Top 10: July 25

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By Christian Hoffmann &
Bernd S. Kamps

 

This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give it early visibility.

25 July

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Summer Picture 001. Since 19 July, we have been preparing the Top 10 from a European beach location. While the friends enjoy the beach, we draft the daily summaries.

Epidemiology

Liang, L., Tseng, C., Ho, H.J. et al. Covid-19 mortality is negatively associated with test number and government effectiveness. Sci Rep 10, 12567 (2020). Full-text: https://doi.org/10.1038/s41598-020-68862-x

In this worldwide cross-sectional study, the authors find that COVID-19 mortality is

  • Negatively associated with
    • Test number per 100 people
    • Government effectiveness score
    • Number of hospital beds
  • Positively associated with
    • Proportion of population aged 65 or older
    • Transport infrastructure quality score

Remember: Government effectiveness!

 

Virology

Viswanathan T, Arya S, Chan SH, et al. Structural basis of RNA cap modification by SARS-CoV-2. Nat Commun 11, 3718 (2020). Full-text: https://doi.org/10.1038/s41467-020-17496-8

Does SARS-CoV-2 use an alarm code to enter cells without bells going off? That’s the proposal by Yogesh K. Gupta and colleagues who explain that the virus possesses the code to waltz right in. The authors report the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 (nps = nonstructural protein) in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine. The nsp16/nsp10 heterodimer is captured in the act of 2′-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. A perfect camouflage: SARS-CoV-2 avoids the induction of the innate immune response mediated by interferon stimulated genes. As a result of these modifications, viral messenger RNA is considered as part of the cell’s own code and not foreign. As genetic disruption of SARS-CoV nsp16 markedly reduces (10-fold) the synthesis of viral RNA, the authors speculate that the ablation of nsp16 activity should trigger an immune response to SARS-CoV-2 infection and limit pathogenesis. They go on to describe a distantly located ligand-binding site in nsp16/10 capable of accommodating small molecules outside of the catalytic pocket. A new class of antiviral drugs on the horizon? Remember that these developments take years.

 

Transmission

Fennelly KP. Particle sizes of infectious aerosols: implications for infection control. Lancet Respir Med, July 24, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30323-4

Is there really evidence that some pathogens are carried only in large droplets? Or would cough aerosols and exhaled breath from patients with various respiratory infections show striking similarities in aerosol size distributions? In case of doubt, how would you protect your family and yourself?

 

Stein-Zamir C, Abramson N, Shoob H, et al. A large COVID-19 outbreak in a high school 10 days after schools’ reopening, Israel, May 2020 separator commenting unavailable. Eurosurveill 2020, Volume 25, Issue 29, 23 July. Full-text: https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.29.2001352

After two months of lockdown, schools in Israel re-opened on 17 May. Ten days later, two cases of SARS-CoV-2 infection were diagnosed in a high school in Jerusalem; the two cases were epidemiologically not linked. Testing of the school community revealed 153 students (attack rate: 13.2%) and 25 staff members (16.6%) who were SARS-CoV-2 positive. Overall, some 260 persons were infected (students, staff members, relatives and friends).

As September approaches, health authorities in other countries should take notice. In the present study, the mass COVID-19 transmission occurred when teenage students returned to their regular classes after a 2-month closure. An extreme heatwave (on 19 May) with temperatures rising to 40 °C and above led to an exemption from facemasks for three days (19–21 May) and continuous air-conditioning. Classes in the first affected school had more than 30 students.

The authors remind that COVID-19 prevention in schools involves

  • Studying in small groups
  • Minimizing student mixing in activities and transportation
  • The wearing of facemasks by both teachers and parents
  • Keeping physical distance and practicing hand hygiene
  • Avoiding school attendance at any sign of illness
  • Learning from home if possible to reduce the need for class attendance
  • Organize outdoors classes in selected cases

Remember the ‘three Cs’: closed spaces with poor ventilation, crowded places and close-contact settings.

 

Immunology

Yang, L., Liu, S., Liu, J. et al. COVID-19: immunopathogenesis and Immunotherapeutics. Sig Transduct Target Ther 5, 128 (2020). Full-text: https://doi.org/10.1038/s41392-020-00243-2

Six pages and 79 references – the ideal weekend read. Zhang and colleagues try and elucidate the mechanisms underlying immune abnormalities in patients with COVID-19. In addition to using potent antiviral drugs (which are still beyond the horizon), the successful management of clinical COVID-19 will include enhancing anti-viral immunity and inhibiting systemic inflammation.

