+++ Virology +++
* * * Next update: 24 November. In the meantime, find the global updates at 7 Days. * * *
Relman DA. Opinion: To stop the next pandemic, we need to unravel the origins of COVID-19. PNAS first published November 3, 2020. Full-text: https://doi.org/10.1073/pnas.2021133117
Important comment. According to David A. Relman from Stanford, “a more complete understanding of the origins of COVID-19 clearly serves the interests of every person in every country on this planet. It will limit further recriminations and diminish the likelihood of conflict; it will lead to more effective responses to this pandemic, as well as efforts to anticipate and prevent the next one. It will also advance our discussions about risky science. And it will do something else: Delineating COVID-19’s origin story will help elucidate the nature of our very precarious coexistence within the biosphere.”
Zheng J, Wong LR, Li K et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature (2020). Full-text: https://doi.org/10.1038/s41586-020-2943-z
SARS-CoV-2-infected K18-hACE2 mice developed dose-dependent lung disease with features similar to severe human COVID-19, including diffuse alveolar damage, inflammatory cell infiltration, tissue injury, lung vascular damage, and death. Remarkably, K18-hACE2 mice also support SARS-CoV-2 replication in the sinonasal epithelium and associated with this pathology develop anosmia, a common feature of human disease.
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Zhang, Q., Chen, C.Z., Swaroop, M. et al. Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro. Cell Discov 6, 80 (2020). https://doi.org/10.1038/s41421-020-00222-5
The authors report that entry of SARS-CoV and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor and that ablation of genes involved in HS biosynthesis or incubating cells with a HS mimetic inhibit Spike-mediated viral entry. After screening of approved drugs they identified various inhibitors: Mitoxantrone, Sunitinib and 7-benzylidenenaltrexone (BNTX).
Murugan NA, Kumar S, Jeyakanthan J, et al. Searching for target-specific and multi-targeting organics for Covid-19 in the Drugbank database with a double scoring approach. Sci Rep 10, 19125 (2020). https://doi.org/10.1038/s41598-020-75762-7
Next study on the use of computational screening approaches to identify lead drug-like compounds for Covid-19. The harvest (selection): Baloxavir marboxil, Phthalocyanine, Tadalafil, Lonafarnib, Nilotinib, Dihydroergotamine.
Miller D, Martin MA, Harel N et al. Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel. Nat Commun 11, 5518 (2020). Full-text: https://doi.org/10.1038/s41467-020-19248-0
This group from Israel has analyzed 212 SARS-CoV-2 sequences, in order to perform a comprehensive analysis to trace the origins and spread of the virus. Travelers returning from the US significantly contributed to viral spread in Israel. The basic reproduction number of the virus was initially around 2.5, dropping by more than two-thirds following the implementation of social distancing measures. Transmission heterogeneity in SARS-CoV-2 spread was high, with between 2-10% of infected individuals resulting in 80% of secondary infections.
Du P, Ding N, Li J, et al. Genomic surveillance of COVID-19 cases in Beijing. Nat Commun. 2020 Oct 30;11(1):5503. PubMed: https://pubmed.gov/33127911. Full-text: https://doi.org/10.1038/s41467-020-19345-0
To understand the genetic characteristics of SARS-CoV-2 in Beijing, the authors collected pharyngeal swabs and sputa samples from 126 patients to perform viral genome sequencing after admission and consent procedures. Here they present genomic surveillance data on 102 imported cases, which account for 17.2% of the total cases in Beijing. Genomic comparisons reveal higher genomic diversity in the imported group compared to both the Wuhan exposure and local transmission groups, indicating continuous genomic evolution during global transmission.
Borges V, Isidrfo J, Cortes-Martins H. Massive dissemination of a SARS-CoV-2 Spike Y839 variant in Portugal. Emerg Microbes Infect 2020 Nov 2;1-58. Full-text: https://doi.org/10.1080/22221751.2020.1844552
Here, the authors track the geotemporal spread of a SARS-CoV-2 variant with a mutation (D839Y) in a potential host-interacting region involving the Spike fusion peptide, which is a target motif of anti-viral drugs that plays a key role in SARS-CoV-2 infectivity. The Spike Y839 variant was most likely imported from Italy in mid-late February and massively disseminated in Portugal during the early epidemic. Between March 14th and April 9th (covering the exponential epidemic phase) the relative frequency of the Spike Y839 variant increased at a rate of 12.1% every three days, being potentially associated with 24.8% of all COVID-19 cases in Portugal during this period. The data supports population/epidemiological (founder) effects contributing to the Y839 variant superspread. This variant was likely one of the first SARS-CoV-2 to be introduced in Portugal, so it might have had more opportunity to spread. Its introduction is strongly linked to an international trade fair in Milan with many Portuguese attendees. The potential existence of selective advantage is also discussed, although experimental validation is required.
