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SARS-CoV-2 proteins

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    Targeting of the NLRP3 HGNC Inflammasome for early COVID-19 MESHD

    Authors: Carlo Marchetti; Kara Mould; Isak W. Tengesdal; William J. Janssen; Charles A. Dinarello

    doi:10.1101/2021.02.24.432734 Date: 2021-02-24 Source: bioRxiv

    Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus MESHD 2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1 HGNC are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1{beta}, triggering both local as well as systemic inflammation MESHD. This cascade of inflammatory cytokines in patients with COVID-19 MESHD is termed Cytokine Release Syndrome ( CRS MESHD), and is associated with poor outcomes and death MESHD. Many studies reveal that blocking IL-1{beta HGNC} activities in COVID-19 MESHD patients reduces disease severity and deaths MESHD. Here we report highly significant circulating levels of IL-1{beta HGNC}, IL-1 Receptor antagonist HGNC, IL-6 HGNC, TNF HGNC, IL-10 HGNC and soluble urokinase plasminogen activator receptor HGNC in COVID-19 MESHD patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 ( NLRP3 HGNC) early in the infection. We observed increased NLRP3 HGNC gene expression in myeloid cells correlated with IL-1{beta HGNC} gene expression and also with elevated circulating IL-1{beta HGNC} levels. We conclude that early in SARS-CoV-2 infection MESHD, NLRP3 HGNC activation takes place and initiates the CRS. Thus, NLRP3 HGNC is a target to reduce the organ damage of inflammatory cytokines of the CRS.

    Cerebrospinal fluid in COVID-19 MESHD neurological complications: no cytokine storm or neuroinflammation.

    Authors: Maria A. Garcia; Paula V. Barreras; Allie Lewis; Gabriel Pinilla; Lori J. Sokoll; Thomas Kickler; Heba Mostafa; Mario Caturegli; Abhay Moghekar; Kathryn C. Fitzgerald; - Hopkins Neuro-COVID-19 Group; Carlos A Pardo

    doi:10.1101/2021.01.10.20249014 Date: 2021-01-12 Source: medRxiv

    BACKGROUND. Neurological complications MESHD occur in COVID-19 MESHD. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 MESHD subjects with neurological complications MESHD and determine presence of neuroinflammatory changes implicated in pathogenesis. METHODS. Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 MESHD subjects with neurological complications categorized by diagnosis ( stroke MESHD, encephalopathy MESHD, headache MESHD) and illness severity (critical, severe, moderate, mild). COVID-19 MESHD CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders MESHD and stroke MESHD controls (n=82). Cytokines ( IL-6 HGNC, TNF-alpha HGNC, IFN-gamma HGNC, IL-10 HGNC, IL-12p70, IL-17A HGNC), inflammation MESHD and coagulation markers (high-sensitivity- C Reactive Protein HGNC [hsCRP], ferritin, fibrinogen HGNC, D-dimer, Factor VIII) and neurofilament light chain ( NF-L HGNC), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA. RESULTS. CSF from COVID-19 MESHD subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis MESHD or specific increases in pro-inflammatory markers or cytokines ( IL-6 HGNC, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 MESHD subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines ( IL-6 HGNC, TNF-alpha HGNC;, IL-12p70) and IL-10 HGNC in CSF of COVID-19 MESHD and non- COVID-19 MESHD stroke MESHD subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke MESHD and critical COVID-19 MESHD. CSF-hsCRP was present almost exclusively in COVID-19 MESHD cases. CONCLUSION. The paucity of neuroinflammatory changes in CSF of COVID-19 MESHD subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation MESHD in pathogenesis of neurological complications in COVID-19 MESHD. Elevated CSF-NF-L indicates neuroaxonal injury MESHD in COVID-19 MESHD cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.

    Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection MESHD

    Authors: Nina Le Bert; Hannah E Clapham; Anthony T Tan; Wan Ni Chia; Christine YL Tham; Jane M Lim; Kamini Kunasegaran; Linda Tan; Charles-Antoine Dutertre; Nivedita Shankar; Joey ME Lim; Louisa Jin Sun; Marina Zahari; Zaw M Tun; Vishakha Kumar; Beng Lee Lim; Siew Hoon Lim; Adeline Chia; Yee-Joo Tan; Paul Anantharajah Tambyah; Shirin Kalimuddin; David CB Lye; Jenny GH Low; Lin-Fa Wang; Wei Yee Wan; Li Yang Hsu; Antonio Bertoletti; Clarence C Tam; Martina Recalde; Paula Casajust; Jitendra Jonnagaddala; Vignesh Subbian; David Vizcaya; Lana YH Lai; Fredrik Nyberg; Daniel R. Morales; Jose D. Posada; Nigam H. Shah; Mengchun Gong; Arani Vivekanantham; Aaron Abend; Evan P Minty; Marc A. Suchard; Peter Rijnbeek; Patrick B Ryan; Daniel Prieto-Alhambra

    doi:10.1101/2020.11.25.399139 Date: 2020-11-27 Source: bioRxiv

    The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between their antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 infection MESHD without symptoms or disease could reveal non-pathological yet protective characteristics. We therefore compared the quantity and function of SARS-CoV-2-specific T cells in a cohort of asymptomatic individuals (n=85) with that of symptomatic COVID-19 MESHD patients (n=76), at different time points after antibody seroconversion. We quantified T cells reactive to structural proteins (M PROTEIN, NP and Spike) using ELISpot assays, and measured the magnitude of cytokine secretion ( IL-2 HGNC, IFN-{gamma HGNC}, IL-4 HGNC, IL-6 HGNC, IL-1{beta}, TNF- and IL-10) in whole blood following T cell activation with SARS-CoV-2 peptide pools as a functional readout. Frequencies of T cells specific for the different SARS-CoV-2 proteins in the early phases of recovery were similar between asymptomatic and symptomatic individuals. However, we detected an increased IFN-{gamma HGNC} and IL-2 HGNC production in asymptomatic compared to symptomatic individuals after activation of SARS-CoV-2-specific T cells in blood. This was associated with a proportional secretion of IL-10 HGNC and pro-inflammatory cytokines ( IL-6 HGNC, TNF HGNC- and IL-1{beta} HGNC) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2 infected MESHD individuals are not characterized by a weak antiviral immunity; on the contrary, they mount a robust and highly functional virus-specific cellular immune response. Their ability to induce a proportionate production of IL-10 HGNC might help to reduce inflammatory events during viral clearance.

    Anakinra To Prevent Respiratory Failure In COVID-19 MESHD

    Authors: Evdoxia Kyriazopoulou; Periklis Panagopoulos; Simeon Metallidis; George Dalekos; Garyfallia Poulakou; Nikolaos Gatselis; Eleni Karakike; Maria Saridaki; Georgia Loli; Aggelos Stefos; Danai Prasianaki; Sarah Georgiadou; Olga Tsachouridou; Vasileios Petrakis; Konstantinos Tsiakos; Maria Kosmidou; Vassiliki Lygoura; Maria Dareioti; Haralampos Milionis; Ilias C Papanikolaou; Karolina Akinosoglou; Dimitra-Melia Myrodia; Areti Gravani; Aliki Stamou; Theologia Gkavogianni; Konstantina Katrini; Theodoros Marantos; Ioannis P Trontzas; Konstantinos Syrigos; Lukas Chatzis; Stamatios Chatzis; Nikolaos Vechlidis; Christina Avgoustou; Stamatios Chalvatzis; Miltiades Kyprianou; Jos WM van der Meer; jesper eugen-olsen; Mihai Netea; Evangelos Giamarellos-Bourboulis

