SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июнь 7, 2021

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 123), non-COVID-19 ICU sepsis 25) and healthy controls 30). Severe acute respiratory syndrome 2 (SARS-CoV-2) RNA was detected plasma or serum (RNAemia) of when neutralizing antibody response low. RNAemia is associated higher 28-day mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age sex). comparable performance to the best protein predictors. Mannose binding lectin pentraxin-3 (PTX3), two activators complement pathway innate immune system, are positively mortality. Machine learning identified 'Age, RNAemia' PTX3' as binary signatures In longitudinal comparisons, have a distinct proteomic trajectory mortality, recovery many liver-derived proteins indicating survival. Finally, system galectin-3-binding (LGALS3BP) interaction partners SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake spike-induced cell-cell fusion vitro.

Язык: Английский

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Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study

The Lancet Rheumatology, Год журнала: 2021, Номер 4(3), С. e177 - e187

Опубликована: Дек. 24, 2021

Язык: Английский

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Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Июль 5, 2021

Early and persistent activation of complement is considered to play a key role in the pathogenesis COVID-19. Complement products orchestrate proinflammatory environment that might be critical for induction maintenance severe inflammatory response SARS-CoV-2 by recruiting cells cellular immune system sites infection shifting their state towards an phenotype. It precedes pathophysiological milestone events like cytokine storm, progressive endothelial injury triggering microangiopathy, further activation, causes acute respiratory distress syndrome (ARDS). To date, application antiviral drugs corticosteroids have shown efficacy early stages infection, but failed ameliorate disease severity patients who progressed COVID-19 pathology. This report demonstrates lectin pathway (LP) recognition molecules system, such as MBL, FCN-2 CL-11, bind S- N-proteins, with subsequent LP-mediated C3b C4b deposition. In addition, our results confirm underline N-protein binds directly LP- effector enzyme MASP-2 activates complement. Inhibition LP using inhibitory monoclonal antibody against effectively blocks activation. FACS analyses transfected HEK-293 expressing S protein robust LP-dependent deposition on cell surface which inhibited antibody. light present results, encouraging performance clinical candidate inhibitor Narsoplimab recently published trials, we suggest targeting provides unsurpassed window therapeutic treatment

Язык: Английский

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Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Pharmacological Reviews, Год журнала: 2021, Номер 73(2), С. 792 - 827

Опубликована: Март 9, 2021

The complement system was discovered at the end of 19th century as a heat-labile plasma component that "complemented" antibodies in killing microbes, hence name "complement." Complement is also part innate immune system, protecting host by recognition pathogen-associated molecular patterns. However, multifunctional far beyond infectious defense. It contributes to organ development, such sculpting neuron synapses, promoting tissue regeneration and repair, rapidly engaging synergizing with number processes, including hemostasis leading thromboinflammation. double-edged sword. Although it usually protects host, may cause damage when dysregulated or overactivated, systemic inflammatory reaction seen trauma sepsis severe coronavirus disease 2019 (COVID-19). Damage-associated patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, transplant dysfunction) chronic neurologic rheumatic activate complement, thereby increasing damaging inflammation. Despite long list diseases potential for ameliorating modulation, only few rare are approved clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust trials. evidence pathogenetic driver many more common suggests an opportunity future therapy, which, however, requires trials; one ongoing example COVID-19 disease. current review aims discuss pathogenesis pharmacological strategies treat these complement-targeted therapies.

Significance Statement

host's defense friend from invading pathogens, maintaining homeostasis. sword, since overactivated becomes enemy, damage, failure, and, worst case, death. A acute candidates avoid complement-dependent ranging well established possible large patient groups like pandemic 2019.

