Daily Science: Virology

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First Papers

  1. Yu F, Yan L, Wang N, et al. Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients. Clin Infect Dis. 2020 Mar 28. PubMed: https://pubmed.gov/32221523. Fulltext: https://doi.org/10.1093/cid/ciaa345 ll (Outstanding) | Is sputum sufficient for diagnosis? In a total of 323 samples from 76 pts, the average viral load in sputum (17429 copies/test) was significantly higher than in throat swabs (2552) and nasal swabs (651). Viral load was also higher in the early and progressive stages than in the recovery stage. If these data are confirmed, collection of specimen would be much easier.


  1. Wölfel R, Corman VM, Guggemos W. et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020, April 1. Full-text: https://doi.org/10.1038/s41586-020-2196-x ll (Outstanding) | Important work, showing active virus replication in upper respiratory tract tissues (in contrast to SARS). In a detailed virological analysis of nine cases, pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 × 108 RNA copies per throat swab, day 4), more than 1000 times higher than seen with SARS-CoV. Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples, in spite of high virus RNA concentration. Blood and urine never yielded virus. Shedding of viral RNA from sputum continued after the end of symptoms.


  1. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-1448. PubMed: https://pubmed.gov/32132184. Full-text: https://doi.org/10.1126/science.abb2762 ll (Outstanding) | Using cryo–electron microscopy, it is shown how SARS-CoV-2 binds to human cells. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Authors present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. The structures provide a basis for the development of therapeutics targeting this crucial interaction.


  1. Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. 2020 May;581(7807):215-220. PubMed: https://pubmed.gov/32225176. Full-text: https://doi.org/10.1038/s41586-020-2180-5 ll (Outstanding) | To elucidate the SARS-CoV-2 RBD and ACE2 interaction at a higher resolution/atomic level, authors used X-ray crystallography. Binding mode was very similar to SARS-CoV, arguing for convergent evolution of both viruses. The epitopes of two SARS-CoV antibodies targeting the RBD were also analysed with the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.


  1. Bouhaddou M, Memon D, Meyer B, et al. The Global Phosphorylation Landscape of SARS-CoV-2 Infection. 2020 Jun 28:S0092-8674(20)30811-4. PubMed: https://pubmed.gov/32645325. Full-text: https://doi.org/10.1016/j.cell.2020.06.034 ll (Outstanding) | Nothing to do next weekend? Then read this incredible work of 66 pages (> 400 references!). In brief: proteomics approaches that globally quantify changes in protein abundance and phosphorylation represent a powerful tool to elucidate mechanisms of viral pathogenesis by providing a snapshot of how cellular pathways and processes are rewired upon infection. Using a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, the 78 (!) authors present the global phosphorylation and protein abundance landscape of SARS-CoV-2 infection, map phosphorylation changes to disrupted kinases and pathways, and use these profiles to find drugs with the potential to treat SARS-CoV-2 infection. In total, 87 compounds (10 FDA-approved drugs) were identified.



Daily Top 10

20 March

Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020 Apr 24;368(6489):409-412. PubMed: https://pubmed.gov/32198291. Full-text: https://doi.org/10.1126/science.abb3405

1 April


Ceraolo C, Giorgi FM. Genomic variance of the 2019-nCoV coronavirus. J Med Virol. 2020 May;92(5):522-528. PubMed: https://pubmed.gov/32027036. Full-text: https://doi.org/10.1002/jmv.25700

Analysis of 56 genomic sequences from distinct patients, showing high sequence similarity (> 99%). A few variable genomic regions exist, mainly at the ORF8 locus (coding for accessory proteins).


Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020 Apr;5(4):536-544. PubMed: https://pubmed.gov/32123347. Full-text: https://doi.org/10.1038/s41564-020-0695-z l (Important)

Consensus statement (a little wordy), defining the place of SARS-CoV-2 (provisionally named 2019-nCoV) within the Coronaviridae.


Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020 Apr;5(4):562-569. PubMed: https://pubmed.gov/32094589. Full-text: https://doi.org/10.1038/s41564-020-0688-y

Important work on viral entry, using a rapid and cost-effective platform with allows to functionally test large groups of viruses for zoonotic potential. Host protease processing during viral entry is a significant barrier for several lineage B viruses. However, bypassing this barrier allows several coronaviruses to enter human cells through an unknown receptor.

3 April


Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 27;367(6485):1444-1448. PubMed: https://pubmed.gov/32132184. Full-text: https://doi.org/10.1126/science.abb2762  ll (Outstanding)

Using cryo–electron microscopy, it is shown how SARS-CoV-2 binds to human cells. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Authors present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. The structures provide a basis for the development of therapeutics targeting this crucial interaction.


Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020 May;581(7807):215-220. PubMed: https://pubmed.gov/32225176. Full-text: https://doi.org/10.1038/s41586-020-2180-5 ll (Outstanding)

To elucidate the SARS-CoV-2 RBD and ACE2 interaction at a higher resolution/atomic level, authors used X-ray crystallography. Binding mode was very similar to SARS-CoV, arguing for convergent evolution of both viruses. The epitopes of two SARS-CoV antibodies targeting the RBD were also analysed with the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.


Shang J, Ye G, Shi K. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020, March 30. https://doi.org/10.1038/s41586-020-2179-y l (IMPORTANT)

How well does SARS-CoV-2 recognize hACE2? Better than other coronaviruses. Compared to SARS-CoV and RaTG13 (isolated from bats), ACE2 binding affinity is higher. Functionally important epitopes in SARS-CoV-2 RBM are described that can potentially be targeted by neutralizing antibody drugs.

6 April


Monto AS, DeJonge P, Callear AP, et al. Coronavirus occurrence and transmission over 8 years in the HIVE cohort of households in Michigan. J Infect Dis. 2020 Apr 4. PubMed: https://pubmed.gov/32246136. Full-text: https://doi.org/10.1093/infdis/jiaa161

Let’s pray that SARS-CoV-2 remembers its origins. And that it behaves like other human coronaviruses (hCoVs). A longitudinal surveillance cohort study of children and their households from Michigan found that hCoV infections were sharply seasonal, showing a peak for different hCoV types (229E, HKU1, NL63, OC43) in February. Over 8 years, almost no hCoV infections occurred after March. Will SARS-CoV-2 remember this? It’s April….

9 April


Kim YI, Kim SG, Kim SM, et al. Infection and Rapid Transmission of SARS-CoV-2 in Ferrets. Cell Host Microbe. 2020 Apr 5.. PubMed: https://pubmed.gov/32259477. Full-text: https://doi.org/10.1016/j.chom.2020.03.023

Ferrets shed the virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. They may represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.

11 April


Shi J, Wen Z, Zhong G, et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science. 2020 Apr 8. PubMed: https://pubmed.gov/32269068. Full-text: https://doi.org/10.1126/science.abb7015

SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks. However, ferrets and cats are permissive to infection and cats susceptible to airborne infection. But cat owners can relax. Experiments were done in a small number of cats exposed to high doses of the virus, probably not representing real-life. It remains also unclear if cats secrete enough coronavirus to pass it on to people.


