pubmed.ncbi.nlm.nih.gov
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urlscan Pro
2600:1901:0:c831::
Public Scan
Submitted URL: https://www.bing.com/ck/a?!&&p=c1da0659e043193cJmltdHM9MTY4MDA0ODAwMCZpZ3VpZD0wNmM5MWE0Yy1iYTc3LTY2MzQtMTVjZS0wODk3Ym...
Effective URL: https://pubmed.ncbi.nlm.nih.gov/32869021/
Submission: On March 29 via manual from US — Scanned from DE
Effective URL: https://pubmed.ncbi.nlm.nih.gov/32869021/
Submission: On March 29 via manual from US — Scanned from DE
Form analysis 10 forms found in the DOM
GET /
<form action="/" method="get" autocomplete="off" class="usa-search usa-search-big search-form content-page-layout" id="search-form" role="search">
<div class="inner-wrap">
<a class="pubmed-logo" aria-label="Pubmed Logo" href="/" data-ga-category="featured_link" data-ga-action="pubmed_logo">
<img src="https://cdn.ncbi.nlm.nih.gov/pubmed/ea38fbec-dc1b-45f8-9ca9-49349cbd35b0/core/images/pubmed-logo-blue.svg" alt="pubmed logo">
</a>
<a href="#" class="search-input-trigger" data-alt-title="Hide search bar" title="Show search bar" aria-label="Show search bar" aria-hidden="true" tabindex="-1">
</a>
<div role="search" class="search-input">
<div class="form-field ">
<label class="usa-sr-only" for="id_term"> Search: </label>
<span class="twitter-typeahead ncbi-autocomplete"><input type="search" name="term" data-skip-ie-scroll-to-top="" data-replace-term-with-exact="" data-exact-query="" placeholder="" class="term-input tt-input" required="required" id="id_term"
spellcheck="false" dir="auto" style="position: relative; vertical-align: top;" aria-owns="id_term_listbox" role="combobox" aria-autocomplete="list" aria-expanded="false"><span role="status" aria-live="polite"
style="position: absolute; padding: 0px; border: 0px; height: 1px; width: 1px; margin-bottom: -1px; margin-right: -1px; overflow: hidden; clip: rect(0px, 0px, 0px, 0px); white-space: nowrap;"></span>
<pre aria-hidden="true"
style="position: absolute; visibility: hidden; white-space: pre; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; word-spacing: 0px; letter-spacing: 0px; text-indent: 0px; text-rendering: auto; text-transform: none;"></pre>
<div role="listbox" class="tt-menu" id="id_term_listbox" aria-expanded="false" style="position: absolute; top: 100%; left: 0px; z-index: 100; display: none;">
<div role="presentation" class="tt-dataset tt-dataset-0"></div>
</div>
</span><a href="#" class="clear-btn" title="Clear search input" role="button" data-pinger-ignore=""></a><button type="submit" class="search-btn" aria-label="Search" data-pinger-ignore=""><span
class="usa-search-submit-text">Search</span></button>
</div>
</div>
<!-- Create alert and Create RSS are buttons that look like links -->
<!-- Better for them to look like buttons but no space -->
<div class="search-links-wrapper content-page-layout">
<div class="search-links">
<a href="/advanced/" class="search-input-link adv-search-link" data-ga-category="featured_link" data-ga-action="adv_search">Advanced</a>
<a href="/clipboard/" class="search-input-link clipboard-link hidden" data-ga-category="featured_link" data-ga-action="clipboard">
Clipboard <span class="amount-in-clipboard"></span>
</a>
</div>
<span class="search-input-link user-guide-link" role="navigation" aria-label="User guide">
<a href="/help/" data-ga-category="featured_link" data-ga-action="user_guide">
User Guide
</a>
</span>
</div>
</div>
</form>POST /results-export-ids/
<form id="save-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<div class="action-panel-control-wrap">
<label for="save-action-format" class="action-panel-label"> Format: </label>
<select id="save-action-format" name="results-format" class="action-panel-selector">
<option value="summary-text">Summary (text)</option>
<option value="pubmed-text">PubMed</option>
<option value="pmid">PMID</option>
<option value="abstract">Abstract (text)</option>
<option value="csv">CSV</option>
</select>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="save" data-ga-label="save"> Create file </button>
<button class="action-panel-cancel" aria-label="Close 'Save citations to file' panel" ref="linksrc=close_save_panel" aria-controls="save-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="save"
data-ga-label="cancel"> Cancel </button>
</div>
</form>POST /send-email/
<form id="email-action-panel-form" class="action-panel-content action-form" action="/send-email/" data-by-search-action="/results-export-email-by-search-data/" data-by-ids-action="/send-email/" data-by-search-method="post" data-by-ids-method="post"
method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<div class="action-panel-control-wrap">
<span class="action-panel-label"> Subject: </span>
<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 32869021 - PubMed</span>
<input type="hidden" name="email-subject" value="1 selected item: 32869021">
<input type="hidden" name="email-subject-hash" value="07727000bda2d2d8fbc1b2d01bb62f124f870afd8011606d068fca107be52528">
</div>
<div class="action-panel-control-wrap">
<label for="email-to" class="action-panel-label required-field-asterisk"> To: </label>
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required="">
