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(searched for: doi:10.1038/s41591-021-01355-0)
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, Hyung J. Chun
Published: 23 June 2021
Frontiers in Immunology, Volume 12; doi:10.3389/fimmu.2021.693085

Abstract:
COVID-19 is a viral disease caused by a novel coronavirus, SARS-CoV-2, and is responsible for a pandemic since being identified in January 2020, resulting in a severe acute respiratory syndrome (SARS). Although most patients with COVID-19 may experience an asymptomatic, mild, or self-limited illness, many patients rapidly develop dyspnea and pneumonia, requiring hospitalization for pulmonary support. Patients with severe COVID-19 symptoms manifest cytokine release syndrome (CRS), which is associated with systemic inflammation, hemodynamic instability, and multi-organ failure (1). Progression from milder respiratory symptoms to acute respiratory distress syndrome (ARDS) is currently believed to be driven largely due to CRS and be one of main reasons for COVID-19 mortality. The CRS phase of SARS-CoV-2 is thought to occur due to an influx of neutrophils and macrophages as well as elevations of inflammatory cytokines, with higher levels of IL-6, IL-1, IL-8, and IL-18 (1, 2). In CRS, a variety of pro-inflammatory cytokines, including IL-1, IL-6, IL-8, CXCL-10, interferon (INF)-induced chemokines, and tumor necrosis factor (TNF)-α are secreted by alveolar macrophages that drive the inflammatory response and promote further influx of neutrophils, monocytes, and other inflammatory cells (1, 3). During the later stages of COVID-19, there are increases in pro-inflammatory cytokines and low levels of antiviral antibodies and adaptive immune responses noted, similar to previously reported results about SARS-CoV, suggesting innate immunity rather than the adaptive immunity as the driving force for excessive inflammation in COVID-19 associated ARDS (3, 4). In Meizlish et al., proteomic profiling of hospitalized patients with COVID-19 revealed prominent signatures of neutrophil activation in those patients with critical illness (5). Markers of neutrophilic activation, such as granulocyte colony-stimulating factor [G-CSF] and interleukin-8 [IL-8] and neutrophil-derived effectors (resistin [RETN], lipocalin-2 [LCN2]) had the greatest discriminatory power in this study for identifying patients with severe COVID-19 (5). This study represented important findings given that neutrophils are often the first responders in the innate immune response but can have notable collateral damage. Complement activation has also been suggested to play an important role and be a distinct entity in severe COVID-19 infection. In Ma et al., circulating markers of complement activation were found to be higher in patients with respiratory failure in COVID-19 compared to those with non-respiratory failure with COVID-19 and influenza (6). The complement pathway can typically be activated by 3 arms: classical pathway, alternative pathway, and lectin pathway. In this study, increased activation of the alterative pathway was noted and was found to be associated with worse outcomes in COVID-19 infection (6). Studies are currently ongoing to shed more light on the adaptive immunity and antibody response associated with COVID-19. There is data that demonstrates the ability of the SARS-CoV-2 virus to elicit neutralizing antibody response in sera and for those antibodies to be isolated (7, 8). There is evidence that the antibody response is largely mounted against the spike and nucleocapsid proteins of the SARS-CoV-2 virus and the severity of infection is associated with an increase in magnitude and breadth of the humoral response (9). The kinetics of the humoral response equally important, in addition to the magnitude of it, as delayed production of neutralizing antibodies has also been showed to be linked to fatality and impaired viral clearance (10). Activation of human innate immune cells, such as macrophages, through binding of viral antigens from SARS-CoV-2 to cell-surface toll-like receptors (TLRs) has been demonstrated to be a vital mediator of COVID-19 immunopathogenesis (11–13). TLRs are a family of 10 transmembrane receptor proteins (TLR1-TLR10) that recognize pathogen-associated molecular patterns (PAMPs) on viruses, bacteria, and other foreign molecules. TLRs play a major role in the initiation of the innate immune response, with the production of inflammatory cytokines, type I IFN, and other mediators (11–13). The SARS-CoV-2 viral spike protein binds to the extracellular domains of various TLRs, with strongest binding to TLR4. It has been shown that pathogenic human coronaviruses induce oxidized phospholipids that promote acute lung injury by increase lung macrophage cytokine/chemokine production via TLR4 (12). Similarly, SARS-CoV specific GU rich ssRNA fragments induce a high level of TNF- α, IL-6, and IL-12 via TLR7 and TLR8 (14). Collectively, recent in vitro and in vivo experiments suggest that TLRs and innate immunity pro-inflammatory signaling may be important in CRS and major immunopathologic consequences. Immunomodulatory agents, which are commonly used in rheumatologic conditions, have garnered interest for COVID-19 and the hyperinflammatory state. Certain agents are being used to target individual mediators of the inflammatory pathway to mitigate CRS; for example, tocilizumab, which is a monoclonal antibody against the receptor for IL-6, has shown some potential benefit for improving lung function and decreasing length of hospitalization in a large single-center trial (15, 16). Other studies have shown conflicting results with little to no benefit for tocilizumab in mortality of patients with COVID-19 (15, 17–19). In addition, studies have investigated the benefit of steroid use in COVID-19 patients, given their ability for broad-based immunosuppression. In a trial from University of Oxford including 6000 patients with COVID-19 taking 6mg dexamethasone daily, there was lower mortality in ventilated patients and those on oxygen therapy, with on overall decrease in 28-day all cause mortality (15). However, the use of steroids has only been indicated in a subset of COVID-19 patients...