    doi:10.1101/2020.10.28.20217455 Date: 2020-10-29 Source: medRxiv

    Introduction The management of pneumonia MESHD caused by SARS-CoV-2 should rely on early recognition of the risk for progression to severe respiratory failure MESHD ( SRF HGNC SRF MESHD) and its prevention. We investigated if early suPAR (soluble urokinase plasminogen activator receptor HGNC)-guided anakinra treatment could prevent COVID-19 MESHD-assocated SRF HGNC. Methods In this open-label prospective trial, 130 patients admitted with SARS-CoV-2 pneumonia SARS-CoV-2 MESHD and suPAR levels [≥]6 g/l were assigned to subcutaneous anakinra 100mg once daily for 10 days. The primary outcome was the incidence of SRF MESHD SRF HGNC at day 14. Secondary outcomes were 30-day mortality, changes in sequential organ failure assessment (SOFA) score, of cytokine-stimulation pattern and of circulating inflammatory mediators. Equal number of propensity score-matched comparators for comorbidities, severity on admission and standard-of care (SOC) were studied. Results The incidence of SRF MESHD SRF HGNC was 22.3% (95% CI, 16.0-30.2%) among anakinra-treated patients and 59.2% (95% CI, 50.6-67.3%; P: 4.6 x 10-8) among SOC comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46). 30-day mortality was 11.5% (95% CI, 7.1-18.2%) and 22.3% (95% CI, 16.0-30.2%) respectively (hazard ratio 0.49; 95% CI 0.25-0.97%; P: 0.041). Anakinra treatment was associated with decrease in SOFA score and in circulating interleukin (IL)-6 HGNC, sCD163 and sIL2-R; the serum IL-10 HGNC/ IL-6 HGNC ratio on day 7 was inversely associated with the change in SOFA score. Duration of stay at the intensive care unit and at hospital was shortened compared to the SOC group; the cost of hospitalization was decreased. Conclusions Early suPAR-guided anakinra treatment is associated with decrease of the risk for SRF MESHD SRF HGNC and restoration of the pro- /anti-inflammatory balance.

    Monocytes and macrophages, targets of SARS-CoV-2: the clue for Covid-19 MESHD immunoparalysis

    Authors: Asma Boumaza; Laetitia Gay; Soraya Mezouar; Aissatou Bailo Diallo; Moise Michel; Benoit Desnues; Didier Raoult; Bernard LA SCOLA; Philippe Halfon; Joana Vitte; Daniel Olive; Jean-Louis Mege

    doi:10.1101/2020.09.17.300996 Date: 2020-09-17 Source: bioRxiv

    To date, the Covid-19 pandemic MESHD Covid-19 pandemic MESHD affected more than 18 million individuals and caused more than 690, 000 deaths. Its clinical expression is pleiomorphic and severity is related to age and comorbidities such as diabetes MESHD and hypertension MESHD. The pathophysiology of the disease relies on aberrant activation of immune system and lymphopenia MESHD that has been recognized as a prognosis marker. We wondered if the myeloid compartment was affected in Covid-19 MESHD and if monocytes and macrophages could be infected by SARS-CoV-2. We show here that SARS-CoV-2 efficiently infects MESHD monocytes and macrophages without any cytopathic effect. Infection was associated with the secretion of immunoregulatory cytokines ( IL-6 HGNC, IL-10 HGNC, TGF-b HGNC) and the induction of a macrophagic specific transcriptional program characterized by the upregulation of M2-type molecules. In addition, we found that in vitro macrophage polarization did not account for the permissivity to SARS-CoV-2, since M1- and M2-type macrophages were similarly infected. Finally, in a cohort of 76 Covid-19 MESHD patients ranging from mild to severe clinical expression, all circulating monocyte subsets were decreased, likely related to massive emigration into tissues. Monocytes from Covid-19 MESHD patients exhibited decreased expression of HLA-DR and increased expression of CD163 HGNC, irrespective of the clinical status. Hence, SARS-CoV-2 drives circulating monocytes and macrophages inducing immunoparalysis of the host for the benefit of Covid-19 MESHD disease progression.

    Daytime variation in SARS-CoV-2 infection MESHD and cytokine production

    Authors: Aissatou Bailo Diallo; Laetitia Gay; Benjamin Coiffard; Marc Leone; Soraya Mezouar; Jean-Louis Mège; Elisa Ghelfi; Chhinder Sodhi; David Hackam; Lester Kobzik; Ben Croker; Douglas Brownfield; Hongpeng Jia; Kristopher A. Sarosiek; Paige D. Hall; Maud Jansen; Kumaran Shanmugarajah; Jessica S. Donington; Florian Krammer; Daved Fremont; Andrzej Joachimiak; Yoshihiro Kawaoka; Vera Tesic; Maria Lucia Madariaga; Patrick C Wilson; Martin Pettersson; Mattew R. Reese; Thomas Rogers; Michelle I Rossulek; Jean G Sathish; Claire Steppan; Martyn Ticehurst; Lawrence W. Updyke; Yuao Zhu; Jun Wang; Arnab K Chatterjee; Andrew D Mesecar; Annaliesa S. Anderson; Charlotte Allerton

