These unique intracellular parasites have managed to reproduce using other cells.. The finding that ACE2 is a primary SARS-CoV-2 receptor has further led to extensive discussion of dysregulation of the renin-angiotensin system, which regulates blood pressure and electrolyte balance.31–33 Conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme (ACE) activates pathways that lead to inflammation, vasoconstriction, oxidation, and fibrosis. A major factor influencing the future of COVID-19 is the ability of recovered people to develop protective immunity. Let's start with some basics. In this article, we’ll answer the question: how do viruses reproduce? Here's that plot: Notice that only parts of the data have linear fits, usually on the front end. At each step, I will calculate the number of infected people and from that calculate the number for the next day. Additionally, replication time (generation time) may be a larger component of understanding virus evolvability than it has been given credit for—likely undervalued because of the difficulties in measuring that trait in multicellular organisms [24, 25]. The exact nature of how viruses, RNA or DNA, replicate inside of a cell is not fully understood. Following uncoating and release of viral RNA into the cytoplasm, translation of open reading frame 1a (ORF1a) and ORF1ab produces the polyproteins pp1a and pp1ab. Potential strategies for treatment. The interferon-stimulated genes are then transcribed into RNA and translated into proteins that suppress viral replication and spread. Drugs that tamp down the pathogenic hyperactive inflammatory response and cytokine storm later in disease progression. Viruses need the reproductive mechanisms of a living cell in order to multiply, but first the virus must get inside the cell. The sequence of the cleavage sites, one located at the border of S1 and S2 subunits, the other (S2′) within S2 just upstream of the fusion peptide, provide substrates for a variety of cellular proteases and determine cleavage efficiency. The number of cases seems small—until they're not, and then it's too late. Copyright © 2020 The Cleveland Clinic Foundation. However, in the real sense they do not really reproduce, but multiply. Solve this simple math problem and enter the result. 1 Summary of mouse hepatitis virus (MHV) replication. Transfusion of convalescent plasma from recovered patients had beneficial outcomes in a small number of SARS and COVID-19 cases.43 Based on preliminary results of convalescent serum as well as in vitro and in vivo neutralization studies, clinical trials will be launched to evaluate the efficacy of spike protein-based vaccines. The ferret model will provide a useful tool to test multiple therapeutic and preventive treatments.8, Based on information in references 1, 10, 13, and 47, The remaining portion of the genome includes interspersed open reading frames for the structural proteins, as well as a number of accessory proteins generally nonessential for replication in tissue culture but capable of suppressing immune responses and enhancing pathogenesis.10,11. What’s all the fuss?" However, bacteriophages (viruses that infect bacteria) have a unique shape, with a geometric head and filamentous tail fibers. ... replicate itself and spread to other carriers. Oh, a numerical calculation is where you break the problem into small time steps. In the host nucleus, the virus does primary transcription to produce necessary proteins for replication. [Ed: The official CDC count did indeed hit 16,605 cases by midday on Friday, March 20, and is now at 32,644 at midday Sunday, March 22.] A virus is an infectious agent that requires a host cell/organism to multiply. Protective host features? Use of this website is subject to the website terms of use and privacy policy. This task is carried out by the viral "copy machine", the polymerase. How do the lungs protect themselves? The information provided is for educational purposes only. [Ed: The official CDC count did indeed hit 16,605 cases by midday on Friday, March 20, and is now at 32,644 at midday Sunday, March 22.]