1. Computational and Systems Biology
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SARS-CoV-2 strategically mimics proteolytic activation of human ENaC

  1. Praveen Anand
  2. Arjun Puranik
  3. Murali Aravamudan
  4. AJ Venkatakrishnan  Is a corresponding author
  5. Venky Soundararajan  Is a corresponding author
  1. nference, India
  2. nference, United States
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Cite this article as: eLife 2020;9:e58603 doi: 10.7554/eLife.58603

Abstract

Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 65 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Praveen Anand

    R&D, nference, Bangalore, India
    Competing interests
    Praveen Anand, The author is an employee of nference..
  2. Arjun Puranik

    Data Science, nference, San Francisco, United States
    Competing interests
    Arjun Puranik, The author is an employee of nference..
  3. Murali Aravamudan

    R&D, nference, Cambridge, United States
    Competing interests
    Murali Aravamudan, The author is an employee of Nference..
  4. AJ Venkatakrishnan

    R&D, nference, Cambridge, United States
    For correspondence
    aj@nference.net
    Competing interests
    AJ Venkatakrishnan, Author is an employee of nference.
  5. Venky Soundararajan

    R&D, nference, Cambridge, United States
    For correspondence
    venky@nference.net
    Competing interests
    Venky Soundararajan, The author is an employee of nference..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7434-9211

Funding

The authors declare that there was no external funding for this work.

Reviewing Editor

  1. Gian Paolo Rossi, University of Padova, Italy

Publication history

  1. Received: May 5, 2020
  2. Accepted: May 25, 2020
  3. Accepted Manuscript published: May 26, 2020 (version 1)
  4. Version of Record published: July 8, 2020 (version 2)

Copyright

© 2020, Anand et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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    Background:

    Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients.

    Methods:

    Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods.

    Results:

    Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76–[104-117] mmHg associated with neurological recovery.

    Conclusions:

    We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention.

    Funding:

    NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB); DOE: DE-AC02-05CH11231 (DM).