Severe Acute Respiratory Syndrome-like Coronaviruses Research Articles

Inhaled Lipid Nanoparticles Alleviate Established Pulmonary Fibrosis.

Pulmonary fibrosis, a sequela of lung injury resulting from severe infection such as severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) infection, is a kind of life-threatening lung disease with limited therapeutic options. Herein, inhalable liposomes encapsulating metformin, a first-line antidiabetic drug that has been reported to effectively reverse pulmonary fibrosis by modulating multiple metabolic pathways, and nintedanib, a well-known antifibrotic drug that has been widely used in the clinic, are developed for pulmonary fibrosis treatment. The composition of liposomes made of neutral, cationic or anionic lipids, and poly(ethylene glycol) (PEG) is optimized by evaluating their retention in the lung after inhalation. Neutral liposomes with suitable PEG shielding are found to be ideal delivery carriers for metformin and nintedanib with significantly prolonged retention in the lung. Moreover, repeated noninvasive aerosol inhalation delivery of metformin and nintedanib loaded liposomes can effectively diminish the development of fibrosis and improve pulmonary function in bleomycin-induced pulmonary fibrosis by promoting myofibroblast deactivation and apoptosis, inhibiting transforming growth factor 1 (TGFβ1) action, suppressing collagen formation, and inducing lipogenic differentiation. Therefore, this work presents a versatile platform with promising clinical translation potential for the noninvasive inhalation delivery of drugs for respiratory disease treatment.

Computational Analysis of the SARS-CoV-2 RBD-ACE2-Binding Process Based on MD and the 3D-RISM Theory.

The binding process of angiotensin-converting enzyme 2 (ACE2) to the receptor-binding domain (RBD) of the severe acute respiratory syndrome-like coronavirus 2 spike protein was investigated using molecular dynamics simulation and the three-dimensional reference interaction-site model theory. The results suggested that the protein-binding process consists of a protein–protein approaching step, followed by a local structural rearrangement step. In the approaching step, the interprotein interaction energy decreased as the proteins approached each other, whereas the solvation free energy increased. As the proteins approached, the glycan of ACE2 first established a hydrogen bond with the RBD. Thereafter, the number of interprotein hydrogen bonds increased rapidly. The solvation free energy increased because of the desolvation of the protein as it approached its partner. The spatial distribution function of the solvent revealed the presence of hydrogen bonds bridged by water molecules on the RBD–ACE2 interface. Finally, principal component analysis revealed that ACE2 showed a pronounced conformational change, whereas there was no significant change in RBD.

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses.

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.

Antiviral Drug Delivery System for Enhanced Bioactivity, Better Metabolism and Pharmacokinetic Characteristics

Antiviral drugs (AvDs) are the primary resource in the global battle against viruses, including the recent fight against corona virus disease 2019 (COVID-19). Most AvDs require multiple medications, and their use frequently leads to drug resistance, since they have poor oral bioavailability and low efficacy due to their low solubility/low permeability. Characterizing the in vivo metabolism and pharmacokinetic characteristics of AvDs may help to solve the problems associated with AvDs and enhance their efficacy. In this review of AvDs, we systematically investigated their structure-based metabolic reactions and related enzymes, their cellular pharmacology, and the effects of metabolism on AvD pharmacodynamics and pharmacokinetics. We further assessed how delivery systems achieve better metabolism and pharmacology of AvDs. This review suggests that suitable nanosystems may help to achieve better pharmacological activity and pharmacokinetic behavior of AvDs by altering drug metabolism through the utilization of advanced nanotechnology and appropriate administration routes. Notably, such AvDs as ribavirin, remdesivir, favipiravir, chloroquine, lopinavir and ritonavir have been confirmed to bind to the severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) receptor and thus may represent anti-COVID-19 treatments. Elucidating the metabolic and pharmacokinetic characteristics of AvDs may help pharmacologists to identify new formulations with high bioavailability and efficacy and help physicians to better treat virus-related diseases, including COVID-19.