</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label"> From: </label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label"> Format: </label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container" style="display: none;">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="email" data-ga-label="send"> Send email </button>
<button class="action-panel-cancel" aria-label="Close 'Email citations' panel" ref="linksrc=close_email_panel" aria-controls="email-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="email" data-ga-label="cancel">
Cancel </button>
</div>
<input type="hidden" name="email-search-details" value="">
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524">
</form><form id="collections-action-panel-form" class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/" data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/" data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100" data-add-to-collection-max-amount="1000" data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio" id="collections-action-panel-new" class="collections-new" name="collections" value="new" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio" id="collections-action-panel-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk"> Name your collection: </label>
<input type="text" name="add-to-new-collection" id="collections-action-panel-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>/]*" title="The following characters are not allowed in the Name field: "&=<>/"
maxlength="100" data-ga-category="save_share" data-ga-action="create_collection" data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label>
<select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore="" data-ga-category="save_share" data-ga-action="collections" data-ga-label="add" disabled=""> Add </button>
<button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections"
data-ga-label="cancel"> Cancel </button>
</div>
</form><form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked="">
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore=""> Add </button>
<button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib"
data-ga-label="cancel"> Cancel </button>
</div>
</form><form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label>
<input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required="" pattern="[^"&=<>/]*" title="The following characters are not allowed in the Name field: "&=<>/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required=""></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked="">
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label"> Email: </label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label"> Frequency: </label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional" style="display: none;">
<label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label"> Report format: </label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label"> Send at most: </label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected="">5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label>
<textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button>
<button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert"
data-ga-label="cancel"> Cancel </button>
</div>
</form>POST /results-export-ids/
<form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post"
data-by-search-method="post" data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<input name="results-format" type="hidden" value="pubmed">
<div class="action-panel-actions">
<button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button>
<button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share"
data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button>
</div>
</form><form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label>
<input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value="" required="" pattern="[^"&=<>/]*" title="The following characters are not allowed in the Name field: "&=<>/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label"> Number of items displayed: </label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button>
<button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button type="button" disabled="" class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button>
</div>
</form><form id="collections-action-dialog-form" class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/" data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/" data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="OxZBPQjdNZUWewgROdIwhvzZWStXO66BBGbeplFKqR0B31GkCrjGsnvwztOnzMtE">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li><input type="radio" id="collections-action-dialog-new" class="collections-new" name="collections" value="new" data-ga-category="collections_button" data-ga-action="click" data-ga-label="collections_radio_new"><label
for="collections-action-dialog-new">Create a new collection</label></li>
<li><input type="radio" id="collections-action-dialog-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="collections_button" data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li>
</ul>
</div>
<div class="controls-wrapper">
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. 2020 Aug 26;2020.08.26.268854.