 

Diagnostics

Tan, C.W., Chia, W.N., Qin, X. et al. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2–spike protein–protein interaction. Nat Biotechnol (2020). Full-text: https://doi.org/10.1038/s41587-020-0631-z

“A robust serological test to detect neutralizing antibodies to SARS-CoV-2 is urgently needed to determine not only the infection rate, herd immunity and predicted humoral protection, but also vaccine efficacy during clinical trials and after large-scale vaccination.” To avoid neutralization tests which require live pathogen and a biosafety level 3 laboratory (BSL3), the authors propose a test based on antibody-mediated blockage of the interaction between the angiotensin-converting enzyme 2 (ACE2) receptor protein and the receptor-binding domain. The test achieved 99.93% specificity and 95–100% sensitivity. Time to completion: 1–2 h. Lab requirement: BSL2.

 

Genetics

van der Made CI, Simons A, Schuurs-Hoeijmakers J, et al. Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA. Published online July 24, 2020. Full-text: https://doi.org/10.1001/jama.2020.13719

When young patients died of COVID-19, we suspected the existence of genetic factors. Here, van der Made and colleagues describe two male brother pairs, 21 to 32 years old, with no history of major chronic disease. They were well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. The authors describe “two families with rare germline variants in an innate immune-sensing gene, toll-like receptor 7 (TLR7), that lead to severe disease in males who inherit the mutated gene on a single copy of their X chromosome. The study implicates TLR7 as a critical node in recognizing SARS-CoV-2 and initiating an early immune response to clear the virus and prevent the development of COVID-19” (Plenge RM. Molecular Underpinnings of Severe Coronavirus Disease 2019. JAMA. Published online July 24, 2020. https://doi.org/10.1001/jama.2020.14015).

 

 

Toyoshima, Y., Nemoto, K., Matsumoto, S. et al. SARS-CoV-2 genomic variations associated with mortality rate of COVID-19. J Hum Genet (2020). Full-text: https://doi.org/10.1038/s10038-020-0808-9

The authors analyzed 12,343 SARS-CoV-2 genome sequences isolated from patients/individuals in six geographic areas and identified a total of 1234 mutations compared with the reference SARS-CoV-2 sequence. They suggest that SARS-CoV-2 mutations as well as BCG-vaccination status and a host genetic factor, HLA genotypes might affect the susceptibility to SARS-CoV-2 infection or severity of COVID-19.

 

Treatment

Riva, L., Yuan, S., Yin, X. et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature (2020). Full-text: https://doi.org/10.1038/s41586-020-2577-1

After profiling a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules, the authors identified 100 molecules that inhibit viral replication. Thirteen were found to be able to achieve therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod and several cysteine protease inhibitors. The known pharmacological and human safety profiles of these compounds might enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.

 

Pediatrics

Salvatore CM, Han JY, Acker KP, et al. Neonatal management and outcomes during the COVID-19 pandemic: an observation cohort study. Lancet Child Adolesc Health,  July 23, 2020. Full-text: https://doi.org/10.1016/S2352-4642(20)30235-2

Transmission of COVID-19 is unlikely to occur if correct hygiene precautions are undertaken. This recommendation is confirmed by the result of an observational cohort study neonates born at three hospitals in New York City to mothers positive for SARS-CoV-2 at delivery. Of a total of 1481 deliveries, 116 (8%) mothers tested positive for SARS-CoV-2; 120 neonates were identified. All neonates were tested at 24 h of life and none were positive for SARS-CoV-2. All mothers were allowed to breastfeed. Of the neonates who completed follow-up at day 5–7 and day 14 of life, none was infected. The message: allowing neonates to room in with their mothers and direct breastfeeding are safe procedures when paired with effective parental education of infant protective strategies.

 

 

Journal Feature

Spinney L. Smallpox and other viruses plagued humans much earlier than suspected. Nature Med 2020, 23 July. Full-text: https://www.nature.com/articles/d41586-020-02083-0

When did humans first die of smallpox? When did the measles virus jump to people? When were the first humans infected by M. tuberculosis? If you like this type of questions, the News Feature by Laura Spinney is for you.

 

Have a nice weekend!