From metaphor to militarized response: the social implications of “we are at war with COVID-19” – crisis, disasters, and pandemics yet to come

PurposeThe purpose of this paper is to analyze the framing of the emergency response to the novel coronavirus (coronavirus disease 2019 [COVID-19]; severe acute respiratory syndrome-like coronavirus [SARS-CoV-2]) in 2020 with wartime combat language. Metaphors have been used throughout American politics and society to frame perceived social problems, to both mobilize support and demobilize opposition. By simplifying and dichotomizing social problems, latent negative consequences frequently emerge, which tend to have a disproportionate impact on minority communities.Design/methodology/approachThis paper used a case study and applied text from presidential press conferences and policy speeches from multiple sources on the War on Poverty, the War on Drugs and the War on COVID-19. The work identified common themes, actions and policies that can lead to other stakeholders adapting the “war” rhetoric.FindingsAn apparent cycle emerged – from disdain to metaphorical “war,” to policy, to law, to consequences and back to disdain – that fueled the American political system and, by extension, systematic oppression. The COVID-19 pandemic appears to be another crucible for this cycle to repeat itself. The series of examples illustrate how public leaders use the “war metaphor” as an all-out victory approach to galvanize policy responses to social issues, crises and natural disasters. By local, national and international stakeholders.Research limitations/implicationsLimitations of this study are the limited use of the metaphor and the time of completing this manuscript. The paper only views the presidential use and interpretation of the war metaphor. The COVID-19 pandemic disaster is persisting and the race for a vaccine is underway. While the authors present the immediate policy impacts, it is too early to understand the long-term policy impacts typically measured over decades.Practical implicationsThis paper contributes to the literature by employing three case studies: the War on Poverty, the War on Drugs and the War on COVID-19 pandemic to draw comparisons between wartime rhetoric, social policies and the sociopolitical implications of those policies, as well as how these policies have the potential to disproportionately affect socially vulnerable populations.Originality/valueThis paper builds on research regarding the use of metaphor, this analysis bridges a knowledge gap by employing the COVID-19 case to the historical use of the war metaphor.

The Asian region and COVID-19: approaches and gaps in controlling the virus

PurposeThe world is facing an unprecedented transformation in its social, economic and financial environments due to the emergence of a new pandemic called coronavirus disease 2019 (COVID-19). The norms on social distancing, lockdowns and sealing of international boundaries are the common measures taken by almost all regions of the world. However, the Asian region is found to have a relatively lesser number of infected cases and deaths due to COVID-19 in comparison to the other regions of the world. The present study has been aimed to review the roles of various factors as approaches, such as technology, business–government collaborations, financial bailouts and policies from government side and geographical and demographical factors of the countries in slowing down the transmission of virus in the Asian region including East Asia, South Asia and South East Asia for controlling COVID-19. Besides, the present study has also emphasised the gaps which have disabled the Asian region in controlling the transmission of virus.Design/methodology/approachFor framing the paper, various articles, national and international reports and academic papers have been reviewed, which are published in the period 2000–2020. The studies are shortlisted on the basis of keywords, such as COVID-19, coronavirus, severe acute respiratory syndrome-like coronavirus ( SARS-CoV-2), pandemic, virus, quarantine, Asia, etc.FindingsThe study has emphasised the roles of government, technology, business–government collaborations and geographical and demographical factors of countries as relevant factors in controlling COVID-19. Also, the study has highlighted inefficient health infrastructure, fear of social stigma and misinformation amongst citizens as those gaps where Asian regions are simultaneously found to be unprepared and inefficient to control the pandemic.Research limitations/implicationsThe present review would aid researchers in explaining the relevance of macro-level factors such as technology, business–government collaborations, government policies and financial bailouts and geographical and demographical factors of the region in controlling the transmission of pandemics and epidemics.Practical implicationsThe study would assist decision makers, governments and individuals in framing of the various strategies and interventions to control pandemics and epidemics.Social implicationsThe present study has explained the relevance of various behavioural and social factors as gaps which are responsible for speeding up the transmission of COVID-19. Here, the study would guide the society in taking various right steps during the phase of pandemic and lockdowns.Originality/valuePreviously, rarely any study has been found which has reviewed the roles of macro-level factors as approaches and gaps in the context of the Asian region to slow down the transmission of COVID-19.

Understanding COVID-19 via comparative analysis of dark proteomes of SARS-CoV-2, human SARS and bat SARS-like coronaviruses.