Язык: Английский

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Beyond neutralization: Fc-dependent antibody effector functions in SARS-CoV-2 infection

Nature reviews. Immunology, Год журнала: 2022, Номер 23(6), С. 381 - 396

Опубликована: Дек. 19, 2022

Язык: Английский

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COVID‐19: immunopathology, pathophysiological mechanisms, and treatment options

The Journal of Pathology, Год журнала: 2021, Номер 254(4), С. 307 - 331

Опубликована: Фев. 17, 2021

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures combat disease. Although most COVID-19 cases are characterised a mild, self-limiting course, considerable subset patients develop more condition, varying from pneumonia and distress (ARDS) multi-organ failure (MOF). Progression is thought occur as result complex interplay between multiple pathophysiological mechanisms, all which may orchestrate SARS-CoV-2 infection contribute organ-specific tissue damage. In this respect, dissecting currently available knowledge immunopathogenesis crucially important, not only improve our understanding its pathophysiology but also fuel rationale both novel repurposed treatment modalities. Various immune-mediated pathways during relevant in context, relate innate immunity, adaptive autoimmunity. Pathological findings specimens with provide valuable information regard well development evidence-based regimens. This review provides an updated overview main pathological changes observed within commonly affected organ systems, special emphasis on immunopathology. Current management strategies for include supportive care use or symptomatic drugs, such dexamethasone, remdesivir, anticoagulants. Ultimately, prevention key COVID-19, requires appropriate attenuate and, above all, effective vaccines. © 2021 The Authors. Journal Pathology published John Wiley & Sons, Ltd. behalf Society Great Britain Ireland.

Язык: Английский

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Crosstalk between the renin–angiotensin, complement and kallikrein–kinin systems in inflammation

Nature reviews. Immunology, Год журнала: 2021, Номер 22(7), С. 411 - 428

Опубликована: Ноя. 10, 2021

Язык: Английский

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Tipping the balance: intricate roles of the complement system in disease and therapy

Seminars in Immunopathology, Год журнала: 2021, Номер 43(6), С. 757 - 771

Опубликована: Окт. 26, 2021

Abstract The ability of the complement system to rapidly and broadly react microbial intruders, apoptotic cells other threats by inducing forceful elimination responses is indispensable for its role as host defense surveillance system. However, danger sensing versatility may come at a steep price patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition cell debris transplants, excessive activation damaged cells, autoimmune events, dysregulation response all induce effector functions that damage rather than protect tissue. Although has long been associated with disease, prevalence, impact complexity complement’s involvement in pathological processes only now becoming fully recognized. While rarely constitutes sole driver it acts initiator, contributor, and/or exacerbator numerous disorders. Identifying factors tip balance protective damaging effects particular disease continues prove challenging. Fortunately, however, molecular insight into functions, improved models, growing clinical experience led greatly understanding side. identification novel complement-mediated indications availability first therapeutic inhibitors also sparked renewed interest developing complement-targeted drugs, which meanwhile new approvals promising candidates late-stage evaluation. More century after description, truly reached clinic recent developments hold great promise diagnosis therapy alike.

Язык: Английский

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A guide to complement biology, pathology and therapeutic opportunity

Nature reviews. Immunology, Год журнала: 2023, Номер 24(2), С. 118 - 141

Опубликована: Сен. 5, 2023

Язык: Английский

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Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19

Annals of Internal Medicine, Год журнала: 2021, Номер 174(9), С. 1261 - 1269

Опубликована: Июль 12, 2021

New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects these drugs not known.To evaluate and HCQ all-cause, in-hospital mortality; degree respiratory failure inflammation; viral clearance in oropharynx.NOR-Solidarity is an independent, add-on, randomized controlled to WHO that included biobanking 3 months clinical follow-up (ClinicalTrials.gov: NCT04321616).23 hospitals Norway.Eligible were adults hospitalized confirmed SARS-CoV-2 infection.Between 28 March 4 October 2020, a total 185 randomly assigned 181 full analysis set. Patients received (n = 42), 52), standard care (SoC) 87).In addition primary end point Solidarity, study-specific outcomes oropharyngeal specimens, failure, inflammatory variables.No significant differences seen between groups mortality during hospitalization. There was marked decrease load oropharynx first week overall, similar decreases 10-day loads among remdesivir, HCQ, SoC groups. Remdesivir did affect variables plasma serum. lack associated symptom duration, level load, inflammation, presence antibodies against at hospital admittance.The had placebo group.Neither nor affected COVID-19.National Clinical Therapy Research Specialist Services, Norway.

Язык: Английский

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