Schematic model of SARS-CoV-2-induction of complement in respiratory epithelial cells. SARS-CoV-2 infects respiratory epithelial cells and induces an interferon response. IFNs signal via the IFN receptor to activate STAT1 via JAK1/2. STAT1 co-operates with RELA to induce transcription of IL6 and complement genes including C3, CFB, C1R and C1S. CFB acts as an alternative pathway C3 convertase to cleave C3 intracellularly to C3a and C3b. C3a engages C3aR and C3b engages CD46 on leukocyte subsets in the lungs to drive inflammation. These events can be pharmacologically targeted with antivirals (e.g., remdesivir), JAK-STAT inhibitors (e.g., ruxolitinib) and/or cell permeable complement inhibitors, including CFBi.
Creationist mode: |  |
News today of what a brilliant job the Intelligent [sic] Designer did with the SARS-VoV-2 virus which is designed to make us sick and die.
An international team of researchers working with Majid Kazemian, assistant professor in the departments of computer science and biochemistry at Purdue University, West Lafayette, Indian, USA, have discovered that a biochemical pathway, known as the immune complement system, is triggered in lung cells by the virus, which might explain why the disease is so difficult to treat.
According to the press release from Purdue University press release:
Within the last few years, scientists have discovered that the immune complement system – a complex system of small proteins produced by the liver that aids, or complements, the body’s antibodies in the fight against blood-borne pathogens – can work inside cells and not just in the bloodstream.The team's findings were published open access in the journal Science Immunology two days ago.
We observed that SARS-CoV2 infection of these lung cells causes expression of an activated complement system in an unprecedented way. This was completely unexpected to us because we were not thinking about activation of this system inside the cells, or at least not lung cells. We typically think of the complement source as the liver.Surprisingly, the study found that this response is triggered in cells of the small structures in the lungs known as alveoli, Kazemian said.
The second finding that I think is important is that the data suggest potential benefit for patients with severe COVID-19 from combinatorial use of an antiviral agent together with an agent that broadly targets complement production or activation within infected cells, These data are promising, but it is important to acknowledge that we carried out the drug treatment experiments in cell lines infected with SARS-CoV2. So, in and of themselves they should not be used to direct treatment of patients.
Majid Kazemian, Joint lead author
Assistant professor
Departments of Computer Science and Biochemistry
Purdue University,
West Lafayette, Indiana, USA
“We observed that SARS-CoV2 infection of these lung cells causes expression of an activated complement system in an unprecedented way,” Kazemian said. “This was completely unexpected to us because we were not thinking about activation of this system inside the cells, or at least not lung cells. We typically think of the complement source as the liver.”
Claudia Kemper, senior investigator and chief of the Complement and Inflammation Research Section of the National Institutes of Health, was among the first to characterize novel roles of the complement system in the immune system. She agreed these latest findings are surprising.
“The complement system is traditionally considered a liver-derived and blood-circulating sentinel system that protects the host against infections by bacteria, fungi and viruses,” she said. “It is unexpected that in the setting of a SARS-CoV2 infection, this system rather turns against the host and contributes to the detrimental tissue inflammation observed in severe COVID-19. We need to think about modulation of this intracellular, local, complement when combating COVID-19.”
The complement system is traditionally considered a liver-derived and blood-circulating sentinel system that protects the host against infections by bacteria, fungi and viruses. It is unexpected that in the setting of a SARS-CoV2 infection, this system rather turns against the host and contributes to the detrimental tissue inflammation observed in severe COVID-19. We need to think about modulation of this intracellular, local, complement when combating COVID-19.Dr. Ben Afzali, an Earl Stadtman Investigator of the National Institute of Health’s National Institute of Diabetes and Digestive and Kidney Diseases, said there are now indications that this has implications for difficulties in treating COVID-19.
A currently unexplored and possibly therapeutically interesting aspect of our observations is also whether the virus utilizes local complement generation and activation to its benefit, for example, for the processes underlying cell infection and replication,
Claudia Kemper, Senior investigator
Complement and Inflammation Research Section (CIRS),
National Heart, Lung, and Blood Institute (NHLBI),
National Institutes of Health (NIH),
Bethesda, MD, USA.
“These findings provide important evidence showing not only that complement-related genes are amongst the most significant pathways induced by SARS-CoV2 in infected cells, but also that activation of complement occurs inside of lung epithelial cells, i.e., locally where infection is present,” he said.