The recently emerged coronavirus designated as SARS-CoV-2 (also known as 2019 novel coronavirus (2019-nCoV) or Wuhan coronavirus) is a causative agent of coronavirus disease 2019 (COVID-19), which is rapidly spreading throughout the world now. More than 1.21 million cases of SARS-CoV-2 infection and more than 67,000 COVID-19-associated mortalities have been reported worldwide till the writing of this article, and these numbers are increasing every passing hour. The World Health Organization (WHO) has declared the SARS-CoV-2 spread as a global public health emergency and admitted COVID-19 as a pandemic now. Multiple sequence alignment data correlated with the already published reports on SARS-CoV-2 evolution indicated that this virus is closely related to the bat severe acute respiratory syndrome-like coronavirus (bat SARS-like CoV) and the well-studied human SARS coronavirus (SARS-CoV). The disordered regions in viral proteins are associated with the viral infectivity and pathogenicity. Therefore, in this study, we have exploited a set of complementary computational approaches to examine the dark proteomes of SARS-CoV-2, bat SARS-like, and human SARS CoVs by analysing the prevalence of intrinsic disorder in their proteins. According to our findings, SARS-CoV-2 proteome contains very significant levels of structural order. In fact, except for nucleocapsid, Nsp8, and ORF6, the vast majority of SARS-CoV-2 proteins are mostly ordered proteins containing less intrinsically disordered protein regions (IDPRs). However, IDPRs found in SARS-CoV-2 proteins are functionally important. For example, cleavage sites in its replicase 1ab polyprotein are found to be highly disordered, and almost all SARS-CoV-2 proteins contains molecular recognition features (MoRFs), which are intrinsic disorder-based protein–protein interaction sites that are commonly utilized by proteins for interaction with specific partners. The results of our extensive investigation of the dark side of SARS-CoV-2 proteome will have important implications in understanding the structural and non-structural biology of SARS or SARS-like coronaviruses.Electronic supplementary materialThe online version of this article (10.1007/s00018-020-03603-x) contains supplementary material, which is available to authorized users.

Discovering genomic patterns in SARS‐CoV‐2 variants

SARS-CoV-2 is a novel severe acute respiratory syndrome-like coronavirus (SARS-CoV), which is responsible of the ongoing world pandemic of COVID-19 disease. Although many approaches are being investigated to address this issue, nowaday there are no vaccines available and there is little evidence supporting the efficiency of potential therapeutic agents. Moreover, the high mutation rate of this virus heavily affects the understanding of its evolution and diffusion mechanisms, and, in turn, the development of effective solutions. In this study, two novel algorithms are provided for finding out recurrent patterns of nucleotide subsequences of different SARS-CoV-2 genomes as a unique signature capable of identifying the most peculiar features of the pathogen. In particular, we provide several subsequence patterns related to the Spike glycoprotein, which is believed to be the main target for developing effective drugs and vaccines against the COVID-19 disease because of its role in the entrance of coronaviruses into host cells. The experimental results, obtained by analyzing 5000 genomes of SARS-CoV-2, have shown that the extracted patterns are able to recognize the Spyke protein in the 99.35% of the considered genomes. In addition, such patterns have proven to be highly discriminating with respect to other pathogenic genomes, such as SARS, Middle East respiratory syndrome, Nipah, and the streptococcus bacteria. We hope that the findings presented in this study can help specialists in speeding up the design of more accurate drugs or vaccines against SARS-CoV-2.

Coronavirus e ambiente: una sfida per il pianeta e per la salute

In late December 2019, some patients were hospitalized with an initial diagnosis of pneumonia of unknown etiology. These patients were epidemiologically linked to a wholesale market of seafood, wild animals and meat located in Wuhan, Hubei province, China. Acute respiratory disease caused by a new Coronavirus SARS-CoV-2, formerly known as 2019-nCoV, afterwards as Coronavirus disease 2019 (COVID-19), spread throughout China and received the attention of the entire world. Analysis of the genomic sequence of COVID-19 showed 88% of identity with two bat-derived severe acute respiratory syndrome-like Coronaviruses. Illegal and sustainable wildlife trade is the second largest direct threat to species after habitat destruction. Each year, hundreds of millions of plants and animals are captured or collected in the wild to be sold as food, pets, medicines, ornaments and for a variety of other reasons. Even the climate crisis could offer dangerous scenarios in addition to another fundamental chapter of the environmental pillar which is the one concerning air quality. There is a solid scientific literature which correlates the incidence of viral infection cases with concentrations of atmospheric particulate matter (e.g. PM10 and PM2.5). Despite the current regulations, which limit the levels of certain atmospheric pollutants, there are still numerous negative health effects deriving from exposure to these agents. However, it can be said that chronic air pollution, such as peaks of concentration of fine dust and other pollutants, acts as a pejorative factor in cases of epidemics. (GCND_planet)

2019_nCoV/SARS-CoV-2: rapid classification of betacoronaviruses and identification of Traditional Chinese Medicine as potential origin of zoonotic coronaviruses.