Shang J, Han N, Chen Z, et al. Compositional diversity and evolutionary pattern of coronavirus accessory proteins. Briefings in Bioinformatics, October 30, 2020, bbaa262. Full-text: https://doi.org/10.1093/bib/bbaa262
Accessory proteins play important roles in the interaction between coronaviruses and their hosts. The authors developed a standardized genome annotation tool for coronavirus (CoroAnnoter) by combining open reading frame prediction, transcription regulatory sequence recognition and homologous alignment. This tool builds a comprehensive profile for coronavirus accessory proteins covering their composition, classification, evolutionary pattern and host interaction.
Han Y, Duan X, Yang L, et al. Identification of SARS-CoV-2 Inhibitors using Lung and Colonic Organoids. Nature 2020, October 28. Full-text: https://doi.org/10.1038/s41586-020-2901-9
The authors developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs, particularly alveolar type II-like cells, were permissive to SARS-CoV-2 infection, and showed robust induction of chemokines upon SARS-CoV-2 infection, similar to what is seen in COVID-19 patients. The authors also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. Both cell models can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.
V’kovski P, Kratzel A, Steiner S, et al. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 2020, published 28 October. Full-text: https://doi.org/10.1038/s41579-020-00468-6
In contrast to the SARS- CoV epidemic of almost 20 years ago, improved technologies, such as transcriptomics, proteomics, single-cell RNA sequencing, global single-cell profiling of patient samples, advanced primary 3D cell cultures and rapid reverse genetics, have been valuable tools to understand and tackle SARS- CoV-2 infections. Follow the authors on a 13-page review of the first discoveries that shape our current understanding of SARS- CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology.
Plante JA, Liu Y, Liu J, et al. Spike mutation D614G alters SARS-CoV-2 fitness. Nature 2020, published 26. October. Full-text: https://doi.org/10.1038/s41586-020-2895-3
The spike protein mutation D614G has become dominant in the current SARS-CoV-2 pandemic. Now, Pei-Yong Shi, Jessica Plante and colleagues show that D614G enhances replication on human lung epithelial cells and primary human airway tissues through an improved infectivity of virions. The mutation might also enhance viral loads in the upper respiratory tract of COVID-19 patients and increase transmission. The authors suggest that therapeutic antibodies should be tested against the circulating G614 virus. Discover why the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19.
Wei J, Alfajaro MM, DeWeirdt PC, et al. Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection. Cell October 20, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.10.028
Using genome-wide CRISPR screens in Vero-E6 cells, Jin Wei and colleagues have found some new host genes that affect infection by SARS-CoV-2 and other pandemic coronaviruses. In addition, the authors discovered pro-viral genes and pathways including HMGB1 which seems to have an epigenetic role in regulating ACE2 expression and thus susceptibility (HMGB1 is a pleiotropic protein that binds nucleosomes regulating chromatin in the nucleus and functions as a secreted alarmin in response to virus infection).
McNamara RP, Caro-Vegas C, Landis JT, et al. High-density amplicon sequencing identifies community spread and ongoing evolution of SARS-CoV-2 in the Southern United States. Cell Rep October 20, 2020. Full-text: https://doi.org/10.1016/j.celrep.2020.108352
The D614G mutation now dominates over the initial human strain defined by the SARS-CoV-2/human/CHN/Wuhan-01/2019 isolate. This study demonstrates continued SARS-CoV-2 evolution in a suburban Southern U.S. region, showing that now 57% of strains carry the spike D614G variant, which was associated with higher genome copy numbers. Given the increasing abundance of D614G, further research into its role in pathogenicity and clinical outcomes is warranted.
Cantuti-Castelvetri L, Ojha R, Pedro LD, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020, published 20 October. Full-text: https://doi.org/10.1126/science.abd2985
For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. Here, Mikael Simons, Ludovico Cantuti-Castelvetri and colleagues report that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. Another potential target for antiviral intervention.