doi: 10.1101/2020.08.26.268854. Preprint
FURIN CLEAVAGE SITE IS KEY TO SARS-COV-2 PATHOGENESIS
Bryan A Johnson 1 , Xuping Xie 2 , Birte Kalveram 3 , Kumari G Lokugamage 1
, Antonio Muruato 1 , Jing Zou 2 , Xianwen Zhang 2 , Terry Juelich 3
, Jennifer K Smith 3 , Lihong Zhang 3 , Nathen Bopp 3 , Craig Schindewolf 1
, Michelle Vu 1 , Abigail Vanderheiden 4 5 6 , Daniele Swetnam 2
, Jessica A Plante 1 , Patricia Aguilar 3 , Kenneth S Plante 1 , Benhur Lee
7 , Scott C Weaver 1 8 , Mehul S Suthar 4 5 6 , Andrew L Routh 2 , Ping
Ren 3 , Zhiqiang Ku 9 , Zhiqiang An 9 , Kari Debbink 10 , Pei Yong Shi 2
8 , Alexander N Freiberg 3 8 , Vineet D Menachery 1 8
Affiliations Expand
AFFILIATIONS
* 1 Department of Microbiology and Immunology, University of Texas Medical
Branch, Galveston, TX, USA.
* 2 Department of Biochemistry and Molecular Biology, University of Texas
Medical Branch, Galveston, TX, USA.
* 3 Department of Pathology, University of Texas Medical Branch, Galveston, TX,
USA.
* 4 Department of Pediatrics, Emory Vaccine Center, Atlanta, GA, USA.
* 5 Emory University School of Medicine, Atlanta, GA, USA.
* 6 Yerkes National Primate Research Center, Atlanta, GA, USA.
* 7 Icahn School of Medicine at Mount Sinai, New York, NY, USA.
* 8 Department of Institute for Human Infection and Immunity, University of
Texas Medical Branch, Galveston, TX, USA.
* 9 Texas Therapeutics Institute, Brown Foundation Institute of Molecular
Medicine, University of Texas Health Science Center at Houston, Houston, USA.
* 10 Bowie State University, Bowie, MD, USA.
* PMID: 32869021
* PMCID: PMC7457603
* DOI: 10.1101/2020.08.26.268854
Free PMC article
Item in Clipboard
FURIN CLEAVAGE SITE IS KEY TO SARS-COV-2 PATHOGENESIS
Bryan A Johnson et al. bioRxiv. 2020.
Free PMC article
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. 2020 Aug 26;2020.08.26.268854.
doi: 10.1101/2020.08.26.268854. Preprint
AUTHORS
Bryan A Johnson 1 , Xuping Xie 2 , Birte Kalveram 3 , Kumari G Lokugamage 1
, Antonio Muruato 1 , Jing Zou 2 , Xianwen Zhang 2 , Terry Juelich 3
, Jennifer K Smith 3 , Lihong Zhang 3 , Nathen Bopp 3 , Craig Schindewolf 1
, Michelle Vu 1 , Abigail Vanderheiden 4 5 6 , Daniele Swetnam 2
, Jessica A Plante 1 , Patricia Aguilar 3 , Kenneth S Plante 1 , Benhur Lee
7 , Scott C Weaver 1 8 , Mehul S Suthar 4 5 6 , Andrew L Routh 2 , Ping
Ren 3 , Zhiqiang Ku 9 , Zhiqiang An 9 , Kari Debbink 10 , Pei Yong Shi 2
8 , Alexander N Freiberg 3 8 , Vineet D Menachery 1 8
AFFILIATIONS
* 1 Department of Microbiology and Immunology, University of Texas Medical
Branch, Galveston, TX, USA.