. When N is 10,000, there will be 2,000 new cases the next day. Let’s Do the Math. In order to replicate, this means that the virus must first produce positive sense mRNA in order to produce necessary enzymes. It says that for a while there, South Korea was really out of control with an infection rate of 0.614. The replication mechanism depends on the viral genome. Attachment: Viral proteins on the capsid or phospholipid envelope interact with A statement of activity from the directors of the Board and the Scientific Directors of the Italian Society of Hypertension, Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients, Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China, Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection, Long-lived memory T lymphocyte responses against SARS coronavirus nucleocapsid protein in SARS-recovered patients, Long-lived effector/central memory T-cell responses to severe acute respiratory syndrome coronavirus (SARS-CoV) S antigen in recovered SARS patients, Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study, Profiling early humoral response to diagnose novel coronavirus disease (COVID-19), Treatment of 5 critically ill patients with COVID-19 with convalescent plasma, Genetic variability of human coronavirus OC43-, 229E-, and NL63-like strains and their association with lower respiratory tract infections of hospitalized infants and immunocompromised patients, Phylogenetic network analysis of SARS-CoV-2 genomes, Computational inference of selection underlying the evolution of the novel coronavirus, SARS-CoV-2, Broad-spectrum coronavirus antiviral drug discovery, An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice, Interferon therapy for COVID-19 and emerging infections: Prospects and concerns, Patient Subsets & Specific Organ Involvement, THE BODY MOUNTS AN INNATE IMMUNE RESPONSE. In order to replicate, viruses need to infect a host cell and hijack the host machinery to make many copies of the viral genome, and lots of viral proteins which are then assembled into new virus particles. Ad Choices, How Fast Does a Virus Spread? FAST FACTS. So then you might think the total will grow by 4,000 every two days. For many plant viruses to be transferred from plant to plant, damage to some of the plants’ cells must occur to allow the virus to enter a new host. Oh, for both Italy and Iran, it looks like there are two different infection rates that are still exponential. The Sars-CoV-2 virus almost certainly originated in bats, which have evolved fierce immune responses to viruses, researchers have discovered. The increases we’re seeing now partly reflect the fact that more people are getting tested—there were clearly more infected people already out there than we knew about, maybe far more. Once the enzymes are translated, replication can take place. It's a frightening trend, one that's likely to continue. San Francisco Chronicle reporter Mike Moffitt did … Bottom. While multiple organs, including the heart, kidneys, liver, and gastrointestinal tract, are injured, it remains to be resolved to what extent tissues are damaged by infection, hypoxia, or the immune response. While physical distancing is an effective control measure to limit acute infection rates, asymptomatic carriers will likely continue to spread the virus, leading to ongoing hotspots of symptomatic infection. With respect to currently circulating SARS-CoV-2 and limited overall testing, it is also unknown whether the virus is affected by seasonal changes. And why is it called exponential growth anyway? It should be a linear function. Copyright © 2020 The Cleveland Clinic Foundation. Without it, the virus would be unable to reproduce. STRATEGIES. The virus that causes Covid-19 is currently spreading around the world.At least six other types of coronavirus are … Now we have something nice. Interaction takes place between spike G protein and specific cell surface receptors. (I like that joke.) The influenza virus has a negative sense RNA genome. RNA viruses usually use the RNA core as a template for synthesis of viral genomic RNA and mRNA. If you are using a mobile device, click on the settings icon to access the Register link. The predominant entry routes are cell type-specific and dependent on availability of select proteases. However, we would like to emphasize that at present, these strategies are investigational only, including the off-label use of existing drugs, and may prove to show no efficacy and could be harmful in controlled clinical trials. Such animal-origin viruses can contain an HA or HA/NA combination that is so different from the same subtype in humans that most people do not have immunity to the new (e.g., novel) virus. Fig. Department of Neuroscience, Cleveland Clinic Lerner Research Institute; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, Department of Cancer Biology, Cleveland Clinic Lerner Research Institute; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, Sign In to Email Alerts with your Email Address. This first takes place in the upper respiratory tract, which includes the nose, mouth, larynx and bronchi. All rights reserved. Although such databases currently reflect a population naïve to the virus, similar studies can be