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Structure, Function, and Evolution of Coronavirus Spike Proteins
The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors leading to viral attachment. The spike protein exists in two structurally distinct conformations prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered leading to membrane fusion. This article reviews current knowledge about the structures and functions of coronavirus spike proteins illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins receptor recognition and membrane fusion in the context of the corresponding functions from other viruses and host cells.
Coronavirus Host Range Expansion and Middle East Respiratory Syndrome Coronavirus Emergence: Biochemical Mechanisms and Evolutionary Perspectives
Coronaviruses have frequently expanded their host range in recent history with two events resulting in severe disease outbreaks in human populations. Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2003 in Southeast Asia and rapidly spread around the world before it was controlled by public health intervention strategies. The 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak represents another prime example of virus emergence from a zoonotic reservoir. Here we review the current knowledge of coronavirus cross-species transmission with particular focus on MERS-CoV. MERS-CoV is still circulating in the human population and the mechanisms governing its cross-species transmission have been only partially elucidated highlighting a need for further investigation. We discuss biochemical determinants mediating MERS-CoV host cell permissivity including virus spike interactions with the MERS-CoV cell surface receptor dipeptidyl peptidase 4 (DPP4) and evolutionary mechanisms that may facilitate host range expansion including recombination mutator alleles and mutational robustness. Understanding these mechanisms can help us better recognize the threat of emergence for currently circulating zoonotic strains.
Biochemical Aspects of Coronavirus Replication and Virus-Host Interaction
Infection by different coronaviruses (CoVs) causes alterations in the transcriptional and translational patterns cell cycle cytoskeleton and apoptosis pathways of the host cells. In addition CoV infection may cause inflammation alter immune and stress responses and modify the coagulation pathways. The balance between the up- and downregulated genes could explain the pathogenesis caused by these viruses. We review specific aspects of CoV-host interactions. CoV genome replication takes place in the cytoplasm in a membrane-protected microenvironment and may control the cell machinery by locating some of their proteins in the host cell nucleus. CoVs initiate translation by cap-dependent and cap-independent mechanisms. CoV transcription involves a discontinuous RNA synthesis (template switching) during the extension of a negative copy of the subgenomic mRNAs. The requirement for base-pairing during transcription has been formally demonstrated in arteriviruses and CoVs. CoV N proteins have RNA chaperone activity that may help initiate template switching. Both viral and cellular proteins are required for replication and transcription and the role of selected proteins is addressed.
A New Coronavirus Emerges, This Time Causing a Pandemic
Similarities and Dissimilarities of COVID-19 and Other Coronavirus Diseases
In less than two decades three deadly zoonotic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 have emerged in humans causing SARS MERS and coronavirus disease 2019 (COVID-19) respectively. The current COVID-19 pandemic poses an unprecedented crisis in health care and social and economic development. It reinforces the cruel fact that CoVs are constantly evolving possessing the genetic malleability to become highly pathogenic in humans. In this review we start with an overview of CoV diseases and the molecular virology of CoVs focusing on similarities and differences between SARS-CoV-2 and its highly pathogenic as well as low-pathogenic counterparts. We then discuss mechanisms underlying pathogenesis and virus-host interactions of SARS-CoV-2 and other CoVs emphasizing the host immune response. Finally we summarize strategies adopted for the prevention and treatment of CoV diseases and discuss approaches to develop effective antivirals and vaccines.
Middle East Respiratory Syndrome: Emergence of a Pathogenic Human Coronavirus
In 2012 a zoonotic coronavirus was identified as the causative agent of Middle East respiratory syndrome and was named MERS coronavirus (MERS-CoV). As of August 11 2016 the virus has infected 1791 patients with a mortality rate of 35.6%. Although MERS-CoV generally causes subclinical or mild disease infection can result in serious outcomes including acute respiratory distress syndrome and multi-organ failure in patients with comorbidities. The virus is endemic in camels in the Arabian Peninsula and Africa and thus poses a consistent threat of frequent reintroduction into human populations. Disease prevalence will increase substantially if the virus mutates to increase human-to-human transmissibility. No therapeutics or vaccines are approved for MERS; thus development of novel therapies is needed. Further since many MERS cases are acquired in healthcare settings public health measures and scrupulous attention to infection control are required to prevent additional MERS outbreaks.
