Top 10: October 11

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By Christian Hoffmann &
Bernd S. Kamps

 

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11 October

Virology

Vann KR, Tencer AH, Kutateladze TG. Inhibition of translation and immune responses by the virulence factor Nsp1 of SARS-CoV-2. Sig Transduct Target Ther 5, 234 (2020). Full-text: https://doi.org/10.1038/s41392-020-00350-0

A major virulence factor of SARS-CoV is the non-structural protein 1 (Nsp1) which suppresses host gene expression by ribosome association (see our July 18 CR Top 10: Thoms M, Buschauer R, Ameismeier M, et al. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science  17 Jul 2020: eabc8665. Full-text: https://doi.org/10.1126/science.abc8665). The authors briefly review Nsp1’s ability to downregulate the innate immune responses. A new drug target?

 

Immunology

Hu F. Chen F, Ou Z, et al. A compromised specific humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract. Cell Mol Immunol (2020). Full-text: https://doi.org/10.1038/s41423-020-00550-2

Do some people have lower levels of and slower generation of viral receptor-binding domain (RBD)-specific IgA and IgG antibodies and fail to create a robust protective humoral immune response? Which might result in SARS-CoV-2 persistence in the gastrointestinal tract and possibly in active viral shedding? That’s the hypothesis of Feng Li, Fengyu Hu and colleagues who report 21 patients who were readmitted for hospitalization after detection of SARS-CoV-2 after discharge. The authors detected SARS-CoV-2 in anal samples (15 of 21, 71.4%). Three patients had active viral replication in their gastrointestinal tracts but not in their respiratory tracts.

 

Pathogenesis

Aid M, Busman-Sahay K, Vidal SJ, et al. Vascular Disease and Thrombosis in SARS-CoV-2 Infected Rhesus Macaques. Cell 2020, published 9 October. Full-text: https://doi.org/10.1016/j.cell.2020.10.005

Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis. Here, Dan Barouch, Malika Aid and colleagues demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. They observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFα, and NF-κB. These results suggest a model in which upregulation of inflammatory and complement pathways leads to recruitment of macrophages and neutrophils, activation of platelets, and triggering of the coagulation cascade, resulting in endothelial damage and thrombosis. The authors conclude that these data might point to therapeutic targets in the interferon, inflammatory, coagulation, and complement pathways.

Graphical abstract (reproduced with permission):

 

 

Ivanisenko NV, Seyrek K, Kolchanov NA, et al. The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications. Cell Death Discov. 6, 101 (2020). https://doi.org/10.1038/s41420-020-00331-w

Cell death pathways might play a key role in SARS-CoV-2 infection. Go on an explorative tour on apoptosis, pyroptosis, and necroptosis which play an important role in viral pathogenesis and host antiviral response. The authors present four open questions.

Figure 2. Induction of cell death via DR activation and SARS/SARS-CoV-2 infection. Reproduced with permission.

 

Li S, Zhang Y Guan Z, et al. SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation. Sig Transduct Target Ther 5, 235 (2020). Full-text: https://doi.org/10.1038/s41392-020-00334-0

The underlying mechanisms of virus-triggered inflammatory responses are still being investigated. Ke Peng, Shufen Li and colleagues report that SARS-CoV-2 infection of lung epithelial cells triggered cell death and inflammatory responses through the activation of caspase-8. (Caspase-8 is a master regulator of several cell death pathways, including apoptosis, necroptosis, and pyroptosis.). The authors present the analysis of postmortem lung sections of fatal COVID-19 patients.

 

Diagnostics

Brandsma E, Verhagen HJMP, van de Laar TJW, et al. Rapid, sensitive and specific SARS coronavirus-2 detection: a multi-center comparison between standard qRT-PCR and CRISPR based DETECTR. J Infect Dis 2020. Full-text: https://doi.org/10.1093/infdis/jiaa641

We will need faster and cheaper alternatives to qRT-PCR. Here Emile van den Akker, Eelke Brandsma and colleagues compare DETECTR (a combination of isothermal reverse transcriptase loop mediated amplification [RT-LAMP] and subsequent Cas12 bystander nuclease activation by amplicon targeting ribonucleoprotein complexes) with qRT-PCR to diagnose COVID-19 on 378 patient samples. The authors report a 95% reproducibility between the two tests. DETECTR was 100% specific for SARS-CoV-2 relative to other human coronaviruses.

Figure 1. Graphic representation of DETECTR assay. Reproduced with permission.

 

Treatment

Rogers R, Shehadeh F, Mylona EK, et al. Convalescent plasma for patients with severe COVID-19: a matched cohort study. Clin Infect Dis 2020, published 10 October. Full-text: https://doi.org/10.1093/cid/ciaa1548

The efficacy of convalescent plasma (CP) for the treatment of COVID-19 remains unclear. In this matched cohort analysis of hospitalized patients with severe COVID-19, 64 patients who received CP a median of 7 days after symptom onset were compared to a matched control group of 177 patients. There was a signal for an increased rate of hospital discharge among patients 65-years-old or greater, but no significant difference in the risk of in-hospital mortality between the two groups.

 

Severe COVID

Overmyer KA, Shishkova E, Miller IJ, et al. Large-scale Multi-omic Analysis of COVID-19 Severity. Cell Systems 2020, published 7 October. Full-text: https://doi.org/10.1016/j.cels.2020.10.003

In this cohort study involving 128 patients with and without COVID-19 diagnosis, Ariel Jaitovich, Katherine Overmyer and colleagues monitored thousands of biomolecules in relation to the COVID-19 disease severity and outcomes. They mapped more than 200 molecular features with high significance to COVID-19 status and severity, many involved in complement activation, dysregulated lipid transport, and neutrophil activation. The authors make their data available through a free web resource – https://covid-omics.app, calling for experts worldwide will continue to mine these data.

Graphical abstract (reproduced with permission):

 




Spanish

If you read Spanish, read Galocha. ¿En qué fase está cada vacuna? El País 2020, published 10 October. Full-text: https://elpais.com/ciencia/2020-10-10/en-que-fase-esta-cada-vacuna.html

La vuelta a la vida anterior pasa por el desarrollo en tiempo récord de una vacuna contra la covid de entre los 213 proyectos en marcha.

Tipos de vacuna. Reproducido con permiso.