conducted once vaccines become available to test the effects of immune pressure on the virus. Although mechanistic insights are as yet unavailable, we do have a good understanding of how other coronaviruses evade interferon’s antiviral activity,18 and also how we could engage antiviral factors to promote interferon activity.19, In general, coronaviruses can potently antagonize antiviral innate immunity by interfering with both interferon production and the cellular antiviral response.20 For instance, mouse coronaviruses and MERS-CoV have accessory proteins that block an interferon response pathway that degrades the viral RNA (by oligoadenylate synthetase and ribonuclease L).21,22. Formation of the RNA replicase–transcriptase complex (RTC) uses rough endoplasmic reticulum (ER)-derived membranes. How the Corona Virus Cleverly uses our own cells of the body to replicate themselves and make thousands of new Corona Viruses. Bats have been implicated as the likely source of SARS-CoV-2, as both SARS-CoV and MERS-CoV are genetically similar to viruses recovered from bats, and bat coronaviruses can use human receptors for cell entry.4 However, phylogenetic studies, looking at sequence-based virus evolution, suggest that the virus is not transmitted directly from bats to humans but rather first infects intermediate animal hosts in close contact with humans. The WIRED conversation illuminates how technology is changing every aspect of our lives—from culture to business, science to design. Ebola Virus do not replicate through any kind of cell division; rather, they use a combination of host and virally encoded enzymes, alongside host cell structures, to produce multiple copies of viruses. So this is an exponential function. Coronaviruses are spherical enveloped viruses containing a single strand of positive-sense RNA (similar to host mRNA) of approximately 26 to 32 kb.10 Their defining morphologic features are club-shaped projections from the viral envelope resembling a crown or a solar corona, made of a highly glycosylated protein, named spike protein. Infectious diseases grow exponentially, not linearly. 1. It's much worse than that. There are two processes used by viruses to replicate: the lytic cycle and lysogenic cycle. Such a “shift” occurred in the spring of 2009, when an H1N1 virus with genes from North American Swine, Eurasian Swine, humans and birds emerged to infect people and quickly spread, causing a pandemic. You can obtain a formula for N as a function of time analytically (using differential equations), but let's solve it numerically first. Her parents would pay her daily, but the amount is only 1 cent today. RNA VIRUS REPLICATION - GENERAL. The primary transcription involves what is known as "cap snatching." The translated structural proteins and genomic RNA are assembled into the viral nucleocapsid and envelope in the ER–Golgi intermediate compartment, and are subsequently released by exocytosis. Takeover occurs. Infectious diseases grow exponentially, not linearly. Let’s Do the Math. Flu, for one, seems to survive longer in cool, dry environments , which … The route or routes of infection thus depend on the proteases available in different cell types and the protease cleavage sites.14 This is also demonstrated by involvement of the cellular serine protease TMPRSS2 (transmembrane protein serine protease 2) and activities of furin and endosomal cathepsins B and L in SARS-CoV-2 entry.12 TMPRSS2 activity is also involved in viral spread and pathogenesis in SARS-CoV-infected and MERS-CoV-infected mouse models.15, Host proteases that cleave the S protein are also potential targets for antiviral drugs (Figure 2). Human coronaviruses, along with influenza virus, human metapneumovirus, respiratory syncytial virus, and rhinovirus, are endemic and cause approximately 15% to 30% of annual respiratory tract infections. Other cellular proteases, eg, furin (in orange), facilitate pH-dependent entry through the endocytic pathway. The COVID-19 coronavirus uses an unusually complex method to replicate itself inside human cells, and experts say the somewhat clunky process could be exploited to stop the virus … A variety of factors can influence how fast these airborne viruses can spread. WIRED is where tomorrow is realized. Nevertheless, current recommendations are to continue treatment.32,33 The complexity of the renin-angiotensin system will require more extensive retrospective analysis of larger and ethnically diverse patient groups. for 1+3, enter 4. Middle. Different ACE2 expression? The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of Condé Nast. If you want to disrupt COVID-19’s intricate self-replication