Wang X, Xu W, Hu G, et al. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell Mol Immunol. 2020 Apr 7. PubMed: https://pubmed.gov/32265513. Full-text: https://doi.org/10.1038/s41423-020-0424-9

It remains unclear whether SARS-CoV-2 can also infect T cells, resulting in lymphocytopenia. Using a model with pseudoviruses, authors showed that SARS-CoV-2 infects (but does not replicate in) T cells through S protein-mediated membrane fusion. T cell lines were significantly more sensitive to SARS-CoV-2 infection when compared with SARS-CoV. Of note, a very low expression level of hACE2 was found, indicating that a novel receptor might mediate SARS-CoV-2 entry into T cells.

12 April


Chu H, Chan JF, Wang Y, et al. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19. Clin Infect Dis. 2020 Apr 9. PubMed: https://pubmed.gov/32270184. Full-text: https://doi.org/10.1093/cid/ciaa410

Cell experiments on replication capacity and the immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung tissues. Both viruses were similar in cell tropism, with both targeting types I and II pneumocytes, and alveolar macrophages. SARS-CoV-2 generated 3.20 x more infectious virus particles than SARS-CoV from the infected lung tissues.


Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020 Apr 9. PubMed: https://pubmed.gov/32273594. Full-text: https://doi.org/10.1038/s41577-020-0308-3

Some thoughts on the immunopathological changes in patients with COVID-19 and how this may provide potential targets for drug discovery and may be important for clinical management.


Wang Q, Zhang Y, Wu L, et al. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 2020 Apr 7. PubMed: https://pubmed.gov/32275855. Full-text: https://doi.org/10.1016/j.cell.2020.03.045 l (Important)

Atomic details of the crystal structure of the C-terminal domain of SARS-CoV-2 spike protein in complex with human ACE2 are presented. The hACE2 binding mode of SARS-CoV-2 seems to be similar to SARS-CoV, but some key residue substitutions slightly strengthen the interaction and lead to higher affinity for receptor binding. Antibody experiments indicate notable differences in antigenicity between SARS-CoV and SARS-CoV-2.

13 April


Gao Y, Yan L, Huang Y, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020 Apr 10. PubMed: https://pubmed.gov/32277040. Full-text: https://doi.org/10.1126/science.abb7498 l (Important)

Using cryogenic electron microscopy, the authors describe the structure of the RNA-dependent RNA polymerase, another central enzyme of the viral replication machinery. It is also shown how remdesivir and sofosbuvir bind to this polymerase.

14 April


Monteil V, Kwon H, Prado P, et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell. 2020 May 14;181(4):905-913.e7. PubMed: https://pubmed.gov/32333836. Full-text: https://doi.org/10.1016/j.cell.2020.04.004

This study shows that human recombinant soluble ACE2 (hrsACE2) blocks SARS-CoV-2 infections of different cells, human blood vessel organoids and human kidney organoids. In ARDS patients, hrsACE2 was ineffective but safe at a broad range of doses. Apeiron Biologics plans a randomized study on 200 COVID-19 patients in April.

20 April


Rockx B, Kuiken T, Herfst S, et al. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science  17 Apr 2020: eabb7314. Full text: https://science.sciencemag.org/content/early/2020/04/16/science.abb7314 l (Important)

This animal study was performed to understand the pathogenesis, showing SARS-CoV-2-infected macaques provide a new model to test therapeutic strategies. Virus was excreted from nose and throat in the absence of clinical signs, and detected in type I and II pneumocytes in foci of diffuse alveolar damage and in ciliated epithelial cells of nasal, bronchial, and bronchiolar mucosae. In SARS-CoV infection, lung lesions were typically more severe, while they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes.

24 April


Sungnak W, Huang N, Bécavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature Medicine, Published: 23 April 2020. Full-text: https://www.nature.com/articles/s41591-020-0868-6 l (Important)

Elegant paper, confirming the expression of ACE2 in multiple tissues shown in previous studies, with added information on tissues not previously investigated, including nasal epithelium and cornea and its co-expression with TMPRSS2. Potential tropism was analyzed by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. These transcripts were found in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission.


27 April


Cohen J. COVID-19 vaccine protects monkeys from new coronavirus, Chinese biotech reports. Science April 23, 2020. Full-text: https://www.sciencemag.org/news/2020/04/covid-19-vaccine-protects-monkeys-new-coronavirus-chinese-biotech-reports

Preliminary results of an old-fashioned vaccine consisting of a chemically inactivated version of the virus (which could be produced easily and in huge quantities). The vaccine worked in 8 rhesus macaques, while no obvious side effects were observed. Sinovac Biotech, an experienced vaccine maker from China, has now started Phase I clinical trials in 144 healthy volunteers to evaluate safety.

28 April


Chu H, Chan JF, Yuen TT, et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study. Lancet Microbe  April 21, 2020. Full-text: https://doi.org/10.1016/S2666-5247(20)30004-5 l (Important)

An elegant study explaining distinct clinical features of COVID-19 and SARS. Authors investigated cell susceptibility, species tropism, replication kinetics, and virus-induced cell damage from both SARS-CoVs, using live infectious virus particles. SARS-CoV-2 replicated more efficiently in human pulmonary cells, indicating that SARS-CoV-2 has most likely adapted better to humans. SARS-CoV-2 replicated significantly less in intestinal cells (might explain lower diarrhea frequency compared to SARS) but better in neuronal cells, highlighting the potential for neurological manifestations.


Huang H, Koyuncu OO, Enquist LW. Pseudorabies Virus Infection Accelerates Degradation of the Kinesin-3 Motor KIF1A. J Virol. 2020 Apr 16;94(9). PubMed: https://pubmed.gov/32075931. Full-text: https://doi.org/10.1128/JVI.01934-19

Pseudorabies virus (PRV), an alphaherpesvirus, is sorted and transported in axons in the anterograde direction by the kinesin-3 motor KIF1A. Why is this of interest? Because it’s currently (April 28, 2020, 7:15 a.m. CET) the headline article of the Journal of Virology, the Journal of the American Society of Microbiology (Impact Factor 4.3). No work, no link on COVID-19, nothing on their website. This journal aims for “reporting important new discoveries and pointing to new directions in research”. Just saying.

30 April


Callaway E. The race for coronavirus vaccines: a graphical guide, Eight ways in which scientists hope to provide immunity to SARS-CoV-2. Nature 2020, 28 April 2020. 580, 576-577. https://doi.org/10.1038/d41586-020-01221-y

Fantastic graphical review on current vaccine development. Easy to understand, it explains different approaches such as virus, viral-vector, nucleic-acid and protein-based vaccines.

1 May

Virology, Immunology

Tang Y, Wu C, Li X. On the origin and continuing evolution of SARS-CoV-2. National Science Review 2020, March 03. https://doi.org/10.1093/nsr/nwaa036. Full-text: https://academic.oup.com/nsr/advance-article/doi/10.1093/nsr/nwaa036/5775463

Authors from China report on a SARS-CoV-2 subtype which seems to be more aggressive and to spread more quickly. This paper has gained much attraction in the media.