    doi:10.1101/2020.09.09.290718 Date: 2020-09-12 Source: bioRxiv

    S. Ray and A. Reddy recently anticipated the implication of circadian rhythm in severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), which is the causative agent of the coronavirus disease MESHD ( Covid-19 MESHD). In addition to its key role in the regulation of biological functions, the circadian rhythm has been suggested as a regulator of viral infections MESHD. Specifically, the time of day of infection was found critical for illness progression, as has been reported for influenza, respiratory syncytial and parainfluenza type 3 viruses. We analyzed circadian rhythm implication in SARS-CoV-2 virus infection MESHD of isolated human monocytes, key actor cells in Covid-19 MESHD disease, from healthy subjects. The circadian gene expression of Bmal1 HGNC and Clock genes was investigated with q-RTPCR. Monocytes were infected with SARS-CoV-2 virus strain and viral infection MESHD was investigated by One-Step qRT-PCR and immunofluorescence. Interleukin (IL)-6 HGNC, IL-1{beta HGNC} and IL-10 HGNC levels were also measured in supernatants of infected monocytes. Using Cosinor analysis, we showed that Bmal1 HGNC and Clock transcripts exhibited circadian rhythm in monocytes with an acrophase and a bathyphase at Zeitgeber Time (ZT)6 and ZT17. After forty-eight hours, the amount of SARS-CoV-2 virus increased in the monocyte infected at ZT6 compared to ZT17. The high virus amount at ZT6 was associated with significant increased release in IL-6 HGNC, IL-1{beta HGNC} and IL-10 HGNC compared to ZT17. Our results suggest that time day of SARS-CoV-2 infection MESHD SARS-CoV-2 infection MESHD affects viral infection and host immune response. They support consideration of circadian rhythm in SARS-CoV-2 disease MESHD progression and we propose circadian rhythm as a novel target for managing viral progression. ImportanceThe implication of circadian rhythm (CR) in pathogenesis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been recently anticipated. The time of day of infection is critical for illness progression as reported for influenza, respiratory syncytial and parainfluenza type 3 viruses. In this study, we wondered if SARS-CoV-2 infection MESHD and cytokine production by human monocytes, innate immune cells affected by Covid-19 MESHD, were regulated by CR. Our results suggest that time day of SARS-CoV-2 infection MESHD affects viral infection and host immune response. They support consideration of circadian rhythm in SARS-CoV-2 disease progression and we propose circadian rhythm as a novel target for managing viral progression.

    Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19 MESHD

    Authors: Miguel Reyes; Michael R. Filbin; Roby P. Bhattacharyya; Abraham Sonny; Arnav Mehta; Kianna Billman; Kyle R. Kays; - MGH COVID-19 Collection & Processing Team; Alexandra-Chloe Villani; Moshe Sade-Feldman; Marcia B. Goldberg; Paul C. Blainey; Nir Hacohen

    doi:10.1101/2020.09.02.280180 Date: 2020-09-02 Source: bioRxiv

    A recent estimate suggests that one in five deaths globally are associated with sepsis MESHD. To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity and our lack of insight into sepsis MESHD immunopathology. These issues are highlighted by the current COVID-19 MESHD COVID-19 MESHD pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis MESHD. We previously reported an expanded CD14 HGNC+ monocyte state, MS1, in patients with bacterial sepsis MESHD or non-infectious critical illness, and validated its expansion in sepsis MESHD across thousands of patients using public transcriptomic data. Despite its marked expansion in the circulation of bacterial sepsis MESHD patients, its relevance to viral sepsis MESHD and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality MESHD and is up-regulated in monocytes from patients with severe COVID-19 MESHD. We found that blood plasma from bacterial sepsis MESHD or COVID-19 MESHD patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 HGNC and IL-10 HGNC. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis MESHD prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections MESHD.

    Immunophenotyping of Circulating Leukocytes Reveal Non-specific Activation of Innate and Adaptive Immune Systems in Multi-System Inflammatory Syndrome of Childhood Temporally Associated with SARS-Cov-2 Infection MESHD: Descriptive Cohort Study