machinery—and bring the virus to a screeching halt—you can’t simply throw a spanner in the works. The S1 subunit mediates ACE2 attachment through the receptor-binding domain. Let’s get started. There are six main stages in a typical virus replication cycle. © 2020 Condé Nast. Like I said, if the infection stayed exponential, the whole world would soon be sick. Wired may earn a portion of sales from products that are purchased through our site as part of our Affiliate Partnerships with retailers. Another critical unresolved aspect of COVID-19 is the establishment of adaptive immunity. Then suddenly, with no change in the infection rate, it explodes. That would be wrong; that’s linear thinking. We wish to thank Drs. Viruses generally come in two forms: rods or spheres. COVID-19: Coronavirus replication, pathogenesis, and therapeutic strategies, DOI:, SARS and MERS: recent insights into emerging coronaviruses, SARS-CoV-2: virus dynamics and host response, SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems, Origin and evolution of pathogenic coronaviruses, Host and viral traits predict zoonotic spillover from mammals, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Infection and rapid transmission of SARS-CoV-2 in ferrets, Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2, Coronaviruses: an overview of their replication and pathogenesis, Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and recep tor binding, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor, Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor, Host cell proteases: critical determinants of coronavirus tropism and pathogenesis, TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection, Probable pangolin origin of SARS-CoV-2 associated with the COVID-19 outbreak, Interferons at age 50: past, current and future impact on biomedicine, Ifit2 deficiency results in uncontrolled neurotropic coronavirus replication and enhanced encephalitis via impaired alpha/beta interferon induction in macrophages, Cell-type-specific activation of the oligoadenylate synthetase-RNase L pathway by a murine coronavirus, Middle East respiratory syndrome coronavirus NS4b protein inhibits host RNase L activation, SARS-CoV-2 is sensitive to type I interferon pretreatment, Type 1 interferons as a potential treatment against COVID-19, A first case of meningitis/encephalitis associated with SARS-Coronavirus-2, Neurological manifestations in COVID-19 caused by SARS-CoV-2, Exploring the pathogenesis of severe acute respiratory syndrome (SARS): the tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells, Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. In the lytic cycle, the virus attaches to the host cell and injects its DNA. To be activated for fusion, the spike protein must be cleaved at 2 sites directly at the cell membrane, through endosomes, or both. Coronavirus spike proteins are key determinants for virus attachment and entry into target cells. The moral here is that individual efforts—especially early on, when it doesn't seem to matter—really, really do matter. But how about just turning an exponential function into a linear function? Not only does each type of coronavirus encode different accessory proteins responsible for allowing the virus to escape cellular innate immune mechanisms, but distinct cell types may respond differently. Severe disease is associated with lymphopenia and an uncontrolled systemic inflammatory response called a cytokine storm, which ultimately leads to multiple organ failure and death.34,35 Autopsy results reveal severe damage to endothelial tissue, vasculitis-like manifestations, and atrophy of secondary lymphoid tissues.35 Early studies in COVID-19 patients showed higher plasma levels of interleukin 2 (IL-2), IL-7, granulocyte colony-stimulating factor, C-X-C motif chemokine 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1a (chemokine [C-C motif] ligand 2), and tumor necrosis factor (TNF), but also anti-inflammatory IL-10, in intensive care patients than in nonintensive care patients.36 Several reports also confirm high levels of IL-6 in severely ill patients.2,37 Retrospective clinical investigation of more patient cohorts without or with preexisting conditions and of those being treated with distinct anti-inflammatory immune modulators, eg, anti-TNF, anti-IL-6, anti-IL12/IL23 or anti-IL-1 beta for immune-mediated inflammatory conditions will provide much-needed guidance on treatment to stem severe COVID-19. VIRAL AND HOST TARGETS FOR THERAPIES AND VACCINES, Cleveland Clinic Center for Continuing Education. What if the infection rate is 0.19 instead of 0.20? Here's what I get for each country: What does this