MacLean O, Orton RJ, Singer JB, et al. No evidence for distinct types in the evolution of SARS-CoV-2.  Virus Evolution, veaa034, https://doi.org/10.1093/ve/veaa034. Full-text: https://academic.oup.com/ve/advance-article/doi/10.1093/ve/veaa034/5827470?searchresult=1

In this paper, Scottish researches now demonstrate very clearly that Tang et al. were wrong and that the major conclusions of that paper cannot be substantiated. Using examples from other viral outbreaks, the authors discuss the difficulty in demonstrating the existence or nature of a functional effect of a viral mutation, and advise against overinterpretation of genomic data during the pandemic. Although rapid publication is critical for unfolding disease outbreaks, thorough and independent peer review should not be bypassed to get results published quickly.


Tay MZ, Poh CM, Rénia L et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0311-8. Full-text: https://www.nature.com/articles/s41577-020-0311-8#citeas

A brilliant overview of the pathophysiology of SARS-CoV-2 infection. How SARS-CoV-2 interacts with the immune system, how dysfunctional immune responses contribute to disease progression and how they could be treated.

3 May

Virology, Immunology

Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020 Apr 30. PubMed: https://pubmed.gov/32353859. Full-text: https://doi.org/10.1038/s41586-020-2286-9

A blueprint for future therapies. This heroic work, emerging from a world-wide collaboration (> 100 co-authors!), systematically maps the interaction landscape between SARS-CoV-2 proteins and human proteins. The authors cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and analyzed the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). In total 66 human proteins or host factors targeted by 69 compounds (29 FDA approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds) were found. Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors.


Yin W, Mao C, Luan X. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by Remdesivir. Science 01 May 2020. Full-text: https://science.sciencemag.org/content/early/2020/04/30/science.abc1560
l (Important)

Convincing data from clinical trials are still lacking (mostly rumours and press releases). However, this work shows how remdesivir inhibits the SARS-CoV-2 RdRp activity in theory. The authors describe the structure of the SARS-CoV-2 RdRp complex in the apo form and in the complex with a template-primer RNA and the active form of remdesivir. The cryo-EM structures reveal how the template-primer RNA is recognized by the enzyme and how chain elongation is inhibited by remdesivir (and why other nucleotides such as EIDD-2801 may be more potent).


Lamers MM, Beumer J, van der Vaart J, et al. SARS-CoV-2 productively infects human gut enterocytes. Science 01 May 2020. Full-text: https://science.sciencemag.org/content/early/2020/04/30/science.abc1669
l (Important)

SARS-CoV and SARS-CoV-2 infected enterocyte lineage cells in a human intestinal organoid model. Similar infection rates of enterocyte-precursors and enterocytes were observed and low levels of ACE2 may be sufficient for viral entry. This study explains why gastrointestinal symptoms are observed in a subset of patients and why viral RNA can be found in rectal swabs, even after nasopharyngeal testing has turned negative.

6 May


Thao TTN, Labroussaa F, Ebert N, et al. Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform. Nature. 2020 May 4. PubMed: https://pubmed.gov/32365353. Full-text: https://doi.org/10.1038/s41586-020-2294-9

An important technical advance, enabling the rapid generation and functional characterization of evolving RNA virus variants. The authors show the functionality of a yeast-based synthetic genomics platform to genetically reconstruct diverse RNA viruses (which are cumbersome to clone and manipulate due to size and instability). They were able to engineer and resurrect chemically-synthetized clones of SARS-CoV-2 in only a week after receipt of the synthetic DNA fragments.


Cyranoski D. Profile of a killer: the complex biology powering the coronavirus pandemic. Nature. 2020, 581, 22-26. Full-text: https://www.nature.com/articles/d41586-020-01315-7

Fantastic, a thrilling feature on what we know about how the virus operates, where it came from and what it might do next. Leading scientists are asked about their hypotheses and current research projects on the origin and on the heterogeneity of the clinical course of COVID-19.


Lau SY, Wang P, Mok BW, et al. Attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction. Emerg Microbes Infect. 2020 Dec;9(1):837-842. PubMed: https://pubmed.gov/32301390. Full-text: https://doi.org/10.1080/22221751.2020.1756700

Viral variants which contain 15-30-bp deletions (Del-mut) or point mutations respectively at the S1/S2 junction are described. Some of them were less pathogenic in a hamster model. It would be interesting to see the prevalence of these variants in asymptomatic infected cases. The potential of the Del-mut variants as an attenuated vaccine or laboratory tool should also be evaluated.

8 May


Bao L, Deng W, Huang B, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020 May 7. PubMed: https://pubmed.gov/32380511. Full-text: https://doi.org/10.1038/s41586-020-2312-y

In transgenic mice bearing human ACE2 and infected with SARS-CoV-2, pathogenicity of the virus was demonstrated. This mouse model will be valuable for evaluating antiviral therapeutics and vaccines as well as understanding the pathogenesis of COVID-19.


Xiao K, Zhai J, Feng Y, et al. Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Nature. 2020 May 7. PubMed: https://pubmed.gov/32380510. Full-text: https://doi.org/10.1038/s41586-020-2313-x l (Important)

In a wildlife rescue center, authors found coronavirus in 25 Malayan pangolins (some of whom were very sick), showing 90-100% amino acid identity with SARS-CoV-2 in different genes. Comparative genomic analysis suggested that SARS-CoV-2 might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus. As the RBD of Pangolin-CoV is virtually identical to that of SARS-CoV-2, the virus in pangolins presents a potential future threat to public health. Pangolins and bats are both nocturnal animals, eat insects, and share overlapping ecological niches, which make pangolins the ideal intermediate host. Stop illegal pangolin trade!

11 May


Yuan M, Wu NC, Zhu X, et al. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science. 2020 May 8;368(6491):630-633. PubMed: https://pubmed.gov/32245784. Full-text: https://doi.org/10.1126/science.abb7269

Molecular insights into how SARS-CoV-2 can be targeted by the humoral immune response. The authors determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor binding domain of the SARS-CoV-2 spike protein.


Zhou H, Chen X, Hu T. A novel bat coronavirus closely related to SARS-CoV-2 contains natural insertions at the S1/S2 cleavage site of the spike protein. Current Biology 2020, May 10. Full-text: https://doi.org/10.1016/j.cub.2020.05.023

A novel bat-derived coronavirus was identified from a metagenomics analysis of samples from 227 bats collected from Yunnan Province between May and October 2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-2 at the scale of the complete genome and 97.2% identity in the 1ab gene, in which it is the closest relative of SARS-CoV-2 reported to date. However, RmYN02 showed low sequence identity (61.3%) in the receptor binding domain and might not bind to ACE2.


Enserink M, Cohen J. Fact-checking Judy Mikovits, the controversial virologist attacking Anthony Fauci in a viral conspiracy video. Science 2020, May 8. Full-text: https://www.sciencemag.org/news/2020/05/fact-checking-judy-mikovits-controversial-virologist-attacking-anthony-fauci-viral

The pandemic has resulted in numerous conspiracy theories and misinformation, mainly spread through social media. WHO has declared an “infodemic” of incorrect information about the virus, which poses risks to global health. In a video that has exploded on social media in the past few days, virologist Judy Mikovits claims the virus is being wrongly blamed for many deaths. Fortunately, there are intelligent science journalists who take the time to refute this crap.