Animal Models, Zoonotic Reservoirs, and Cross-Species Transmission of Emerging Human-Infecting Coronaviruses
Over the past three decades coronavirus (CoV) diseases have impacted humans more than any other emerging infectious disease. The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) the causative agent of COVID-19 (coronavirus disease 2019) has resulted in huge economic disruptions and loss of human lives. The SARS-CoV-2 genome was found to mutate more rapidly due to sustained transmission in humans and potentially animals resulting in variants of concern (VOCs) that threaten global human health. However the primary difficulties are filling in the current knowledge gaps in terms of the origin and modalities of emergence for these viruses. Because many CoVs threatening human health are suspected to have a zoonotic origin identifying the animal hosts implicated in the spillover or spillback events would be beneficial for current pandemic management and to prevent future outbreaks. In this review wesummarize the animal models zoonotic reservoirs and cross-species transmission of the emerging human CoVs. Finally we comment on potential sources of SARS-CoV-2 Omicron VOCs and the new SARS-CoV-2 recombinants currently under investigation.
Continuous and Discontinuous RNA Synthesis in Coronaviruses
Replication of the coronavirus genome requires continuous RNA synthesis whereas transcription is a discontinuous process unique among RNA viruses. Transcription includes a template switch during the synthesis of subgenomic negative-strand RNAs to add a copy of the leader sequence. Coronavirus transcription is regulated by multiple factors including the extent of base-pairing between transcription-regulating sequences of positive and negative polarity viral and cell protein–RNA binding and high-order RNA-RNA interactions. Coronavirus RNA synthesis is performed by a replication-transcription complex that includes viral and cell proteins that recognize cis-acting RNA elements mainly located in the highly structured 5′ and 3′ untranslated regions. In addition to many viral nonstructural proteins the presence of cell nuclear proteins and the viral nucleocapsid protein increases virus amplification efficacy. Coronavirus RNA synthesis is connected with the formation of double-membrane vesicles and convoluted membranes. Coronaviruses encode proofreading machinery unique in the RNA virus world to ensure the maintenance of their large genome size.
Comparative Pathogenesis of Severe Acute Respiratory Syndrome Coronaviruses
Over the last two decades the world has witnessed the global spread of two genetically related highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. However the impact of these outbreaks differed significantly with respect to the hospitalizations and fatalities seen worldwide. While many studies have been performed recently on SARS-CoV-2 a comparative pathogenesis analysis with SARS-CoV may further provide critical insights into the mechanisms of disease that drive coronavirus-induced respiratory disease. In this review we comprehensively describe clinical and experimental observations related to transmission and pathogenesis of SARS-CoV-2 in comparison with SARS-CoV focusing on human animal and in vitro studies. By deciphering the similarities and disparities of SARS-CoV and SARS-CoV-2 in terms of transmission and pathogenesis mechanisms we offer insights into the divergent characteristics of these two viruses. This information may also be relevant to assessing potential novel introductions of genetically related highly pathogenic coronaviruses.
Three-Dimensional Imaging of Viral Infections
Video 4 Animation showing the membranous network assembled by severe acute respiratory syndrome (SARS) coronavirus in Vero E6 cells. Reproduced with permission from Reference 59.
Three-dimensional (3D) imaging technologies are beginning to have significant impact in the field of virology as they are helping us understand how viruses take control of cells. In this article we review several methodologies for 3D imaging of cells and show how these technologies are contributing to the study of viral infections and the characterization of specialized structures formed in virus-infected cells. We include 3D reconstruction by transmission electron microscopy (TEM) using serial sections electron tomography and focused ion beam scanning electron microscopy (FIB-SEM). We summarize from these methods selected contributions to our understanding of viral entry replication morphogenesis egress and propagation and changes in the spatial architecture of virus-infected cells. In combination with live-cell imaging correlative microscopy and new techniques for molecular mapping in situ the availability of these methods for 3D imaging is expected to provide deeper insights into understanding the structural and dynamic aspects of viral infection.