    Authors: Michael J. Carter; Matthew Fish; Aislinn Jennings; Katie J. Doores; Paul Wellman; Jeffrey Seow; Sam Acors; Emma Timms; Julia Kenny; Stuart Neil; Michael H. Malim; Shane M. Tibby; Manu Shankar-Hari

    id:10.20944/preprints202007.0252.v1 Date: 2020-07-12 Source: Preprints.org

    We describe the innate and adaptive immune system trajectory in Multi-system inflammatory syndrome MESHD of childhood (MIS-C), at acute(within 72 hours of hospitalization), resolution (at clinical improvement) and convalescent phase. In our cohort, in the acute phase, 68% of the children were SARS-CoV-2 seropositive, with hypercytokinenemia (high interleukin(IL)-1beta HGNC, IL-6 HGNC, IL-8 HGNC, IL-10 HGNC, IL-17 HGNC, interferon gamma HGNC), procoagulant state, myocardial dysfunction MESHD, activated neutrophils and monocytes; differential T and B cell subset lymphopenia MESHD; activated chemokine receptor type-7 positive and gamma-delta T cell subsets; antigen presenting cells had reduced HLA-DR expression; and B-cell class-switch responses occurred with illness resolution. MIS-C is an immunopathogenic illness associated with SARS-CoV-2 infections MESHD in children.

    Clinical characteristics, outcomes and follow-up of COVID-19 MESHD infection in cancer patients

    Authors: Minghao Fang; Jianmin Ling; Yanqing Wu; Zhaohua Wang; Le Yang

    doi:10.21203/rs.3.rs-33276/v1 Date: 2020-06-04 Source: ResearchSquare

    Purpose: The study is to describe the clinical characteristics, outcomes and follow-up  of cancer MESHD patients with COVID-19 MESHD. Methods: Clinical records, demographic data, signs and symptoms, laboratory results, cytokine profiles, chest CT scans, comorbidities, treatments, clinical outcomes, and RT-PCR of SARS-CoV-2 after discharge were retrospectively collected for fifty-six cancer MESHD patients with laboratory-confirmed COVID-19 MESHD pneumonia MESHD who were admitted to Tongji Hospital of Huazhong University of Science and Technology, Wuhan, China, from Feb 1 to Apr 1 HGNC, 2020. Evidence of cytokine profiles were assessed by testing for the IL1β HGNC, IL2R HGNC, IL6 HGNC, IL8 HGNC, IL10 HGNC, and TNF - α HGNC in the peripheral blood of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infected cancer MESHD patients. Results: Of 2143 patients with COVID-19 MESHD, 56 cancer MESHD patients were included. The patients were divided into two groups, as cancer MESHD survivors, and cancer MESHD non-survivors. 12 (21%) patients with lymphopenia MESHD (0.5 [0.3-0.7]) had died during hospital stay. In non-survivors, IL2R HGNC, IL6 HGNC, and IL10 HGNC were higher. 3(6.8%) cancer MESHD survivors with COVID-19 MESHD had positive RT-PCR test results again shortly after discharge. Conclusion: The mortality rate of COVID-19 MESHD among cancer MESHD patients are considerable. Cancer non-survivors are characterized by more severe lymphopenia MESHD and a higher levels of cytokines. Recovered cancer MESHD survivors still may be virus carriers.

    Clinical characteristics of 34 COVID-19 MESHD patients admitted to ICU in Hangzhou, China

    Authors: Yi Zheng; Lijun Sun; Mi Xu; Jian Pan; Yuntao Zhang; Xueling Fang; Qiang Fang; Hongliu Cai

    doi:10.1101/2020.04.12.20062604 Date: 2020-04-15 Source: medRxiv

    Introduction: The purpose of the study was to summarize the clinical and laboratory characteristics of the coronavirus disease 2019 MESHD patients admitted to intensive care unit. Methods: We tracked the data until March 5, 2020. The cases in our cohort were divided into cases only received noninvasive ventilation (NIV) and cases required invasive mechanical ventilation (IMV). The characteristics between the two groups were compared. Results: 34 cases were included in the study. The complications rate (including, acute liver injury MESHD, acute cardiac injury MESHD and acute kidney injury MESHD) were higher in IMV cases. Lymphocytopenia and neutrophilia occurred in most cases in both groups on the admission day, however, lymphocyte levels dropped progressively and more severe lymphopenia MESHD occurred in IMV group. Increased amounts of plasma IL-6 HGNC and IL-10 HGNC were found in both groups on the admission day, the progressive decrease of which occurred in NIV cases rather than IMV cases, and the levels were higher in IMV cases during hospitalization. Conclusions: Lymphocytopenia MESHD, neutrophilia, and increase of IL-6 HGNC and IL-10 HGNC occurred in SARS-CoV-2 infected MESHD patients in ICU, however, the dynamics of those were significantly different in IMV cases and NIV cases during hospitalization.

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MeSH Disease
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SARS-CoV-2 Proteins


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