The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine ...residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.
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•The spike protein of SARS-CoV-2 harbors a multibasic S1/S2 site•The host cell protease furin cleaves the SARS-CoV-2 spike protein at the S1/S2 site•Cleavage at the S1/S2 site is essential for spike-driven viral entry into lung cells
Coronavirus spike proteins are activated by host cell proteases. Hoffmann and colleagues show that the pandemic SARS-CoV-2 harbors a highly cleavable S1/S2 cleavage site not found in closely related coronaviruses. Cleavage at this site is mediated by furin and is required for viral entry into human lung cells.
Reactive oxygen species (ROS) are created in cells during oxidative phosphorylation by the respiratory chain in the mitochondria or by the family of NADPH oxidase (NOX) complexes. The first ...discovered and most studied of these complexes, NOX2, mediates the oxidative burst in phagocytes. ROS generated by NOX2 are dreadful weapons: while being essential to kill ingested pathogens they can also cause degenerative changes on tissue if production and release are not balanced by sufficient detoxification. In the last fifteen years evidence has been accumulating that ROS are also integral signaling molecules and are important for regulating autoimmunity and immune-mediated inflammatory diseases. It seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity (the bright side of ROS) and minimizes collateral tissue damage (the dark side of ROS). Herein, we review studies from rodent models of arthritis, lupus, and neurodegenerative diseases that show that low NOX2-derived ROS production is linked to disease and elaborate on the underlying cellular and molecular mechanisms and the translation of these results to disease in humans.
•ROS are created during oxidative phosphorylation and by NADPH oxidase complexes.•ROS-induced signaling regulates immune reactions and can prevent autoimmunity.•Prolonged and uncontrolled ROS production can cause collateral tissue damage.•Temporally and spatial balance of ROS levels is essential to sustain homeostasis.
While there are numerous studies showing that neutrophil extracellular traps (NETs) contribute to autoimmune inflammation and cause bystander tissue injury, human individuals with genetic impairments ...in NET formation curiously often suffer from exacerbated autoimmune diseases and/or chronic inflammatory conditions. These findings are confirmed in some mouse models of systemic lupus erythematosus (SLE) and gouty arthritis, where an absence of neutrophils or impairment of NET formation leads to exacerbation of autoimmunity and chronic inflammation. Thus, aside from their role as archetypical pro-inflammatory cells, neutrophils in general, and NETs in particular, can also interrupt the self-amplifying loop of cell activation and cell recruitment that characterizes neutrophilic inflammation. Here, we review the current state-of-the-science regarding anti-inflammatory and immune-regulatory action of NETs. We give an overview about the mechanistic involvement of NET-associated neutrophil serine proteases and suggest how tailored induction of NET formation could be exploited for the treatment of chronic autoinflammatory disorders.
Skyrmions in magnetic materials offer attractive perspectives for future spintronic applications since they are topologically stabilized spin structures on the nanometre scale, which can be ...manipulated with electric current densities that are by orders of magnitude lower than those required for moving domain walls. So far, they were restricted to bulk magnets with a particular chiral crystal symmetry greatly limiting the number of available systems and the adjustability of their properties. Recently, it has been experimentally discovered that magnetic skyrmion phases can also occur in ultra-thin transition metal films at surfaces. Here we present an understanding of skyrmions in such systems based on first-principles electronic structure theory. We demonstrate that the properties of magnetic skyrmions at transition metal interfaces such as their diameter and their stability can be tuned by the structure and composition of the interface and that a description beyond a micromagnetic model is required in such systems.
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses ...depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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•SARS-CoV-2 uses the SARS-CoV receptor ACE2 for host cell entry•The spike protein of SARS-CoV-2 is primed by TMPRSS2•Antibodies against SARS-CoV spike may offer some protection against SARS-CoV-2
The emerging SARS-coronavirus 2 (SARS-CoV-2) threatens public health. Hoffmann and coworkers show that SARS-CoV-2 infection depends on the host cell factors ACE2 and TMPRSS2 and can be blocked by a clinically proven protease inhibitor. These findings might help to establish options for prevention and treatment.
