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PMC:7293470 JSONTXT 17 Projects

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Id Subject Object Predicate Lexical cue
T1 0-20 Sentence denotes Surviving the storm:
T2 21-42 Sentence denotes Dealing with COVID-19
T3 44-364 Sentence denotes Although most of the 4.7 million individuals infected to date with COVID-19 (SARS-CoV-2) worldwide remain asymptomatic or have transient symptoms followed by complete recovery, approximately 316 thousand (6.7%) have died [1], most often from acute respiratory distress syndrome (ARDS) leading to organ failure and death.
T4 365-656 Sentence denotes The components that contribute to morbidity include forceful activation of both innate and adaptive immune pathways that release a cytokine storm which causes extensive damage to lung alveolar endothelium, oxygen insufficiency and downstream bystander damage to the heart, liver and kidneys.
T5 657-890 Sentence denotes Recent publications predicted immunological processes anticipated in COVID-19 patients based on previous findings in severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MARS) and sepsis patients [2], [3], [4].
T6 891-1340 Sentence denotes To reiterate, upon binding to the ACE2 (angiotensin-converting enzyme-2) receptor via its spike (S) protein, the SARS-CoV-2 virus infects alveolar epithelial cells, triggering the complement cascade and inducing fibrin deposition leading to platelet aggregation and macrophage activation resulting in metabolic changes in arachidonic acid with release of thromboxane A2 and secretion of IL-1β, IL-6, TNF-α, platelet activating factor & nitric oxide.
T7 1341-1581 Sentence denotes In addition infection induces neutrophil activation, aggregation and degranulation with release of O2 radicals and proteases and CCR4+CCR6+Th17 cell activation with secretion of IL-2, IL-7, IFN-γ, G-CSF and chemokines CCL2, CCL3 and CXCl10.
T8 1582-1708 Sentence denotes This focused collection of highly inflammatory factors in the lungs causes serious endothelial damage and respiratory failure.
T9 1709-1867 Sentence denotes As well, ACE2 is expressed on heart, liver and kidney cells that may also be infected and gravely damaged by SARS-CoV-2, leading to fatal multi-organ failure.
T10 1868-2051 Sentence denotes In addition to current approaches such as glucocorticoids for treating advanced COVID-19 patients, there may be other drug combinations that could be helpful, some being bifunctional.
T11 2052-2346 Sentence denotes As relevant examples reviewed in [5], pharmacological drugs for treatment of patients with asthma and/or chronic obstructive pulmonary disease (COPD) were developed to include both β2-agonists to relax airway smooth muscle constriction and muscarinic receptor antagonists to block M3 receptors.
T12 2347-2503 Sentence denotes Another bifunctional drug was formulated to antagonize the receptors for platelet-activating factor and histamine, and mast cell secretion-blocking effects.
T13 2504-2648 Sentence denotes A third anti-inflammatory drug combined an antagonist for the thromboxane receptor and cysteinyl-leukotriene antagonists into the same molecule.
T14 2649-2895 Sentence denotes A bifunctional antibody construct was also developed for IL-4 and IL-13 to reduce the IL-4-dependent rise in serum IgE and IL-13-dependent airway hyperresponsiveness, lung inflammation, mucin gene expression and serum chitinase responses in mice.
T15 2896-3060 Sentence denotes In this vein, bifunctional immunotherapeutic approaches could be developed for treatment of the cytokine storm in COVID-19 patients with ARDS at high risk of death.
T16 3061-3408 Sentence denotes Proven and developing therapies that downregulate receptors for IL-1β, TNF-α, IL-6 and IL-2 as well as those which block macrophage migration inhibitory factor (MIF) and its homolog MIF2 through CD74 and potentially CXCR2&4 for MIF are all potential inhibitors of cytokine storm effects and could be combined or designed for bifunctional activity.
T17 3409-3589 Sentence denotes We are developing a second generation bifunctional drug called DRhQ that can simultaneously bind to and inhibit both the TCR and CD74 through distinct regions of the construct [6].
T18 3590-3818 Sentence denotes DRhQ is comprised of the HLA-DRα1 domain with an L50Q amino acid substitution (to enhance binding affinity for CD74) linked to an autoantigen peptide (myelin oligodendroglial cell glycoprotein, i.e. MOG-35-55 peptide) (Fig. 1 ).
T19 3819-4046 Sentence denotes DRhQ was derived from soluble MHC Class II α1-β1-antigenic peptide constructs originally designed to ligate specific T cell receptors as the distal components of the trimolecular complex (called Recombinant TCR ligands – RTLs).