Daly JL, Simonetti B, Klein K, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science 2020, published 20 October. Full-text: https://doi.org/10.1126/science.abd3072
Again, Neuropilin-1. Step-by-step: 1) SARS-CoV-2 uses the viral Spike (S) protein for host cell attachment and entry. 2) The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. 3) Cleavage of S generates a polybasic Arg-Arg-Ala-Arg C-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that 4) binds to cell surface Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) receptors. Now Yohei Yamauchi, James Daly and colleagues show that the S1 CendR motif directly bound NRP1. Blocking this interaction using RNAi or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 binding to the CendR peptide in S1 is thus likely to play a role in the increased infectivity of SARS-CoV-2 compared with SARS-CoV. The authors conclude that the ability to target this specific interaction might provide a route for COVID-19 therapies.
Rattanapisit K, Shanmugaraj B, Manopwisedjaroen S. et al. Rapid production of SARS-CoV-2 receptor binding domain (RBD) and spike specific monoclonal antibody CR3022 in Nicotiana benthamiana. Sci Rep 10, 17698 (2020). Full-text: https://doi.org/10.1038/s41598-020-74904-1
This study demonstrates the rapid production of the RBD of SARS-CoV-2 and mAb CR3022 in Nicotiana benthamiana using a transient expression system. The plant-produced RBD showed specific binding to the receptor of SARS-CoV-2 (ACE2), confirming its structural integrity. Further, the plant-produced mAb CR3022 exhibited binding to SARS-CoV-2, but it failed to neutralize the virus in vitro. Overall, this study provides a proof-of-principle for the rapid production of SARS-CoV-2 antigens or monoclonal antibodies in a plant expression system in order to produce diagnostic reagents, vaccines and therapeutics.
Lu S, Zhao Y, Yu W, et al. Comparison of nonhuman primates identified the suitable model for COVID-19. Signal Transduct Target Ther. 2020 Oct 19;5(1):157. PubMed: https://pubmed.gov/32814760. Full-text: https://doi.org/10.1038/s41392-020-00269-6
The authors characterized SARS-CoV-2 infection in three nonhuman primate species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Susceptibilities of Old World and New World monkeys to SARS-CoV-2 differed markedly. Macaca mulatta seemed to be the most suitable for modeling COVID-19.
Gordon DE, Hiatt J, Bouhaddou M, et al. (Total: 200 authors) Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science 2020, published 15 October. Full-text: https://doi.org/10.1126/science.abe9403
Nevan Krogan, David Gordon and colleagues – a group of 200 researchers – uncovered molecular processes used by coronaviruses MERS, SARS-CoV1 and SARS-CoV2 to manipulate host cells. The researchers from six countries found 73 human proteins with which components of all three types of the virus enter into bonds and thus influence the survival of infected cells in culture. Host factors that functionally impinge on coronavirus proliferation include Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 Orf9b. The consortium also discovered cell surface molecules that are influenced by all three coronaviruses and that bind to already approved drugs, for example an antipsychotic and an anti-inflammatory drug.
Riddell S, Goldie S, Hill A, et al. The effect of temperature on persistence of SARS-CoV-2 on common surfaces. Virol J 17, 145 (2020). Full-text: https://doi.org/10.1186/s12985-020-01418-7
It might seem that SARS-CoV-2 could remain infectious for longer time periods than generally considered until recently. Shane Riddell et al. measured the survival rates of infectious SARS-CoV-2 on several common surface types. They incubated the inoculated surfaces at 20 °C, 30 °C and 40 °C and sampled at various time points. The authors report isolation of viable virus for up to 28 days at 20 °C from common surfaces such as glass, stainless steel and both paper and polymer banknotes. A temperature of 40 °C, however, didn’t seem to suit the virus: it survived less than 24 h.
Note of the Editor: After more than 6 months living in the new SARS-CoV-2 world, this study might not change my behavior.
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?
Bruchez A, Sha K, Johnson J, et al. MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science 2020, published 9 October. Full-text: https://doi.org/10.1126/science.abb3753
The concerted efforts of antiviral factors within cells are central to host cell defense. Without these factors, the cell remains defenseless against potentially harmful pathogens (Wells 2020). Here, the authors show that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against Ebola virus (EBOV). They show that CIITA induces resistance by up-regulation of the p41 isoform of CD74, which blocks cathepsin-mediated cleavage of viral GPs, thereby preventing viral fusion. CD74 p41 can also block the endosomal entry pathway of coronaviruses, including SARS-CoV-2.
See also the comment by Wells, AI, Coyne CB. Inhibiting Ebola virus and SARS-CoV-2 entry. Science 2020, published 9 October. Full-text: https://doi.org/10.1126/science.abe2977
Ebola cell entry. Graphic: Kellie Loloski/Science. Reproduced with permission.