tell us? A first step in understanding SARS pathogenesis, The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2, Angiotensin converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system, Renin-angiotensin system inhibition in cardiovascular patients at the time of COVID19: much ado for nothing? RNA viruses that do not have a DNA phase Viruses that replicate via RNA intermediates need an RNA-dependent RNA-polymerase to replicate their RNA, but animal cells do not seem to possess a suitable enzyme. The “cytokine storm” induced as a host response to rampant virus replication may be targeted by administration of select anti-inflammatory immune modulators, which are already given to patients with inflammatory disorders. Released virus can infect other cells and can replicate within the parent cell through binding to CEACAM-1. Viruses are intracellular obligate parasites, which means that they cannot replicate or express their genes without the help of a living cell.A single virus particle (virion) is in and of itself essentially inert. ! From the perspective of the virus, the purpose of viral replication is to … At that rate, it will grow from 8,000 on Wednesday to 16,000 on Friday, and 32,000 by Sunday. Virus assembly occurs within vesicles, followed by virus release by fusion of virion-containing vesicles with the plasma membrane. The large number of host antiviral mechanisms and distinct viral antagonism at different steps in the virus replication cycle have made it difficult to identify the most relevant ones. Iran and Italy both had significant decreases in rates. Small change, right? Ferrets can be infected, with intraspecies transmission,8 and cats can also be infected and transmit the virus to other cats, while dogs have low susceptibility. The infection process is initiated with adsorption of virus on the host cell. They use the genetic mechanism of living cells to replicate. This is not unique to coronaviruses, as endemics and pandemics also occur when novel influenza A virus strains emerge in the human population from an animal host.5 Similar to introduction of Ebolavirus and human immunodeficiency virus 1 by mammals, many other viruses circulating in wild animals have the potential for zoonotic transmission.6, SARS-CoV-2, the causative agent for the pandemic corona virus disease of 2019 (COVID-19) outbreak, was first found in Wuhan, China, and initial analysis of viral RNA obtained from patients hospitalized in late 2019 revealed it was 96% identical at the whole-genome level to a bat SARS-like coronavirus.7, Uniquely, SARS-CoV-2 can be transmitted by people who are infected but have no symptoms, not just by symptomatic patients. But here's the important part. A capsid is … Upper left. The replication cycle can be blocked at several stages using single or combined treatment paradigms: virus entry can be inhibited by antispike antibodies elicited by vaccines to block attachment or by preventing fusion using relevant protease inhibitors. It is at this stage a distinction between susceptibility and permissibility of a host cell is made. We also thank David Schumick, Center for Medical Art and Photography, Cleveland Clinic, for expert artwork. ... A variety of factors can influence how fast these airborne viruses can spread. How viruses do this depends mainly on the type of nucleic acid DNA or RNA they contain, which is either one or the other but never both. Positive sense cRNA is then made from the original negative sense RNA, using the enzymes. That’s why viruses … What this means is that the viral endonuclease (PB2) cuts the 5' methylguanosine cap as well as ten to thirteen nucleotides from the RNA. HIV infects white blood cells in the body’s immune system called T-helper cells (also called CD4 cells). But what about real data? Molecular techniques are used to compare the DNA and RNA of viruses and find out more about where they come from. About 12 hours after infection, the viruses are released from the host cell, usually resulting in its death. However, it is unknown if any of these animals can transmit the virus to humans.9. Viruses do not leave fossil remains, so they are difficult to trace through time. These then self-assemble into viral macromolecular structures in the host cell. Finally, it looks like the US and France are in similar situations, but France is just a few days ahead. They can’t do this on their own. By the way, that graph is generated by a simple Python script, and you can change the numbers to see what happens. E.g. I have Googled it and looked in my book, but I can't seem to find it. You, all by yourself, can be a superhero and save lives. How viruses replicate. The