* 2 Department of Biochemistry and Molecular Biology, University of Texas
Medical Branch, Galveston, TX, USA.
* 3 Department of Pathology, University of Texas Medical Branch, Galveston, TX,
USA.
* 4 Department of Pediatrics, Emory Vaccine Center, Atlanta, GA, USA.
* 5 Emory University School of Medicine, Atlanta, GA, USA.
* 6 Yerkes National Primate Research Center, Atlanta, GA, USA.
* 7 Icahn School of Medicine at Mount Sinai, New York, NY, USA.
* 8 Department of Institute for Human Infection and Immunity, University of
Texas Medical Branch, Galveston, TX, USA.
* 9 Texas Therapeutics Institute, Brown Foundation Institute of Molecular
Medicine, University of Texas Health Science Center at Houston, Houston, USA.
* 10 Bowie State University, Bowie, MD, USA.
* PMID: 32869021
* PMCID: PMC7457603
* DOI: 10.1101/2020.08.26.268854
Item in Clipboard
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UPDATE IN
* Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.
Johnson BA, Xie X, Bailey AL, Kalveram B, Lokugamage KG, Muruato A, Zou J,
Zhang X, Juelich T, Smith JK, Zhang L, Bopp N, Schindewolf C, Vu M,
Vanderheiden A, Winkler ES, Swetnam D, Plante JA, Aguilar P, Plante KS, Popov
V, Lee B, Weaver SC, Suthar MS, Routh AL, Ren P, Ku Z, An Z, Debbink K,
Diamond MS, Shi PY, Freiberg AN, Menachery VD. Johnson BA, et al. Nature.
2021 Mar;591(7849):293-299. doi: 10.1038/s41586-021-03237-4. Epub 2021 Jan
25. Nature. 2021. PMID: 33494095 Free PMC article.
ABSTRACT
SARS-CoV-2 has resulted in a global pandemic and shutdown economies around the
world. Sequence analysis indicates that the novel coronavirus (CoV) has an
insertion of a furin cleavage site (PRRAR) in its spike protein. Absent in other
group 2B CoVs, the insertion may be a key factor in the replication and
virulence of SARS-CoV-2. To explore this question, we generated a SARS-CoV-2
mutant lacking the furin cleavage site (ΔPRRA) in the spike protein. This mutant
virus replicated with faster kinetics and improved fitness in Vero E6 cells. The
mutant virus also had reduced spike protein processing as compared to wild-type
SARS-CoV-2. In contrast, the ΔPRRA had reduced replication in Calu3 cells, a
human respiratory cell line, and had attenuated disease in a hamster
pathogenesis model. Despite the reduced disease, the ΔPRRA mutant offered robust
protection from SARS-CoV-2 rechallenge. Importantly, plaque reduction
neutralization tests (PRNT 50 ) with COVID-19 patient sera and monoclonal
antibodies against the receptor-binding domain found a shift, with the mutant
virus resulting in consistently reduced PRNT 50 titers. Together, these results
demonstrate a critical role for the furin cleavage site insertion in SARS-CoV-2
replication and pathogenesis. In addition, these findings illustrate the
importance of this insertion in evaluating neutralization and other downstream
SARS-CoV-2 assays.
Importance: As COVID-19 has impacted the world, understanding how SARS-CoV-2
replicates and causes virulence offers potential pathways to disrupt its
disease. By removing the furin cleavage site, we demonstrate the importance of
this insertion to SARS-CoV-2 replication and pathogenesis. In addition, the
findings with Vero cells indicate the likelihood of cell culture adaptations in
virus stocks that can influence reagent generation and interpretation of a wide
range of data including neutralization and drug efficacy. Overall, our work
highlights the importance of this key motif in SARS-CoV-2 infection and
pathogenesis.