12 May


Hui KPY, Cheung MC, Perera RAPM, et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med. 2020 May 7. PubMed: https://pubmed.gov/32386571. Full-text: https://doi.org/10.1016/S2213-2600(20)30193-4  l (Important)

More insights into transmissibility and pathogenesis. Using ex-vivo cultures, authors evaluated tissue and cellular tropism of SARS-CoV-2 in the human respiratory tract and conjunctiva in comparison with other coronaviruses. In the bronchus and in the conjunctiva, SARS-CoV-2 replication competence was higher than SARS-CoV. In the lung, it was similar to SARS-CoV but lower than MERS-CoV.


Corey L, Mascola JR, Fauci AS, Collins FS. A strategic approach to COVID-19 vaccine R&D. Science Policy Forum, May 11, 2020. Full-text https://science.sciencemag.org/content/early/2020/05/08/science.abc5312

The full development pathway for an effective vaccine for SARS-CoV-2 will require that industry, government, and academia collaborate in unprecedented ways, each adding their individual strengths. Authors discuss one such collaborative program that has recently emerged: the ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) public-private partnership.


Bost P, Giladi A, Liu Y, et al. Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell May 07, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.05.006

A computational method is proposed that globally scans unmapped scRNA-seq data for the presence of viral RNA, enabling transcriptional cell sorting of infected versus bystander cells. It is shown how SARS-CoV-2 infects epithelial cells and alters the immune landscape in patients with severe disease.


Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020 May 9;395(10235):1517-1520. PubMed: https://pubmed.gov/32311318. Full-text: https://doi.org/10.1016/S0140-6736(20)30920-X

Brief but nice review and several hypotheses about SARS-CoV-2 pathogenesis. What happens during the second week – when resident macrophages initiating lung inflammatory responses are unable to contain SARS-CoV-2 infection and when both innate and adaptive immune responses are insufficient to curb the viral replication and the patient doesn’t recover quickly.

17 May


Gao Y, Yan L, Huang Y, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science  15 May 2020: Vol. 368, Issue 6492, pp. 779-782. Full-text:  https://doi.org/10.1126/science.abb7498

Another study analyzing the RNA synthesizing machine. Using cryoelectron microscopy, the authors determined a 2.9 angstrom resolution structure of the RNA-dependent RNA polymerase (also known as nsp12), which catalyzes the synthesis of viral RNA, in complex with two cofactors, nsp7 and nsp8.

18 May


Munster  VJ, Feldmann F, Williamson BN, et al. Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature 2020. https://doi.org/10.1038/s41586-020-2324-7 l (Important)

SARS-CoV-2 caused respiratory disease in 8 infected rhesus macaques, lasting 8-16 days. Pulmonary infiltrates were visible in lung radiographs. High viral loads were detected in swabs as well as in bronchoalveolar lavages. Taken together, this rhesus macaque “model” recapitulates COVID-19, with regard to virus replication and shedding, the presence of pulmonary infiltrates, histological lesions and seroconversion.


Sia SF, Yan L, Chin AWH. et al. Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. Nature 2020. https://doi.org/10.1038/s41586-020-2342-5

In most cases, you don’t need monkeys. Golden Syrian hamsters may also work as an animal model. SARS-CoV-2 transmitted efficiently from inoculated hamsters to naïve hamsters by direct contact and via aerosols. Transmission via fomites in soiled cages was less efficient. Inoculated and naturally-infected hamsters showed apparent weight loss, and all animals recovered with the detection of neutralizing antibodies.

22 May


Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020 May 20:eabc4776. PubMed: https://pubmed.gov/32434946. Full-text: https://doi.org/10.1126/science.abc4776 l (Important)

No re-infection in macaques. Following initial viral clearance and on day 35 following initial viral infection, 9 rhesus macaques were re-challenged with the same doses of virus that were utilized for the primary infection. Very limited viral RNA was observed in bronchoalveolar lavage on day 1, with no viral RNA detected at subsequent timepoints. These data show that SARS-CoV-2 infection induced protective immunity against re-exposure in non-human primates.


23 May


Hillen HS, Kokic G, Farnung L et al. Structure of replicating SARS-CoV-2 polymerase. Nature 2020. Full-text:  https://doi.org/10.1038/s41586-020-2368-8.

The cryo-electron microscopic structure of the SARS-CoV-2 RdRp in its active form, mimicking the replicating enzyme. Long helical extensions in nsp8 protrude along exiting RNA, forming positively charged ‘sliding poles’. These sliding poles can account for the known processivity of the RdRp that is required for replicating the long coronavirus genome. A nice video provides an animation of the replication machine.


Zhang X, Tan Y, Ling Y, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature. 2020 May 20. PubMed: https://pubmed.gov/32434211. Full-text: https://doi.org/10.1038/s41586-020-2355-0  ll (Outstanding)

Viral variants do not affect outcome. This important study on 326 cases found at least two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Patients infected with these different clades did not exhibit significant difference in clinical features, mutation rate or transmissibility. Lymphocytopenia, especially a reduced CD4+ and CD8+ T cell counts upon admission, was predictive of disease progression. High levels of IL-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age, lymphocytopenia, and its associated cytokine storm.


Yu , Tostanoski LH, Peter L, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science  20 May 2020. Full-text:  https://doi.org/10.1126/science.abc6284

A series of different DNA vaccine candidates expressing different forms of the spike protein were evaluated in 35 rhesus macaques. Vaccinated animals (especially those receiving a vaccine encoding the full-length spike protein) developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans. Protection was likely not sterilizing but instead appeared to be mediated by rapid immunologic control following challenge.

29 May

Virology, Immunology

Shen B, Yi X, Sun Y, et al. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell May 27, 2020. Full-text: https://www.sciencedirect.com/science/article/pii/S0092867420306279
l (Important)

Molecular insights into the pathogenesis of SARS-CoV-2 infection. Authors applied proteomic and metabolomic technologies to analyze the proteome and metabolome of sera from COVID-19 patients and several control groups. Pathway analyses and network enrichment analyses of the 93 differentially expressed proteins showed that 50 of these proteins belong to three major pathways, namely activation of the complement system, macrophage function and platelet degranulation. It was found that 80 significantly changed metabolites were also involved in the three biological processes revealed in the proteomic analysis.


Park A, Iwasaki A. Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19. Cell Host Microbe. 2020 Jun 10;27(6):870-878. PubMed: https://pubmed.gov/32464097. Full-text: https://doi.org/10.1016/j.chom.2020.05.008 l (Important)

The interferon (IFN) response constitutes the major first line of defense against viruses. This complex host defense strategy can, with accurate understanding of its biology, be translated into safe and effective antiviral therapies. In their comprehensive review, authors describe the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discuss the potential use of IFNs as a treatment strategy.


30 May


Peng Q, Peng R, Yuan B, et al. Structural and biochemical characterization of nsp12-nsp7-nsp8 core polymerase complex from SARS-CoV-2. Cell Reports. May 30, 2020. Full-text: https://10.1016/j.celrep.2020.107774

The replication of coronavirus is operated by a set of non-structural proteins (nsps) encoded by the open-reading frame 1a (ORF1a) and ORF1ab in its genome, which are initially translated as polyproteins followed by proteolysis cleavage for maturation. These proteins assemble into a multi-subunit polymerase complex to mediate the transcription and replication of viral genome. Among them, nsp12 is the catalytic subunit with RNA-dependent RNA polymerase (RdRp) activity. The nsp12 itself is capable of conducting polymerase reaction with extremely low efficiency, whereas the presence of nsp7 and nsp8 cofactors remarkably stimulates its polymerase activity. Using cryo-EM, near-atomic resolution structure of SARS-CoV-2 nsp12-nsp7-nsp8 core polymerase complex is described.