Human Coronavirus: Host-Pathogen Interaction
Human coronavirus (HCoV) infection causes respiratory diseases with mild to severe outcomes. In the last 15 years we have witnessed the emergence of two zoonotic highly pathogenic HCoVs: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Replication of HCoV is regulated by a diversity of host factors and induces drastic alterations in cellular structure and physiology. Activation of critical signaling pathways during HCoV infection modulates the induction of antiviral immune response and contributes to the pathogenesis of HCoV. Recent studies have begun to reveal some fundamental aspects of the intricate HCoV-host interaction in mechanistic detail. In this review we summarize the current knowledge of host factors co-opted and signaling pathways activated during HCoV infection with an emphasis on HCoV-infection-induced stress response autophagy apoptosis and innate immunity. The cross talk among these pathways as well as the modulatory strategies utilized by HCoV is also discussed.
The Flow Physics of Face Masks
Although face masks have been used for over a century to provide protection against airborne pathogens and pollutants close scrutiny of their effectiveness has peaked in the past two years in response to the COVID-19 pandemic. The simplicity of face masks belies the complexity of the physical phenomena that determine their effectiveness as a defense against airborne infections. This complexity is rooted in the fact that the effectiveness of face masks depends on the combined effects of respiratory aerodynamics filtration flow physics droplet dynamics and their interactions with porous materials structural dynamics physiology and even human behavior. At its core however the face mask is a flow-handling device and in the current review we take a flow physics–centric view of face masks and the key phenomena that underlie their function. We summarize the state of the art in experimental measurements as well as the growing body of computational studies that have contributed to our understanding of the factors that determine the effectiveness of face masks. The review also lays out some of the important open questions and technical challenges associated with the effectiveness of face masks.
Severe Acute Respiratory Syndrome (SARS): A Year in Review
Severe acute respiratory syndrome (SARS) emerged from China as an untreatable and rapidly spreading respiratory illness of unknown etiology. Following point source exposure in February 2003 more than a dozen guests infected at a Hong Kong hotel seeded multi-country outbreaks that persisted through the spring of 2003. The World Health Organization responded by invoking traditional public health measures and advanced technologies to control the illness and contain the cause. A novel coronavirus was implicated and its entire genome was sequenced by mid-April 2003. The urgency of responding to this threat focused scientific endeavor and stimulated global collaboration. Through real-time application of accumulating knowledge the world proved capable of arresting the first pandemic threat of the twenty-first century despite early respiratory-borne spread and global susceptibility. This review synthesizes lessons learned from this remarkable achievement. These lessons can be applied to re-emergence of SARS or to the next pandemic threat to arise.
Glycan Engagement by Viruses: Receptor Switches and Specificity
A large number of viruses including many human pathogens bind cell-surface glycans during the initial steps of infection. Viral glycan receptors such as glycosaminoglycans and sialic acid–containing carbohydrates are often negatively charged but neutral glycans such as histo–blood group antigens can also function as receptors. The engagement of glycans facilitates attachment and entry and consequently is often a key determinant of the host range tissue tropism pathogenicity and transmissibility of viruses. Here we review current knowledge about virus-glycan interactions using representative crystal structures of viral attachment proteins in complex with glycans. We illuminate the determinants of specificity utilized by different glycan-binding viruses and explore the potential of these interactions for switching receptor specificities within or even between glycan classes. A detailed understanding of these parameters is important for the prediction of binding sites where structural information is not available and is invaluable for the development of antiviral therapeutics.
Thinking Outside the Triangle: Replication Fidelity of the Largest RNA Viruses
When judged by ubiquity adaptation and emergence of new diseases RNA viruses are arguably the most successful biological organisms. This success has been attributed to a defect of sorts: high mutation rates (low fidelity) resulting in mutant swarms that allow rapid selection for fitness in new environments. Studies of viruses with small RNA genomes have identified fidelity determinants in viral RNA-dependent RNA polymerases and have shown that RNA viruses likely replicate within a limited fidelity range to maintain fitness. In this review we compare the fidelity of small RNA viruses with that of the largest RNA viruses the coronaviruses. Coronaviruses encode the first known viral RNA proofreading exoribonuclease a function that likely allowed expansion of the coronavirus genome and that dramatically increases replication fidelity and the range of tolerated variation. We propose models for regulation of coronavirus fidelity and discuss the implications of altered fidelity for RNA virus replication pathogenesis and evolution.