Article summary: A deletion of the furin cleavage site in SARS-CoV-2 amplifies
replication in Vero cells, but attenuates replication in respiratory cells and
pathogenesis in vivo. Loss of the furin site also reduces susceptibility to
neutralization in vitro .
CONFLICT OF INTEREST STATEMENT
Competing interests
X.X., V.D.M., and P.-Y.S. have filed a patent on the reverse genetic system and
reporter SARS-CoV-2. Other authors declare no competing interests.
FIGURES
Figure 1.. Distinct replication, spike cleavage, and…
Figure 1.. Distinct replication, spike cleavage, and competition for ΔPRRA.
A) Generation of a SARS-CoV-2…
Figure 1.. Distinct replication, spike cleavage, and competition for ΔPRRA.
A) Generation of a SARS-CoV-2 mutant deleting the furin cleavage site insertion
from the spike protein. B) Structure of the SARS-CoV-2 spike trimer with a focus
on the furin cleavage site (inset). Modeled using the SARS-CoV-1 trimer
structure (PDB 6ACD) (14), the WT SARS-CoV-2 trimer (grey) with SARS-CoV-2 PRRA
deletion mutant monomer overlay (red). The loop (inset), which is unresolved on
SARS-CoV-2 structures (AA 691–702), is shown in cyan on SARS-CoV-2 with the PRRA
sequence in blue. The loop region in the PRRA deletion mutant is shown in pink.
C) Viral titer from Vero E6 cells infected with WT SARS-CoV-2 (black) or ΔPRRA
(blue) at MOI 0.01 (N=3). D) Purified SARS-CoV, SARS-CoV-2 WT, and ΔPRRA virions
were probed with anti-spike or anti-nucleocapsid antibody. Full length (FL),
S1/S2 cleavage form, and S2’ annotated. E) Competition assay between SARS-CoV-2
WT (black) and ΔPRRA (blue) showing RNA percentage based on quantitative RT-PCR
at 50:50, 90:10, 10:90, 99:1, and 1:99 WT/ΔPRRA ratio (N=3 per group). F) Viral
titer from Calu3 2B4 cells infected with WT SARS-CoV-2 (black) or ΔPRRA (blue)
at MOI 0.01 (N=3). G) Purified SARS-CoV, SARS-CoV-2 WT, and ΔPRRA virions were
probed with anti-spike or anti-nucleocapsid antibody. Full length (FL), S1/S2
cleavage form, and S2’ annotated. P-values based on Student T-test and are
marked as indicated: *<0.05 ***<0.001.
Figure 2.. In vivo attenuation of ΔPRRA…
Figure 2.. In vivo attenuation of ΔPRRA mutant.
A) Primary SARS-CoV-2 challenge schematic. Two groups…
Figure 2.. In vivo attenuation of ΔPRRA mutant.
A) Primary SARS-CoV-2 challenge schematic. Two groups of male hamsters (N=4)
were challenged with 105 plaque forming units of either SARS-CoV-2 WT or ΔPRRA
mutant and evaluated over a 28 day time course for B) weight loss, C) disease
score, D) viral titer from nasal wash, and E) viral RNA from oral swabs. F)
Schematic for rechallenge of previously infected hamsters. Twenty eight DPI,
hamsters from SARS-CoV-2 WT and ΔPRRA were rechallenged with 105 PFU of
SARS-CoV-2 WT and evaluated for G) weight loss, H) disease score, I) viral titer
from nasal wash, and E) viral RNA from oral swabs. P-values based on Student
T-test and are marked as indicated: *<0.05 **<0.01 ***<0.001.
Figure 3.. Antibody neutralization of ΔPRRA mutant.
Figure 3.. Antibody neutralization of ΔPRRA mutant.
A) Schematic for SARS-CoV-2 ΔPRRA reporter virus expressing…
Figure 3.. Antibody neutralization of ΔPRRA mutant.