3 June


Jamrozik E, Selgelid MJ. COVID-19 human challenge studies: ethical issues. Lancet Infect Dis. 2020 May 29:S1473-3099(20)30438-2. PubMed: https://pubmed.gov/32479747. Full-text: https://doi.org/10.1016/S1473-3099(20)30438-2

Human challenge studies could accelerate vaccine development, helping to test multiple candidate   vaccines. This personal view on ethical issues explains why this will be difficult. This is bad news. However, this is also somewhat good news (exception today!), as the authors argue that human challenge studies can “reasonably be considered ethically acceptable insofar as such studies are accepted internationally and by the communities in which they are done, can realistically be expected to accelerate or improve vaccine development, have considerable potential to directly benefit participants, are designed to limit and minimise risks to participants, and are done with strict infection control measures to limit and reduce third-party risks.”

4 June


Jamrozik E, Selgelid MJ. COVID-19 human challenge studies: ethical issues. Lancet Infect Dis. 2020 May 29:S1473-3099(20)30438-2. PubMed: https://pubmed.gov/32479747 . Full-text: https://doi.org/10.1016/S1473-3099(20)30438-2

Human challenge studies could accelerate vaccine development, helping to test multiple candidate   vaccines. This personal view on ethical issues explains why this will be difficult. This is bad news. However, this is also somewhat good news (exception today!), as the authors argue that human challenge studies can “reasonably be considered ethically acceptable insofar as such studies are accepted internationally and by the communities in which they are done, can realistically be expected to accelerate or improve vaccine development, have considerable potential to directly benefit participants, are designed to limit and minimise risks to participants, and are done with strict infection control measures to limit and reduce third-party risks.”


6 June


Sun SH, Chen Q, Gu HJ, et al. A Mouse Model of SARS-CoV-2 Infection and Pathogenesis. Cell Host Microbe. 2020 May 27:S1931-3128(20)30302-4. PubMed: https://pubmed.gov/32485164. Full-text: https://doi.org/10.1016/j.chom.2020.05.020

Human ACE2 knockin mice were generated by using CRISPR-Cas9 technology. Bottom line: SARS-CoV-2 led to robust replication in the lung, trachea, and brain. SARS-CoV-2 caused interstitial pneumonia and elevated cytokines. A high dose of virus could establish infection via an intragastric route.

7 June


Cyranoski D. The biggest mystery: what it will take to trace the coronavirus source. Nature 2020, June 05. Full-text: https://www.nature.com/articles/d41586-020-01541-z

Elegant article summarizing the current (and limited) knowledge of the origin of SARS-CoV-2. Most researchers say the more likely explanation is that bats passed it to an intermediate animal, which then spread it to people. However, this finding will be tricky, as will calming speculations of a “lab escape”. This would require a forensic investigation, looking for viruses that matched the genetic sequence of SARS-CoV-2 and. Authorities would need to take samples from the lab, interview staff, review lab books and records of safety incidents, and see what types of experiment researchers had done.

8 June

Virology, Vaccine

Wang H, Zhang Y, Huang B, et al. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell 2020, June 06. Full-text: https://doi.org/10.1016/j.cell.2020.06.008

Will this be the first vaccine? Compared with the adenovirus-vectored and the DNA vaccine, inactivated vaccine development and production is a conventional and mature technology (main pro: large amounts of vaccine doses can be easily manufactured, main con: safety issues, including an antibody-dependent worsening of the infection). BBIBP-CorV, an inactivated SARS-CoV-2 vaccine, induced high levels of neutralizing antibody in several animal models, including 8 rhesus macaques,  protecting them against SARS-CoV-2 infection. There was no observable antibody-dependent infection enhancement or immunopathological exacerbation. A Phase I clinical trial of BBIBP-CorV is currently in progress and a Phase II clinical trial has recently been initiated.

12 June


Day T, Gandon S, Lion S, et al. On the evolutionary epidemiology of SARS-CoV-2. Curr Biol 2020, June 11. Full-text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287426  ll (Outstanding)

Outstanding essay about what little is currently known about the evolution of SARS-CoV-2. At present, there is a lack of compelling evidence that any existing variants impact the progression, severity, or transmission of COVID-19 in an adaptive manner. The authors discuss the potential evolutionary routes that SARS-CoV-2 might take and dispel some of the current misinformation that is circulating in the media.


Gussow AB, Auslander N, Faure G, Wolf YI, Zhang F, Koonin EV. Genomic determinants of pathogenicity in SARS-CoV-2 and other human coronaviruses. Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15193-15199. PubMed: https://pubmed.gov/32522874. Full-text: https://doi.org/10.1073/pnas.2008176117

This in-depth molecular analysis reconstructs key genomic features that differentiate SARS-CoV-2, SARS-CoV and MERS-CoV from less pathogenic coronaviruses. Exploring the regions identified within the nucleocapsid that predict the high case fatality rate of coronaviruses, the authors found that these deletions and insertions result in substantial enhancement of motifs that determine nuclear localization. The deletions, insertions, and substitutions in the N proteins of the high-CFR coronaviruses map to two monopartite nuclear localization signals. These findings imply an important role of the subcellular localization of the nucleocapsid protein in coronavirus pathogenicity.

21 June


Wu KE, Fazal FM, Parker KR, et al. RNA-GPS Predicts SARS-CoV-2 RNA Residency to Host Mitochondria and Nucleolus. Cell Systems, June 20, 2020. Full-text: https://doi.org/10.1016/j.cels.2020.06.008

SARS-CoV-2 genomic and subgenomic RNA (sgRNA) transcripts hijack the host cell’s machinery. But where is the viral RNA localized in the cell? Computational modeling of SARS-CoV-2 viral RNA subcellular residency across eight subcellular neighborhoods, predicted the SARS-CoV-2 RNA genome and sgRNAs to be enriched towards the host mitochondrial matrix and nucleolus. The authors interpret the mitochondrial residency signal as an indicator of intracellular RNA trafficking with respect to double-membrane vesicles, a critical stage in the coronavirus life cycle.

26 June


Barr IG, Rynehart C, Whitney P, et al. SARS-CoV-2 does not replicate in embryonated hen’s eggs or in MDCK cell lines. Eurosurveillance Volume 25, Issue 25, 25/Jun/2020. Full-text: https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.25.2001122

This study showed that even if a clinical sample, containing both human influenza and SARS-CoV-2, was inoculated into substrates used to prepare seeds for influenza vaccine production (embryonated chicken eggs or MDCK-based cell lines), SARS-CoV-2 would be unlikely to be propagated and would be undetectable after a small number of passages. This finding reassures influenza vaccine production staff and laboratory scientists who might be concerned about potential exposure to SARS-CoV-2 and also suggests that loss of potentially important influenza candidate vaccine viruses or final vaccine lots due to SARS-CoV-2 contamination is unlikely.