The current outbreak of a novel severe acute respiratory syndrome‐like coronavirus, 2019_nCoV (now named SARS‐CoV‐2), illustrated difficulties in identifying a novel coronavirus and its natural host, as the coding sequences of various Betacoronavirus species can be highly diverse. By means of whole‐genome sequence comparisons, we demonstrate that the noncoding flanks of the viral genome can be used to correctly separate the recognized four betacoronavirus subspecies. The conservation would be sufficient to define target sequences that could, in theory, classify novel virus species into their subspecies. Only 253 upstream noncoding sequences of Sarbecovirus are sufficient to identify genetic similarities between species of this subgenus. Furthermore, it was investigated which bat species have commercial value in China, and would thus likely be handled for trading purposes. A number of coronavirus genomes have been published that were obtained from such bat species. These bats are used in Traditional Chinese Medicine, and their handling poses a potential risk to cause zoonotic coronavirus epidemics.Significance and Impact of the StudyThe noncoding upstream and downstream flanks of coronavirus genomes allow for rapid classification of novel Betacoronavirus species and correct identification of genetic relationships. Although bats are the likely natural host of 2019_nCoV, the exact bat species that serves as the natural host of the virus remains as yet unknown. Chinese bat species with commercial value were identified as natural reservoirs of coronaviruses and are used in Traditional Chinese Medicine. Since their trading provides a potential risk for spreading zoonoses, a change in these practices is highly recommended.

Bat Severe Acute Respiratory Syndrome-Like Coronavirus WIV1 Encodes an Extra Accessory Protein, ORFX, Involved in Modulation of the Host Immune Response.

Bats harbor severe acute respiratory syndrome (SARS)-like coronaviruses (SL-CoVs) from which the causative agent of the 2002-2003 SARS pandemic is thought to have originated. However, despite the fact that a large number of genetically diverse SL-CoV sequences have been detected in bats, only two strains (named WIV1 and WIV16) have been successfully cultured in vitro These two strains differ from SARS-CoV only in containing an extra open reading frame (ORF) (named ORFX), between ORF6 and ORF7, which has no homology to any known protein sequences. In this study, we constructed a full-length cDNA clone of SL-CoV WIV1 (rWIV1), an ORFX deletion mutant (rWIV1-ΔX), and a green fluorescent protein (GFP)-expressing mutant (rWIV1-GFP-ΔX). Northern blotting and fluorescence microscopy indicate that ORFX was expressed during WIV1 infection. A virus infection assay showed that rWIV1-ΔX replicated as efficiently as rWIV1 in Vero E6, Calu-3, and HeLa-hACE2 cells. Further study showed that ORFX could inhibit interferon production and activate NF-κB. Our results demonstrate for the first time that the unique ORFX in the WIV1 strain is a functional gene involving modulation of the host immune response but is not essential for in vitro viral replication. Bats harbor genetically diverse SARS-like coronaviruses (SL-CoVs), and some of them have the potential for interspecies transmission. A unique open reading frame (ORFX) was identified in the genomes of two recently isolated bat SL-CoV strains (WIV1 and -16). It will therefore be critical to clarify whether and how this protein contributes to virulence during viral infection. Here we revealed that the unique ORFX is a functional gene that is involved in the modulation of the host immune response but is not essential for in vitro viral replication. Our results provide important information for further exploration of the ORFX function in the future. Moreover, the reverse genetics system we constructed will be helpful for study of the pathogenesis of this group of viruses and to develop therapeutics for future control of emerging SARS-like infections.

Isolation and characterization of a novel alphaherpesvirus in fruit bats.

Bats are known to harbor emerging RNA viruses. Recent studies have used high-throughput sequencing technology to identify various virus species, including DNA viruses that are harbored by bats; however, little is known about the nature of these potentially novel viruses. Here, we report the characterization of a novel herpesvirus isolated from an Indonesian pteropodid bat. The virus, tentatively named fruit bat alphaherpesvirus 1 (FBAHV1), has a double-stranded DNA genome of 149,459 bp. The phylogenetic analyses suggested that FBAHV1 is phylogenetically grouped with simplexviruses within the subfamily Alphaherpesvirinae. Inoculation of FBAHV1 into laboratory mice caused a lethal infection. Virus infection was observed in lung, liver, and brain tissue. Serological and PCR screening revealed that fruit bats infected with FBAHV1 or its related virus are widely distributed in Indonesia. The identification of FBAHV1 makes a considerable contribution to our understanding of simplexviruses associated with bats. Bats are known to harbor emerging viruses, such as lyssaviruses, henipaviruses, severe acute respiratory syndrome-like coronaviruses, and filoviruses. Although alphaherpesviruses are disseminated in humans and other animals, there is little information about their distribution in bats. Here, we isolated a previously unknown alphaherpesvirus from an Indonesian fruit bat. Genome sequence analysis suggested that the virus is a member of the genus Simplexvirus within the subfamily Alphaherpesvirinae, which also includes common human viruses, such as herpes simplex virus 1 and herpes simplex virus 2. FBAHV1 is the first bat-derived alphaherpesvirus whose complete genome has been sequenced.

