{"id":1419,"date":"2021-08-06T21:26:47","date_gmt":"2021-08-06T21:26:47","guid":{"rendered":"http:\/\/wp.cov19longhaulfoundation.org\/?p=1419"},"modified":"2021-08-06T21:26:47","modified_gmt":"2021-08-06T21:26:47","slug":"direct-activation-of-the-alternative-complement-pathway-by-sars-cov-2-spike-proteins-is-blocked-by-factor-d-inhibition","status":"publish","type":"post","link":"https:\/\/cov19longhaulfoundation.org\/?p=1419","title":{"rendered":"Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition"},"content":{"rendered":"\n<p>Authors: <a href=\"javascript:;\">Jia Yu<\/a>,\u00a0<a href=\"javascript:;\">Xuan Yuan<\/a>,\u00a0<a href=\"javascript:;\">Hang Chen<\/a>,\u00a0<a href=\"javascript:;\">Shruti Chaturvedi<\/a>,\u00a0<a href=\"javascript:;\">Evan M. Braunstein<\/a>,\u00a0<a href=\"javascript:;\">Robert A. Brodsky<\/a><\/p>\n\n\n\n<p style=\"font-size:24px\">Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous\/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1<em>PIGA<\/em>null target cells, and complement factor Bb is increased in the supernatant from spike protein\u2013treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.<\/p>\n\n\n\n<p class=\"has-large-font-size\">For More Information: <a href=\"https:\/\/ashpublications.org\/blood\/article\/136\/18\/2080\/463611\/Direct-activation-of-the-alternative-complement\" target=\"_blank\" rel=\"noreferrer noopener\">https:\/\/ashpublications.org\/blood\/article\/136\/18\/2080\/463611\/Direct-activation-of-the-alternative-complement<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Authors: Jia Yu,\u00a0Xuan Yuan,\u00a0Hang Chen,\u00a0Shruti Chaturvedi,\u00a0Evan M. Braunstein,\u00a0Robert A. Brodsky Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous\/arterial thrombosis, stroke, [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":1420,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[90,760,108,269,403,423,551,616],"tags":[],"class_list":["post-1419","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-clots-bleeds","category-complement-system","category-d-dimer","category-kidney","category-organ-failure","category-pathway","category-stroke","category-vascular-system"],"_links":{"self":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/1419","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=1419"}],"version-history":[{"count":0,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/1419\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/media\/1420"}],"wp:attachment":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1419"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=1419"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=1419"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}