytokine expression in NV1-treated compared to control SARS-CoV-2-infected tg-mice hACE2 were analyzed initially using Prism version 8 (GraphPad).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    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 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.

    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 10.1101/2021.02.08.430254v1 on bioRxiv