Identification of Diverse Alphacoronaviruses and Genomic Characterization of a Novel Severe Acute Respiratory Syndrome-Like Coronavirus from Bats in China

Although many severe acute respiratory syndrome-like coronaviruses (SARS-like CoVs) have been identified in bats in China, Europe, and Africa, most have a genetic organization significantly distinct from human/civet SARS CoVs in the receptor-binding domain (RBD), which mediates receptor binding and determines the host spectrum, resulting in their failure to cause human infections and making them unlikely progenitors of human/civet SARS CoVs. Here, a viral metagenomic analysis of 268 bat rectal swabs collected from four counties in Yunnan Province has identified hundreds of sequences relating to alpha- and betacoronaviruses. Phylogenetic analysis based on a conserved region of the RNA-dependent RNA polymerase gene revealed that alphacoronaviruses had diversities with some obvious differences from those reported previously. Full genomic analysis of a new SARS-like CoV from Baoshan (LYRa11) showed that it was 29,805 nucleotides (nt) in length with 13 open reading frames (ORFs), sharing 91% nucleotide identity with human/civet SARS CoVs and the most recently reported SARS-like CoV Rs3367, while sharing 89% with other bat SARS-like CoVs. Notably, it showed the highest sequence identity with the S gene of SARS CoVs and Rs3367, especially in the RBD region. Antigenic analysis showed that the S1 domain of LYRa11 could be efficiently recognized by SARS-convalescent human serum, indicating that LYRa11 is a novel virus antigenically close to SARS CoV. Recombination analyses indicate that LYRa11 is likely a recombinant descended from parental lineages that had evolved into a number of bat SARS-like CoVs. Although many severe acute respiratory syndrome-like coronaviruses (SARS-like CoVs) have been discovered in bats worldwide, there are significant different genic structures, particularly in the S1 domain, which are responsible for host tropism determination, between bat SARS-like CoVs and human SARS CoVs, indicating that most reported bat SARS-like CoVs are not the progenitors of human SARS CoV. We have identified diverse alphacoronaviruses and a close relative (LYRa11) to SARS CoV in bats collected in Yunnan, China. Further analysis showed that alpha- and betacoronaviruses have different circulation and transmission dynamics in bat populations. Notably, full genomic sequencing and antigenic study demonstrated that LYRa11 is phylogenetically and antigenically closely related to SARS CoV. Recombination analyses indicate that LYRa11 is a recombinant from certain bat SARS-like CoVs circulating in Yunnan Province.

Severe acute respiratory syndrome: an update.

An international outbreak of severe acute respiratory syndrome, a recently recognized syndrome caused by the newly identified severe acute respiratory syndrome-associated coronavirus, began in November 2002 and ended in July 2003. Since then, a large body of research on the syndrome has been published; the most updated developments are summarized here. Recent findings suggest that animal severe acute respiratory syndrome-like coronaviruses may have been transmitted to humans without detection for years before the recent outbreak, and that such transmission may be continuing today. The 2002-2003 outbreak probably originated from similar animal-to-human transmission, but selection and purification of the animal severe acute respiratory syndrome-like virus appears to have occurred, creating the more virulent severe acute respiratory syndrome-associated coronavirus. Recent studies have documented that severe acute respiratory syndrome-associated coronavirus is primarily transmitted via contact and/or respiratory droplets and that the combination of standard, contact, and droplet precautions is generally effective for its control. It has been shown that severe acute respiratory syndrome-associated coronavirus is typically relatively inefficiently transmitted, with the notable exception of transmission during superspreading events. Insights into the pathogenesis of severe acute respiratory syndrome have been made: one study suggests that human leukocyte antigen HLA-B*4601 is a possible risk factor for more severe disease, while another identifies angiotensin-converting enzyme 2 as a cellular receptor for severe acute respiratory syndrome-associated coronavirus. Promising treatments have been identified, including interferons, an anti-spike monoclonal antibody, and fusion inhibitors. In addition, many promising vaccines are currently in development. New findings regarding severe acute respiratory syndrome are continuing to be discovered at an unprecedented pace, permitting a better understanding of the disease and enabling better preparation for its possible return.