3 July


Korber B, Fischer WM, Gnanakaran S, et al. Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell July 02, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.06.043
l (Important)

Based on 28,576 sequences until May 29, 2020, the authors show that a SARS-CoV-2 variant carrying the Spike protein amino acid change D614G (caused by an A-to-G nucleotide mutation at position 23,403 in the Wuhan reference strain) has become the most prevalent form in the global pandemic within a month. G614 has replaced D614 as the dominant pandemic form and the consistent increase of G614 at regional levels may indicate a fitness advantage. Moreover, G614 is associated with lower RT-PCR CT in the upper respiratory tract, suggestive of higher viral loads in patients. The G614 variant also grows to higher titers as pseudotyped virions. However, there was no association between G614 and disease severity.


Grubaugh ND, Hanage WP, Rasmussen AL. Making sense of mutation: what D614G means for the COVID-19 pandemic remains unclear. Cell July 02, 2020. Full-text:  https://doi.org/10.1016/j.cell.2020.06.040

Comment on the above work. Main message = title. While clinical and in vitro data suggest that D614G changes the virus phenotype, the impact of the mutation on transmission, disease, vaccine and therapeutic development are largely unknown. As these forces can work in tandem, it’s often hard to differentiate when a virus mutation becomes common through fitness or by chance. It is even harder to determine if a single mutation will change the outcome of an infection, or a pandemic.

8 July


Sharma A, Garcia G, Arumugaswami V, Svendsen CN. Human iPSC-Derived Cardiomyocytes are Susceptible to SARS-CoV-2 Infection. bioRxiv. 2020 Apr 21:2020.04.21.051912. PubMed: https://pubmed.gov/32511402. Full-text: https://doi.org/10.1101/2020.04.21.051912

In this study, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used as a model to examine the mechanisms of cardiomyocyte-specific infection by SARS-CoV-2. Microscopy and RNA-sequencing demonstrated that SARS-CoV-2 can enter hiPSC-CMs via ACE2. Viral replication and cytopathic effect induce hiPSC-CM apoptosis and cessation of beating after 72 hours of infection.


Qian Q, Fan L, Liu W, et al. Direct evidence of active SARS-CoV-2 replication in the intestine. Clin Inf Dis 2020, July 8. Full-text: https://doi.org/10.1093/cid/ciaa925

The virus is not only in the heart but also in the rectum. In this case report, quantitative RT-PCR was performed on rectal tissue specimens obtained from surgical resection in a COVID-19 patient with rectal adenocarcinoma. RNA of SARS-CoV-2 was detected in surgically resected rectal specimens, but not in samples collected 37 days after discharge. Notably, coinciding with rectal tissues of surgical specimens nucleic acid positive for SARS-CoV-2, typical coronavirus virions in rectal tissue were observed under electron microscopy. Moreover, abundant lymphocytes and macrophages (some are SARS-CoV-2 positive) infiltrating the lamina propria were found with no significant mucosal damage.

11 July


Wong YC, Lau SY, Wang KK, et al. Natural transmission of bat-like SARS-CoV-2ΔPRRA variants in COVID-19 patients. Clin Infect Dis July 10, 2020. Full-text: https://doi.org/10.1093/cid/ciaa953

SARS-CoV-2 contains the furin cleavage PRRA motif in the S1/S2 region, which enhances viral pathogenicity but is absent in closely related bat and pangolin coronaviruses. It remains unknown if bat-like coronaviral variants without PRRA (ΔPRRA) can establish natural infection in humans. In this study, these variants were readily detected among acute patients, including a family cluster showing that these variants exist naturally and are currently transmitting in COVID-19 patients. Although these variants only consisted of a very small fraction in the wild type viral challenge stock, they were also consistently detected in intranasally inoculated hamsters.

13 July


Chan KH, Sridhar S, Zhang RR, et al. Factors affecting stability and infectivity of SARS-CoV-2. J Hosp Infect. 2020 Jul 8. PubMed: https://pubmed.gov/32652214. Full-text: https://doi.org/10.1016/j.jhin.2020.07.009

Dry heat is bad, damp cold is good (for the virus). Dried SARS-CoV-2 virus on glass retained viability for over 3-4 days at room temperature and for 14 days at 4°C, but lost viability rapidly (within one day) at 37°C. SARS-CoV-2 in solution remained viable for much longer under the same different temperature conditions. Commonly used fixatives, nucleic acid extraction methods and heat inactivation were found to significantly reduce viral infectivity.


Wang, X., Xu, W., Hu, G. et al. Retraction Note to: SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell Mol Immunol (2020). Full-text: https://doi.org/10.1038/s41423-020-0498-4

The authors have retracted this article (which has been discussed in the Virology chapter of the 4th issue of covidreference.com) after it came to the authors’ attention that in order to support the conclusions of the study, the authors should have used primary T cells instead of T cell lines. In addition, there were concerns that the flow cytometry methodology applied here was flawed. These points resulted in the conclusions being considered invalid. The question remains why the reviewers (a highly ranked Cell journal would have at least 2-4 for each paper) did not see this. But again, good news: bad science will not stand the test of time.


Abritis A, Marcus A, Oransky I. An ‘alarming’ and ‘exceptionally high’ rate of COVID-19 retractions? Account Res. 2020 Jul 7. PubMed: https://pubmed.gov/32634321. Full-text: https://doi.org/10.1080/08989621.2020.1793675

While we’re at it: See the title. The authors say no. It should also be noted that COVID-19 papers are being subjected to a high rate of scrutiny, which means that flaws are being detected more frequently than they might otherwise.

14 July


Pollock DD, Castoe TA, Perry BW, et al. Viral CpG deficiency provides no evidence that dogs were intermediate hosts for SARS-CoV-2. Mol Biol Evol. 2020 Jul 13. PubMed: https://pubmed.gov/32658964 . Full-text: https://doi.org/10.1093/molbev/msaa178

No, dogs are not intermediate hosts. The authors clearly refute the conclusions of another group that dogs are a likely intermediate host of a SARS-CoV-2 ancestor, highlighting major flaws in the inference process and analysis.

18 July


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.

22 July


Cai Y, Zhang J, Xiao T, et al. Distinct conformational states of SARS-CoV-2 spike protein.  Science  21 Jul 2020. Full-text: https://doi.org/10.1126/science.abd4251

The authors report two cryo-EM structures, derived from a preparation of the full-length S protein, representing its pre-fusion (2.9Å resolution) and post-fusion (3.0Å resolution) conformations, respectively, and identify a structure near the fusion peptide – the fusion peptide proximal region (FPPR), which may play a critical role in the fusogenic structural rearrangements of S protein. Discover why the study raises potential concerns about current vaccine strategies.

25 July


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 (by 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.

29 July


Chen J, Malone B, Llewellyn E, et al. Structural basis for helicase-polymerase coupling in the SARS-CoV-2 replication-transcription complex. Cell 2020, 27 July, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.07.033

The SARS-CoV-2 genome is replicated and transcribed by the RNA-dependent RNA polymerase holoenzyme (subunits nsp7/nsp82/nsp12) along with accessory factors such as the nsp13 helicase. Elizabeth A. Campbell, Seth A. Darst and colleagues now present a cryo-electron microscopic structure of the SARS-CoV-2 holo-RdRp with an RNA template-product with two molecules of the nsp13 helicase and identify a new potential target for future antiviral drugs.