Ethics of Conducting Clinical Research in an Outbreak Setting
The conduct of clinical trials during the West Africa Ebola outbreak in 2014 highlighted many ethical challenges. How these challenges were addressed what clinical studies were conducted during that outbreak and the lessons learned for dealing with future outbreaks were the subject of a National Academy of Medicine committee report titled Integrating Clinical Research into Epidemic Response: The Ebola Experience. This report suggested improvements for research during subsequent emerging or re-emerging outbreaks and is summarized in this review. We also discuss the current Ebola outbreak in the Democratic Republic of the Congo and highlight how the dialogue has changed and how successful clinical trials have been implemented. We conclude with a description of productive efforts to include pregnant women and children in therapeutic and vaccine trials during outbreaks that are currently ongoing.
Structural Basis of SARS-CoV-2– and SARS-CoV–Receptor Binding and Small-Molecule Blockers as Potential Therapeutics
Over the past two decades deadly coronaviruses with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic have majorly challenged public health. The path for virus invasion into humans and other hosts is mediated by host–pathogen interactions specifically virus–receptor binding. An in-depth understanding of the virus–receptor binding mechanism is a prerequisite for the discovery of vaccines antibodies and small-molecule inhibitors that can interrupt this interaction and prevent or cure infection. In this review we discuss the viral entry mechanism the known structural aspects of virus–receptor interactions (SARS-CoV-2 S/humanACE2 SARS-CoV S/humanACE2 and MERS-CoV S/humanDPP4) the key protein domains and amino acid residues involved in binding and the small-molecule inhibitors and other drugs that have (as of June 2020) exhibited therapeutic potential. Specifically we review the potential clinical utility of two transmembrane serine protease 2 (TMPRSS2)-targeting protease inhibitors nafamostat mesylate and camostat mesylate as well as two novel potent fusion inhibitors and the repurposed Ebola drug remdesivir which is specific to RNA-dependent RNA polymerase against human coronaviruses including SARS-CoV-2.
Airborne Transmission of SARS-CoV-2: Evidence and Implications for Engineering Controls
Since late 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally causing a pandemic (coronavirus disease 2019 or COVID-19) with dire consequences including widespread death long-term illness and societal and economic disruption. Although initially uncertain evidence is now overwhelming that SARS-CoV-2 is transmitted primarily through small respiratory droplets and aerosols emitted by infected individuals. As a result many effective nonpharmaceutical interventions for slowing virus transmission operate by blocking filtering or diluting respiratory aerosol particularly in indoor environments. In this review we discuss the evidence for airborne transmission of SARS-CoV-2 and implications for engineering solutions to reduce transmission risk.
Structure-Based Vaccine Antigen Design
Enabled by new approaches for rapid identification and selection of human monoclonal antibodies atomic-level structural information for viral surface proteins and capacity for precision engineering of protein immunogens and self-assembling nanoparticles a new era of antigen design and display options has evolved. While HIV-1 vaccine development has been a driving force behind these technologies and concepts clinical proof-of-concept for structure-based vaccine design may first be achieved for respiratory syncytial virus (RSV) where conformation-dependent access to neutralization-sensitive epitopes on the fusion glycoprotein determines the capacity to induce potent neutralizing activity. Success with RSV has motivated structure-based stabilization of other class I viral fusion proteins for use as immunogens and demonstrated the importance of structural information for developing vaccines against other viral pathogens particularly difficult targets that have resisted prior vaccine development efforts. Solving viral surface protein structures also supports rapid vaccine antigen design and application of platform manufacturing approaches for emerging pathogens.
COVID-19 and the Environment: Short-Run and Potential Long-Run Impacts
This review examines observed and hypothesized environmental impacts of the coronavirus disease 2019 (COVID-19) pandemic. Impacts are considered along two axes: timescale (from initial widespread sheltering to a future after the economic recovery) and causal link (from direct impacts of protective measures to cascading impacts of policy choices and market and behavioral responses). The available literature documents both positive and negative environmental consequences. These include many early reports of positive impacts (such as clearer skies and wildlife returning to vacated areas). However it has become clear both that those benefits were largely temporary and that the prolonged health and economic disruptions pose acute risks to many terrestrial and marine ecosystems. Furthermore this review was completed just as the Omicron variant emerged. Given the pandemic's persistence the long timescales of cascading impacts and the inherent lags in research and publication this review provides an early view of what will eventually be known about the environmental impacts of the pandemic.