•Stromal cells are of mesenchymal origin and provide the structure and support the function of organs.•Multiomics has unveiled the origins and previously unknown functional diversity of stromal ...cells.•Stromal cells such as fibroblasts are now considered members of the innate immune system.•Specific therapeutic targeting of pathogenic fibroblast subsets shows promise for curing inflammatory diseases.
In the last fifteen years it has become apparent that tissue-resident mesenchymal cells such as fibroblasts, which are the structural elements of all organs, play a cardinal role in the pathology of immune-mediated inflammatory diseases. We now know that all fibroblasts originate from universal pan-organ cellular ancestors and that they are diversified into more specific subsets according to the functional needs of their home tissue-and its activation state. In arthritis, a plethora of activated joint-resident and migrating fibroblast types have been recently described that are central for pathogenesis and persistence of inflammatory joint-disease. Here we provide a current overview on the multiple inflammatory and immune-related functions of fibroblasts and how they could be curbed to induce long-lasting abatement of disease.
Hyperactivated local tissue is a cardinal feature of immune-mediated inflammatory diseases of various organs such as the joints, the gut, the skin, or the lungs. Tissue-resident structural and ...stromal cells, which get primed during repeated or long-lasting bouts of inflammation form the basis of this sensitization of the tissue. During priming, cells change their metabolism to make them fit for the heightened energy demands that occur during persistent inflammation. Epigenetic changes and, curiously, an activation of intracellularly expressed parts of the complement system drive this metabolic invigoration and enable tissue-resident cells and infiltrating immune cells to employ an arsenal of inflammatory functions, including activation of inflammasomes. Here we provide a current overview on complement activation and inflammatory transformation in tissue-occupying cells, focusing on fibroblasts during arthritis, and illustrate ways how therapeutics directed at complement C3 could potentially target the complosome to unprime cells in the tissue and induce long-lasting abatement of inflammation.
•Tissue-resident cells and infiltrating immune cells shape local inflammatory responses.•The intracellularly complement system (aka the complosome) controls cell metabolism and function.•Mechanistic and structural details of the complosome are in the focus of current research.•C3-inhibiting peptides are promising candidates to curb tissue inflammation without immune suppression.
The rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike protein raised concerns that the ...virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent patients or individuals vaccinated with the BioNTech-Pfizer vaccine (BNT162b2) with 12- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1 (Astra Zeneca-Oxford)/BNT162b2 vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.
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•Omicron uses human and animal ACE2 for host cell entry•Omicron is resistant against neutralization by several therapeutic antibodies•Omicron efficiently evades antibodies from infected or 2 × BNT-vaccinated patients•Omicron moderately evades antibodies induced by 3 × BNT or heterologous vaccination
The SARS-CoV-2 Omicron variant is rapidly spreading worldwide and a public health concern. Experiments show that this variant is resistant against several therapeutic antibodies for COVID-19 and efficiently evades antibodies induced upon infection or double BNT162b2 vaccination, but not triple BNT162b2 or ChAdOx1/BNT162b2 vaccination.
The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. ...However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from BNT162b2-vaccinated individuals. These results suggest that SARS-CoV-2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.
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•B.1.1.7, B.1.351, and P.1 do not show augmented host cell entry•Entry inhibitors under clinical evaluation block all variants•B.1.351 and P.1 can escape from therapeutic antibodies•B.1.351 and P.1 evade antibodies induced by infection and vaccination
Comparison of the SARS-CoV-2 variants B.1.1.7, B.1.351, and P.1 shows that inhibitors under clinical evaluation are still effective in blocking entry, though the B.1.351 and P.1 variants evade antibody responses induced upon infection as well as vaccination and evade certain therapeutic antibodies.
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