30 July


Shin D, Mukherjee R, Grewe D et al. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature 2020, published 29 July. Full-text: https://doi.org/10.1038/s41586-020-2601-5

The papain-like protease PLpro, an essential coronavirus enzyme required for generating a functional replicase complex, is also implicated in evasion mechanisms against host anti-viral immune responses. Now Ivan Dikic and colleagues from Frankfurt Goethe University show that SCoV2-PLpro attenuates type I interferon responses and that inhibition of SCoV2-PLpro with the naphthalene-based inhibitor GRL-0617 impairs virus-induced cytopathogenic effects, fosters the anti-viral interferon pathway and reduces viral replication in infected cells. The authors conclude that targeting of SCoV2-PLpro could suppress SARS-CoV-2 infection and promote anti-viral immunity.

2 August


Xiong X, Qu K, Ciazynska KA, et al. A thermostable, closed SARS-CoV-2 spike protein trimer. Nat Struct Mol Biol. 2020 Jul 31. PubMed: https://pubmed.gov/32737467. Full-text: https://doi.org/10.1038/s41594-020-0478-5

The spike (S) protein which mediates receptor binding and cell entry exhibits substantial conformational flexibility. It transitions from closed to open conformations to expose its receptor-binding site and, subsequently, from pre-fusion to post-fusion conformations to mediate fusion of viral and cellular membranes. John Briggs, Xiaoli Xiong and colleagues now design mutations in the spike protein to allow the production of thermostable, disulfide-bonded S-protein trimers that are trapped in the closed, pre-fusion state. Furthermore, they demonstrate that the designed, thermostable, closed S trimer can be used in serological assays. They anticipate a wide array of potential applications as a reagent for serology, virology and as an immunogen.

4 August


Huang Y, Yang C, Xu X et al. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin 2020, published 3 August. Full-text: https://www.nature.com/articles/s41401-020-0485-4

The spike protein of SARS-CoV-2 plays a key role in the receptor recognition and cell membrane fusion process. In this review, Shu-wen Liu, Wei Xu and colleagues from Southern Medical University, Guangzhou, China, highlight recent research advances in the structure, function and development of antiviral drugs targeting the S protein. Six pages, 86 references.

10 August


Wolff G, Limpnes RW, Zevenhoven-Dobbe JC, et al. A molecular pore spans the double membrane of the coronavirus replication organelle. Science  06 Aug 2020: eabd3629. Full-text: https://doi.org/10.1126/science.abd3629

Coronavirus replication is associated with virus-induced cytosolic double-membrane vesicles, which may provide a tailored micro-environment for viral RNA synthesis in the infected cell. Using cellular electron cryo-microscopy, the authors visualized a molecular pore complex that spans both membranes of the double-membrane vesicle and would allow export of RNA to the cytosol. Although the exact mode of function of this molecular pore remains to be elucidated, it would clearly represent a key structure in the viral replication cycle that may offer a specific drug target.

13 August


Starr TN, Greaney AJ, Hilton SK, et al. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. Cell August 11, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.08.012

The receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. These researchers from Seattle have systematically changed every amino acid in the RBD and determine the effects of the substitutions on Spike expression, folding, and ACE2 binding. The work identifies structurally constrained regions that would be ideal targets for COVID-19 countermeasures and demonstrates that mutations in the virus which enhance ACE2 affinity can be engineered but have not, to date, been naturally selected during the pandemic.

15 August


Sun Z, Cai X, Gu C et al. Survival of SARS-COV-2 under liquid medium, dry filter paper and acidic conditions. Cell Discov 6, 57 (2020). Full-text: https://doi.org/10.1038/s41421-020-00191-9

Zhenghong Yuan, Youhua Xie, Di Qu and colleagues show that SARS-COV-2 can survive for 3 days in liquid medium or on dry filter paper. At high titers, the virus might also be able to survive under acidic conditions that mimic the gastric environment.

16 August


Alm E, Broberg EK, Connor T.  Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020. Eurosurveillance Volume 25, Issue 32, 13/Aug/2020. Full-text: https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2020.25.32.2001410

How do genetic clades distribute between European countries? Erik Alm and colleagues have applied the available nomenclatures to describe broad geographical and temporal trends in the distribution of SARS-CoV-2 genetic clades and discuss potential genomic surveillance objectives at the European level.

17 August


Sarkar M, Saha S. Structural insight into the role of novel SARS-CoV-2 E protein: A potential target for vaccine development and other therapeutic strategies. PLoS ONE August 13, 15(8). Full-text:  https://doi.org/10.1371/journal.pone.0237300 Full-text:

Coronaviruses have four main structural proteins: Nucleocapsid protein (N), Spike protein (S), Membrane protein (M), and Envelope protein (E). The E protein is the smallest and is involved in a wide spectrum of functional repertoire. Using the bioinformatics and structural modelling approach, the authors modelled the structure of E and give insights into the functional role of this protein that has a low disparity and low mutability.


Lau SKP, Wong ACP, Luk HKH, Li KSM, Fung J, He Z, et al. Differential tropism of SARS-CoV and SARS-CoV-2 in bat cells. Emerg Infect Dis. 2020 Dec [date cited]. Full-text:  https://doi.org/10.3201/eid2612.202308

SARS-CoV-2 did not replicate efficiently in 13 bat cell lines, whereas SARS-CoV replicated efficiently in kidney cells of its ancestral host, the Rhinolophus sinicus bat, suggesting different evolutionary origins. Structural modeling showed that RBD/RsACE2 binding may contribute to the differential cellular tropism. Although SARS-CoV-2 is closely related to SARS-CoVs in bats and pangolins, none of the existing animal viruses represents the immediate ancestor of SARS-CoV-2.

19 August


Ke Z, Oton J, Qu K, et al. Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature 2020, published 17 August. Full-text: https://doi.org/10.1038/s41586-020-2665-2

Fully understanding how SARS-CoV-2 Spike (S) proteins function and how they interact with the immune system, requires knowledge of the structures, conformations and distributions of S trimers within virions. Now John Briggs and colleagues collect viral particles from infected cells and determine the high-resolution structure, conformational flexibility and distribution of S trimers in situ on the virion surface. They express optimism that cryo-electron microscopy can be used to study antibody binding to S in the context of the viral surface. Such studies would provide insights into how neutralizing antibodies block virus infection, particularly for antibodies against membrane-proximal regions of S, and could thus inform design of immunogens for vaccination.


Turoňová B, Sikora M, Schürmann C, et al. In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges. Science 2020, published 18 August. Full-text: https://science.sciencemag.org/content/early/2020/08/17/science.abd5223

If you are not a virologist, cryo electron tomography, sub-tomogram averaging and molecular dynamics simulations may all be Greek to you. To structurally analyze the SARS-CoV-2 Spike (S) protein in situ, Martin Beck, Jacomina Locker, Gerhard Hummer and colleagues did exactly that. They show that the stalk domain of S contains three hinges, giving the head unexpected orientational freedom, and propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat.