A) Schematic for SARS-CoV-2 ΔPRRA reporter virus expressing mNeonGreen (mNG)
gene in place of ORF7 equivalent to previously described WT SARS-CoV-2 mNG
virus. B) Plaque reduction neutralization (PRNT50) values as measured by changes
to mNG expression. PRNT50 values plotted as Log (1/serum dilution) with ΔPRRA on
Y axis and WT-SARS-CoV-2. C-E) Representative curves from C) low, D)
intermediate, and E) high neutralizing COVID-19 patient sera. F-H)
Neutralization curves from mAB-1 (F), mAB-2 (G), and mAB-3 (H), N=3.
See this image and copyright information in PMC
SIMILAR ARTICLES
* Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.
Johnson BA, Xie X, Bailey AL, Kalveram B, Lokugamage KG, Muruato A, Zou J,
Zhang X, Juelich T, Smith JK, Zhang L, Bopp N, Schindewolf C, Vu M,
Vanderheiden A, Winkler ES, Swetnam D, Plante JA, Aguilar P, Plante KS, Popov
V, Lee B, Weaver SC, Suthar MS, Routh AL, Ren P, Ku Z, An Z, Debbink K,
Diamond MS, Shi PY, Freiberg AN, Menachery VD. Johnson BA, et al. Nature.
2021 Mar;591(7849):293-299. doi: 10.1038/s41586-021-03237-4. Epub 2021 Jan
25. Nature. 2021. PMID: 33494095 Free PMC article.
* Abstracts of Presentations at the Association of Clinical Scientists 143rd
Meeting Louisville, KY May 11-14,2022.
[No authors listed] [No authors listed] Ann Clin Lab Sci. 2022
May;52(3):511-525. Ann Clin Lab Sci. 2022. PMID: 35777803 No abstract
available.
* Identification of Common Deletions in the Spike Protein of Severe Acute
Respiratory Syndrome Coronavirus 2.
Liu Z, Zheng H, Lin H, Li M, Yuan R, Peng J, Xiong Q, Sun J, Li B, Wu J, Yi
L, Peng X, Zhang H, Zhang W, Hulswit RJG, Loman N, Rambaut A, Ke C, Bowden
TA, Pybus OG, Lu J. Liu Z, et al. J Virol. 2020 Aug 17;94(17):e00790-20. doi:
10.1128/JVI.00790-20. Print 2020 Aug 17. J Virol. 2020. PMID: 32571797 Free
PMC article.
* QTQTN motif upstream of the furin-cleavage site plays a key role in
SARS-CoV-2 infection and pathogenesis.
Vu MN, Lokugamage KG, Plante JA, Scharton D, Bailey AO, Sotcheff S, Swetnam
DM, Johnson BA, Schindewolf C, Alvarado RE, Crocquet-Valdes PA, Debbink K,
Weaver SC, Walker DH, Russell WK, Routh AL, Plante KS, Menachery VD. Vu MN,
et al. Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2205690119. doi:
10.1073/pnas.2205690119. Epub 2022 Jul 26. Proc Natl Acad Sci U S A. 2022.
PMID: 35881779 Free PMC article.
* SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using
serum from acutely infected hospitalized COVID-19 patients.
Klimstra WB, Tilston-Lunel NL, Nambulli S, Boslett J, McMillen CM, Gilliland
T, Dunn MD, Sun C, Wheeler SE, Wells A, Hartman AL, McElroy AK, Reed DS,
Rennick LJ, Duprex WP. Klimstra WB, et al. J Gen Virol. 2020
Nov;101(11):1156-1169. doi: 10.1099/jgv.0.001481. Epub 2020 Aug 21. J Gen
Virol. 2020. PMID: 32821033 Free PMC article.
See all similar articles
REFERENCES
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Viruses 12(2020). - PMC - PubMed
2. 1. Dong E., Du H. & Gardner L. An interactive web-based dashboard to track
COVID-19 in real time. Lancet Infect Dis 20, 533–534 (2020). - PMC -
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