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By Christian Hoffmann &
Bernd S. Kamps

18 July

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Virology

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

A major virulence factor of SARS-CoV is the non-structural protein 1 (Nsp1) which suppresses host gene expression by ribosome association. Using cryo-electron microscopy, these researchers from Munich have characterized the interaction of Nsp1 of SARS-CoV-2 with the human translation machinery. Nsp1 effectively blocks innate immune responses that would otherwise facilitate clearance of the infection. The next step (and probably the next Science paper) is the structural characterization of the inhibitory mechanisms.

 

Immunology

Li Q, Wu J, Nie J, et al. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell July 17, 2020 Full-text: https://doi.org/10.1016/j.cell.2020.07.012

This work may be of high relevance for antibody and vaccine development. The authors investigated 80 variants and 26 glycosylation site modifications of the spike protein of SARS-CoV-2 for the infectivity and reactivity to a panel of neutralizing antibodies and sera from convalescent patients. D614G, along with several variants containing both D614G and another amino acid change, were significantly more infectious. Most variants and the majority of glycosylation deletions were less infectious. However, some variants and N234Q glycosylation were markedly resistant to neutralizing antibodies.

 

Codo AC, Davanzo GG, de Brito Monteiro L, et al. Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis dependent axis. Cell Metabolism July 17, 2020. Full-text: https://doi.org/10.1016/j.cmet.2020.07.007

Why diabetes is bad (if uncontrolled). Elevated glucose levels directly induce viral replication and pro-inflammatory cytokine expression. Glycolytic flux is required for CoV-2 replication. Virus-induced mtROS production stabilizes HIF-1α, which in turn upregulates glycolytic genes and IL-1β expression. These data may explain why uncontrolled diabetes is a risk factor for severe COVID-19. The mtROS/HIF-1α/glycolysis-axis could be a treatment target.

 

Sariol A, Perlman S. Lessons for COVID-19 immunity from other coronavirus infections. Immunity July 14, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.07.005

In this comprehensive review, these two researchers describe the immune responses to other coronaviruses and discuss their relevance to the SARS-CoV-2 immune response. They also address crucial questions for COVID-19 immunity.

 

Diagnostics

Collier Dam Assennato SM, Warne B, et al. Point of care nucleic acid testing for SARS-CoV-2 in hospitalised patients: a clinical validation trial and implementation study. Cell Rep Med 2020, July 15, 2020. Full-text: https://doi.org/10.1016/j.xcrm.2020.100062

This will be the future (at least in hospitals). A point of care (POC) nucleic acid amplification testing (NAAT) was evaluated in 149 participants with parallel combined nasal/throat swabbing for POC versus standard time to result was 2.6 versus 26.4 hours. In an implementation study, POC testing increases isolation room availability, avoids bed closures, allows discharge to care homes and expedites access to hospital procedures.

 

Clinical

Pham TD, Huang CH, Wirz OF, et al. SARS-CoV-2 RNAemia in a Healthy Blood Donor 40 Days After Respiratory Illness Resolution. Ann Int Med Jul 17, 2020. Full-text: https://doi.org/10.7326/L20-0725

What happened here? The authors describe a case of donor RNAemia more than one month after symptom resolution. Plasma viral RNA was reproducibly detected at a time point that exceeded recommendations for deferral based on time since symptom resolution (14 days). Given the low viral load, however, these data suggest that this donor posed a limited but uncertain risk to the safety of the blood supply.

 

Treatment

The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. NEJM July 17, 2020. Full-text: https://doi.org/10.1056/NEJMoa2021436

Applause to these UK researchers! These first peer-reviewed results of the incredibly huge RECOVERY trial show that dexamethasone works in critically ill patients. In this open-label trial (comparing a range of treatments), hospitalized patients were randomized to receive oral or intravenous dexa (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. Overall, 482 patients (22.9%) in the dexa group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83). Death rate was lower among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support (17.8% vs. 14.0%).

 

Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19. Ann Int Med, Jul 16. Full-text: https://doi.org/10.7326/M20-4207

The last piece of the puzzle that HCQ doesn’t work, even when given early. Symptomatic, nonhospitalized adults with lab-confirmed or probable COVID-19 and high-risk exposure were randomized within 4 days of symptom onset to HCQ (800 mg once, followed by 600 mg at 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo. Among 423 patients, change in symptom severity over 14 days did not differ. At 14 days, 24% receiving HCQ had ongoing symptoms compared with 30% receiving placebo (p = 0.21). Adverse events occurred in 43% versus 22%. Although many letters can be expected (dosage wrong, too low, too high, too late, too early, wrong patients, too many unconfirmed patients etc), the lesson is learned: HCQ does NOT substantially reduce symptom severity in outpatients with early, mild COVID-19. Please, let’s forget it. Completely.

 

Schluger NW. The Saga of Hydroxychloroquine and COVID-19: A Cautionary Tale. Ann Int Med 2020, Jul 6. Full-text: https://doi.org/10.7326/M20-5041

Editorial, commenting on the above data. The saga of hydroxychloroquine and COVID-19 will likely reach its sad end. Many good ideas in medicine do not work. Some thoughts on how this HCQ hype could have happened.

 

Pruijssers AJ, George AS, Schäfer A, et al. Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. Cell Reports, July 14, 2020. Full-text: https://doi.org/10.1016/j.celrep.2020.107940

Good to know that remdesivir works in cells. It potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures. In mice infected (with a chimeric virus), remdesivir diminished lung viral load and improved pulmonary function.