“This may explain why targeting the complement system outside of cells and in the circulation has, in general, been disappointing in COVID-19. We should probably consider using inhibitors of complement gene transcription or complement protein activation that are cell permeable and act intracellularly instead.”
Afzali cautions that appropriate clinical trials should be conducted to establish whether a combination treatment provides a survival benefit. “The second finding that I think is important is that the data suggest potential benefit for patients with severe COVID-19 from combinatorial use of anThese findings provide important evidence showing not only that complement-related genes are amongst the most significant pathways induced by SARS-CoV2 in infected cells, but also that activation of complement occurs inside of lung epithelial cells, i.e., locally where infection is present. This may explain why targeting the complement system outside of cells and in the circulation has, in general, been disappointing in COVID-19. We should probably consider using inhibitors of complement gene transcription or complement protein activation that are cell permeable and act intracellularly instead.antiviral agent together with an agent that broadly targets complement production or activation within infected cells,” he said. “These data are promising, but it is important to acknowledge that we carried out the drug treatment experiments in cell lines infected with SARS-CoV2. So, in and of themselves they should not be used to direct treatment of patients."
Dr. Ben Afzali, Joint lead author
Immunoregulation Section, Kidney Diseases Branch,
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),
NIH, Bethesda, MD, USA.
Kemper added that the unexpected findings bring more questions.
“A currently unexplored and possibly therapeutically interesting aspect of our observations is also whether the virus utilizes local complement generation and activation to its benefit, for example, for the processes underlying cell infection and replication,” she said.
About Purdue University
Purdue University is a top public research institution developing practical solutions to today’s toughest challenges. Ranked the No. 5 Most Innovative University in the United States by U.S. News & World Report, Purdue delivers world-changing research and out-of-this-world discovery. Committed to hands-on and online, real-world learning, Purdue offers a transformative education to all. Committed to affordability and accessibility, Purdue has frozen tuition and most fees at 2012-13 levels, enabling more students than ever to graduate debt-free. See how Purdue never stops in the persistent pursuit of the next giant leap at https://purdue.edu/.
So, there we have it. Whoever designed the SARS-CoV-2 virus even designed it so it would turn the immune defences it also allegedly designed to protect us from its designs, against us. Another example of the lengths creationism's Intelligent [sic] Designer went to to create the worst pandemic to befall mankind since the 1919 'Spanish' flu. No wonder Creationists think it is such a brilliant designer and are at the same time, in awe of it and absolutely terrified of what it can do to them if it so decides to.Abstract
Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-κB as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines, but did not affect NF-κB-regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-κB-signaling could potentially have clinical application for severe COVID-19.
Yan, Bingyu; Freiwald, Tilo; Chauss, Daniel; Wang, Luopin; West, Erin; Mirabelli, Carmen; Zhang, Charles J; Nichols, Eva-Maria; Malik, Nazish; Gregory, Richard; Bantscheff, Marcus; Ghidelli-Disse, Sonja; Kolev, Martin; Frum, Tristan; Spence, Jason R; Sexton, Jonathan Z.; Alysandratos, Konstantinos D.; Kotton, Darrell N.; Pittaluga, Stefania; Bibby, Jack; Niyonzima, Nathalie; Olson, Matthew R; Kordasti, Shahram; Portilla, Didier; Wobus, Christiane E; Laurence, Arian; Lionakis, Michail S; Kemper, Claudia; Afzali, Behdad; Kazemian, Majid
SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation
Science Immunology 6(58), eabg0833 DOI: 10.1126/sciimmunol.abg0833
Copyright: © 2021 The authors. Published by the American Association for the Advancement of Science
Open access
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
Creationist mode: |  |
Back in the real world, I'm still waiting for a creationist to explain why they so vehemently reject the scientific evidence for evolution by natural selection when that is the only explanation for parasites such as the SARS-CoV-2 virus that doesn't leave their favourite deity sounding like a malevolent, pestilential, misanthropic, sadist who hates its creation and is forever designing ways to make it suffer and die. According to Johns Hopkins University Coronavirus Resource Centre today, to date, there have been 134,305,119 cases of Covid-19 with 2,907,871 deaths, worldwide. Approximately 25% of these have been in the USA.
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