Model of the S protein. The three individual chains of S are shown in shades of red, N-glycosylation in blue, lipids of the ER-like membrane in gray with phosphates in green; “hip,” “knee” and “ankle” mark positions of the three flexible hinges. Reproduced with permission.

23 August


Zhao P, Praissman JL, Grant OC, et al. Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor. bioRxiv. 2020 Jul 24:2020.06.25.172403. PubMed: https://pubmed.gov/32743578. Full-text: https://doi.org/10.1101/2020.06.25.172403

A detailed understanding of SARS-CoV-2 Spike binding to ACE2 is critical for elucidating the mechanisms of viral binding and entry, as well as for the rational design of effective therapeutics. Here Lance Wells, Peng Zhao and colleagues utilize glycomics-informed glycoproteomics to characterize site-specific microheterogeneity of glycosylation for a recombinant trimer Spike mimetic immunogen and for a soluble version of human ACE2. The authors generate molecular dynamics simulations of each glycoprotein alone and interacting with one another. Their data and related similar findings might provide a framework to facilitate the production of immunogens, vaccines, antibodies, and inhibitors as well as providing additional information regarding mechanisms by which glycan microheterogeneity is achieved.


25 August


Wang Z, Zhang L, Wu M. Human-viral chimera: a novel protein affecting viral virulence and driving host T-cell immunity. Sig Transduct Target Ther 5, 167 (2020). Full-text: https://doi.org/10.1038/s41392-020-00272-x

Zhenling Wang, Li Zhang and Min Wu discuss the paper by Ho et al. (see below) which shows that RNA viruses like influenza A can produce previously unrecognized chimeric proteins containing both viral and human genetic information, which can then affect virulence and modulate T cell responses in hosts. They conclude that this finding could lend critical insight into designing novel approaches to control emerging viral infections, such as SARS-CoV-2. (Ho JSY, Angel M, Ma Y, et al. Hybrid Gene Origination Creates Human-Virus Chimeric Proteins during Infection. Cell. 2020 Jun 25;181(7):1502-1517.e23. PubMed: https://pubmed.gov/32559462. Full-text: https://doi.org/10.1016/j.cell.2020.05.035)


Latinne A, Hu B, Olival KJ et al. Origin and cross-species transmission of bat coronaviruses in China. Nat Commun 11, 4235 (2020). Full-text: https://www.nature.com/articles/s41467-020-17687-3

All coronaviruses (CoV) known to infect humans are zoonotic, or of animal origin, with many thought to originate in bat hosts. Now Peter Daszak, Alice Latinne and colleagues analyze their macroevolution, cross-species transmission and dispersal and present a phylogenetic analysis suggesting a likely origin for SARS-CoV-2 in bats of the genus Rhinolophus. They also show that host-switching occurs more frequently and across more distantly related host taxa in alpha- than beta-CoVs and is more highly constrained by phylogenetic distance for beta-CoVs. The authors identify the host taxa and geographic regions that define hotspots of CoV evolutionary diversity in China that could help target bat-CoV discovery for proactive zoonotic disease surveillance.

26 August

Virology, Immunology

To KK, Hung IF, Ip JD, et al. COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clinical Infectious Diseases, 25 August 2020,  ciaa1275. Full-text:  https://doi.org/10.1093/cid/ciaa1275

The first case of re-infection? During recent weeks, there has been probably no other case report gaining so much media attention as this 33-year old gentleman residing in Hong Kong. By the end of March, a mildly symptomatic SARS-CoV-2 infection was confirmed by a positive posterior oropharyngeal saliva PCR on March 26, 2020. On August 15, 142 days later, the patient returned to Hong Kong from Spain via the United Kingdom and was tested positive by SARS-CoV-2 RT-PCR on the posterior oropharyngeal saliva taken for entry screening at the Hong Kong airport. Of note, the patient remained asymptomatic during the second episode but had elevated CRP, relatively high viral load with gradual decline, and seroconversion of SARS-CoV-2 IgG during the second episode, suggesting that this was a genuine episode of acute infection. Viral genomes from first and second episodes belonged to different clades/lineages. Kwok-Yung Yuen, Kelvin Kai-Wang To and colleagues discuss several implications of this case.


Damas J, Hughes GM, Keough KC, et al. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates. PNAS August 21, 2020 Full-text: https://doi.org/10.1073/pnas.2010146117

Joana Damas and colleagues utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. A large number of mammals were identified that can potentially be infected by SARS-CoV-2 via their ACE2 proteins. Species with the highest risk for SARS-CoV-2 infection were wildlife and endangered species. However, the authors urge caution not to overinterpret their predictions, given the limited infectivity data for the species studied.

28 August


Dinnon KH, Leist SR, Schäfer A et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature, August 27, 2020. Full-text: https://doi.org/10.1038/s41586-020-2708-8

Unfortunately, standard laboratory mice do not support infection with SARS-CoV-2 due to incompatibility of the S protein to the murine ortholog (mACE2) of the human receptor, complicating model development. Sometimes it is better to modify the virus (vs the mouse): Kenneth H. Dinnon et al. altered the SARS-CoV-2 receptor binding domain allowing viral entry via mACE, using reverse genetics to remodel the interaction between S and mACE2. This resulted in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged standard lab mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in HFH4-hACE2 transgenic mice. This model may be helpful in studying COVID-19 pathogenesis.

31 August


O’Leary VB, Ovsepian SV. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Trends in Genetics. Published August 26, 2020. Full-text: https://doi.org/10.1016/j.tig.2020.08.014

Brief review of the genome of SARS-CoV-2. Valerie Bríd O’Leary and Saak Victor Ovsepian also provide a fun fact you should know before you die: The SARS-CoV-2 non-structural protein 3 has a 46% similarity to a protein also found in a ray-finned fish Labrus bergylta (Ballan wrasse), a protogynous hermaphrodite, that begins life as a female yet with territorial dominance becomes male. If you are tempted to try CoV-2-protein: wrasses have firm meat and taste excellent.


Sardar R, Satish D, Birla S. Integrative analyses of SARS-CoV-2 genomes from different geographical locations reveal unique features potentially consequential to host-virus interaction, pathogenesis and clues for novel therapies. Heliyon August 20, 2020. Full-text: https://doi.org/10.1016/j.heliyon.2020.e04658

Integrative analysis of SARS-CoV-2 genome sequences from different countries, confirming unique features absent in other evolutionarily related coronavirus family genomes, which presumably confer unique infection, transmission and virulence capabilities to the virus. This work explores the functional impact of the virus mutations on its proteins and interaction of its genes with host antiviral mechanisms.

8 September


Callaway E. The coronavirus is mutating — does it matter? Nature 2020, published 8 September. Full-text: https://www.nature.com/articles/d41586-020-02544-6

Is there evolutionary pressure on the virus to spread better? Maybe later, but not now. At a time when nearly everyone on the planet is susceptible, “every single person that it comes to is a good piece of meat (William Hanage)”. Follow Ewen Callaway on a ‘Current Knowledge Tour’ about SARS-CoV-2 mutations

‘Closed’ and ‘open’ conformations of the spike protein on SARS-CoV-2, which binds to receptors on human cells. A common mutation (circled) seems to make the protein favour open conformations, which might mean the virus can enter cells more easily. Source: Structural data from K. Shen & J. Luban. Reproduced with permission.