T20 4047-4366 Sentence denotes As partial TCR agonists these constructs, containing various disease-associated MHC and antigenic peptide components, could indeed inhibit MHC-restricted antigen specific T cells, but translation of RTL1000 for human use in a Phase 1 clinical trial (showing safety and tolerability) required MHC-matched recipients [7].
T21 4367-4656 Sentence denotes Thus, the simpler DRhQ construct was designed, retaining just the conserved-in-human DRα1 domain (without the polymorphic HLA-DRβ1 domain) linked to the MOG-35-55 peptide extension, with the added benefit that it can be administered to all recipients without need for tissue type matching.
T22 4657-4870 Sentence denotes This has enabled use of the DRα1-MOG-35-55 construct to reverse ongoing neuroinflammation and disease signs in animal models of multiple sclerosis, stroke, methamphetamine disorders and traumatic brain injury [8].
T23 4871-5222 Sentence denotes These and other studies ([9], [10], [11] & unpublished data) revealed down-regulation of multiple proinflammatory components driven by both innate and adaptive immune responses that also contribute to the SARS-CoV-2 cytokine storm, including complement receptor C5aR1, platelet activation, IL-1β, IL-2, IL-6, TNF-α, CCR2 (receptor for CCL2) and CXCR2.
T24 5223-5510 Sentence denotes Of further importance, a partial HLA-DP RTL construct could inhibit activated pleural T cell infiltrates from patients with beryllium-induced lung fibroma [12], suggesting more-directly-relevant activity that could be potentially beneficial as a treatment of COVID-19 patients with ARDS.
T25 5511-5602 Sentence denotes Fig. 1 Dual activities of DRhQ that could block the “Cytokine Storm” induced by SARS-CoV-2.
T26 5603-5753 Sentence denotes DRhQ is a bifunctional drug comprised of the HLA-DRα1 domain covalently linked to human myelin oligodendroglial cell glycoprotein (MOG)-35-55 peptide.
T27 5754-6013 Sentence denotes Due to its unique design, DRhQ can bind to and inhibit both T cell receptors and the MHC “invariant” chain, CD74, that serves as the receptor for the proinflammatory homologs, MIF and MIF2, resulting in blockade of multiple contributors to the Cytokine Storm.
T28 6014-6025 Sentence denotes DRhQ image:
T29 6026-6113 Sentence denotes Green = DRα1L50Q domain; Dark green line = linker; Black = MOG-35-55 peptide extension.
T30 6114-6222 Sentence denotes Development of new generation immunologically based cytokine storm inhibitors remains an important endeavor.
T31 6223-6478 Sentence denotes Even if a successful vaccine is developed for COVID-19 patients, there will be ongoing mortality in vulnerable populations after vaccination as has been observed in flu virus and other current or future coronavirus infections as well as those with sepsis.
T32 6479-6663 Sentence denotes In these conditions, resolution or chronicity of disease depends upon the strength of regulatory immune processes which appear to be compromised in COVID-19 patients that develop ARDS.
T33 6664-6722 Sentence denotes To this end, the DRhQ construct could lend a helping hand.
T34 6724-6739 Sentence denotes Acknowledgement
T35 6740-6842 Sentence denotes The authors wish to thank Ashley Headrick for help in preparing and submitting the commentary article.
T36 6844-6851 Sentence denotes Funding
T37 6852-7265 Sentence denotes This work was funded by the 10.13039/100000738Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Awards 2I01 BX000226 and IMMA-010-19F (AAV), Senior Research Career Scientist Award 1IK6BX004209 (AAV) and the 10.13039/100000060National Institute of Allergy and Infectious Diseases award R44AI122574 (AAV).
T38 7266-7365 Sentence denotes The contents do not represent the views of the Department of Veterans Affairs or the US Government.
T39 7367-7401 Sentence denotes Availability of data and materials
T40 7402-7526 Sentence denotes The datasets used and/or analyzed during previous studies are available from the corresponding author on reasonable request.
T41 7528-7548 Sentence denotes Author contributions
T42 7549-7624 Sentence denotes The commentary article was written, edited and reviewed by AAV, HO and RMR.
T43 7625-7673 Sentence denotes All authors read and approved the final article.
T44 7675-7694 Sentence denotes Competing Interests
T45 7695-7911 Sentence denotes Drs. Vandenbark, Offner, Meza-Romero, and OHSU have a significant financial interest in Artielle ImmunoTherapeutics, Inc., a company that may have a commercial interest in the results of this research and technology.
T46 7912-8069 Sentence denotes This potential conflict of interest has been reviewed and managed by the OHSU and VA Portland Health Care System Conflict of Interest in Research Committees.