, Joseph C. Gonzalez, Benjamin L. Sievers, Vamsee Mallajosyula, Megha Dubey, Yik-Ling Bowie Cheng, Kim Quyen Thi Tran, Srijoni Chakraborty, Arianna Cassidy, Steven T. Chen, et al.
Published: 25 May 2021
bioRxiv; doi:10.1101/2021.05.25.445649

Abstract:
Serologic markers that predict severe COVID-19 disease trajectories could enable early medical interventions and reduce morbidity and mortality. We found that distinct features of IgG Fab and Fc domain structures were present within three days of a positive test that predicted two separate disease trajectories in a prospective cohort of patients with COVID-19. One trajectory was defined by early production of neutralizing antibodies and led to mild disease. A distinct trajectory, characterized by an initial period of mild symptoms followed by rapid progression to more severe outcomes, was predicted by the absence of early neutralizing antibody responses with concomitant production of afucosylated IgGs. Elevated frequencies of monocytes expressing the receptor for afucosylated IgGs, FcγRIIIa (CD16a), were an additional antecedent in patients with the more severe outcomes. In mechanistic studies, afucosylated immune complexes in the lung triggered an inflammatory infiltrate and cytokine production that was dependent on CD16a. Finally, in healthy subjects, mRNA SARS-CoV-2 vaccination elicited neutralizing antibodies that were enriched for Fc fucosylation and sialylation and distinct from both infection-induced trajectories. These data show the importance of combined Fab and Fc domain functions in the antiviral response, define an early antibody signature in people who progressed to more severe COVID-19 outcomes and have implications for novel therapeutic strategies targeting FcγRIIIa pathways.
Published: 15 May 2021
Abstract:
Background The worldwide pandemic caused by SARS-CoV-2 has claimed millions of lives and has had a profound effect on global life. Understanding the pathogenicity of the virus and the body’s response to infection is crucial in improving patient management, prognosis, and therapeutic strategies. To address this, we performed functional transcriptomic profiling to better understand the generic and specific effects of SARS-CoV-2 infection. Methods Whole blood RNA sequencing was used to profile a well characterised cohort of patients hospitalised with COVID-19, during the first wave of the pandemic prior to the availability of approved COVID-19 treatments and who went on to survive or die of COVID-19, and patients hospitalised with influenza virus infection between 2017 and 2019. Clinical parameters between patient groups were compared, and several bioinformatic tools were used to assess differences in transcript abundances and cellular composition. Results The analyses revealed contrasting innate and adaptive immune programmes, with transcripts and cell subsets associated with the innate immune response elevated in patients with influenza, and those involved in the adaptive immune response elevated in patients with COVID-19. Topological analysis identified additional gene signatures that differentiated patients with COVID-19 from patients with influenza, including insulin resistance, mitochondrial oxidative stress and interferon signalling. An efficient adaptive immune response was furthermore associated with patient survival, while an inflammatory response predicted death in patients with COVID-19. A potential prognostic signature was found based on a selection of transcript abundances, associated with circulating immunoglobulins, nucleosome assembly, cytokine production and T cell activation, in the blood transcriptome of COVID-19 patients, upon admission to hospital, which can be used to stratify patients likely to survive or die. Conclusions The results identified distinct immunological signatures between SARS-CoV-2 and influenza, prognostic of disease progression and indicative of different targeted therapies. The altered transcript abundances associated with COVID-19 survivors can be used to predict more severe outcomes in patients with COVID-19.
Published: 19 February 2021
Abstract:
Background SARS-CoV-2 shedding dynamics influence the risk of transmission and clinical manifestations of COVID-19. Yet, the relationships between SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) and age, sex and COVID-19 severity remain unclear. Methods Using systematic review, we developed a dataset of case characteristics (age, sex and COVID-19 severity) and quantitative respiratory viral loads (rVLs). We then conducted stratified analyses to assess SARS-CoV-2 shedding across disease course, COVID-19 severity, the respiratory tract, sex and age groups (aged 0 to 17 years, 18 to 59 years, and 60 years or older). Results The systematic dataset included 1,266 adults and 136 children with COVID-19. In the URT, adults with severe COVID-19 had higher rVLs at 1 day from symptom onset (DFSO) than adults (P = 0.005) or children (P = 0.017) with nonsevere illness. Between 1-10 DFSO, severe adults had comparable rates of SARS-CoV-2 clearance from the URT as nonsevere adults (P = 0.479) and nonsevere children (P = 0.863). In the LRT, severe adults showed higher rVLs post-symptom onset than nonsevere adults (P = 0.006). In the analyzed period (4-10 DFSO), severely affected adults had no significant trend in SARS-CoV-2 clearance from LRT (P = 0.105), whereas nonsevere adults showed a clear trend (P < 0.001). After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of the duration of respiratory shedding. The estimated accuracy for using URT shedding as a prognostic indicator for COVID-19 severity was up to 65%, whereas it was up to 81% for LRT shedding. Conclusions High, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. After symptom onset, severe cases tended to have slightly higher URT shedding than their nonsevere counterparts. Disease severity, rather than age or sex, predicted SARS-CoV-2 kinetics. LRT specimens more accurately prognosticate COVID-19 severity than do URT specimens. Funding Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, NSERC Senior Industrial Research Chair and the Toronto COVID-19 Action Fund.
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