replication cycle can be blocked at several stages using single or combined treatment paradigms: virus entry can be inhibited by antispike antibodies elicited by vaccines to block attachment or by preventing fusion using relevant protease inhibitors.12 RTC formation and transcription-replication events can be targeted using viral protease inhibitors or nucleoside analogues (GS-5734 or EIDD-1931).48 Interferon (IFN) responsiveness can be increased by early exogenous IFN treatment,24 IFN inducer treatment, repression of viral IFN antagonists, and enhancement of host antiviral IFN pathways. Most DNA viruses assemble in the nucleus while most RNA viruses develop solely in cytoplasm. A better understanding of the precise functions of the SARS-CoV-2 accessory proteins, especially their interaction with innate immune pathways could lead to novel antiviral drugs that promote the innate immune response. By Wednesday it had grown to around 8,000. With the genetic material of the virus released, the virus is now able to take control of the cell. However, the ongoing yearly infection rates by historically circulating coronaviruses,44 as well as evidence for already distinct SARS-CoV-2 variants45 suggest that established immunity may be insufficient to avoid recurring infections. These in turn are processed by viral proteases (encoded by ORF1a) to yield 16 nonstructural proteins. We do not capture any email address. A cell's membrane is made out of protein molecules, and some molecules have specially shaped receptors, or landing sites, where other molecules with matching shapes can land and dock. Maybe this popular parable will give you a feel for exponential growth: A kid wants to boost her allowance, and she proposes an unusual deal. The variola virus can replicate itself without using any of the host cell's replication organelles. The protective host features underlying the asymptomatic infections are currently unknown, as testing within many countries is limited to people presenting with symptoms such as severe shortness of breath, coughing, and fever. You can get all sorts of data online—I'm using coronavirus numbers from Our World in Data. When a mammal has the misfortune of being infected with two (or more) respiratory viruses at once, as the viruses replicate, the two genetic decks can be shuffled together and then redealt. Please help!! Concern about potential spread of SARS-CoV-2 to household cats has emerged from a news report of infection in a tiger in the Bronx Zoo. Suppose we have a population, and a certain number (N) of them are carrying the Covid-19 virus. So how do you model the spread of a viral infection? First, since part of the plot is linear, this means it is indeed exponential growth. MHV binds to the host-cell receptor CEACAM-1 through interaction of the spike (S) glycoprotein. What if you could reduce the infection rate by just a little bit? In tissue culture, poliovirus enters cells and replicates in six to eight hours, yielding 10,000 to 100,000 virus particles per cell. For a virus to spread, it must first find a way into a cell. For each infected person, there is some probability that they’ll pass it on to others. Renin-angiotensin system dysregulation? But here's the crazy part: This is like a car that is moving, but the speed depends on where it is. Viruses that replicate through DNA use the same mechanisms the host cell uses to create its own DNA, a process that includes a kind of "proof-reading" of the genetic material being copied. Fortunately, that lasted only about five days, and then it stopped being exponential. Interferons I and III are cytokines with critical roles in the innate immune response against viral infections.17 Virus-infected cells induce and secrete interferon I molecules that bind to the cell surface receptor IFNAR (interferon III uses a different receptor), thereby triggering the Jak-Stat (Janus kinase/signal transducer and activator of transcription) signaling pathway that switches on many antiviral genes. Viruses are not capable of replicating their genes by themselves. These defences drive viruses to replicate … Use of this site constitutes acceptance of our User Agreement (updated 1/1/20) and Privacy Policy and Cookie Statement (updated 1/1/20) and Your California Privacy Rights. ACE2 activity counterbalances this pathway by cleaving both angiotensin I and angiotensin II to shorter peptides, which use distinct receptors to promote vasodilation, as well as anti-inflammatory, antioxidant, and antifibrosis activity. Using the rate of change formula above, I get the following infected update expression: Just to be clear on the notation here, Ni is the i’th day and Ni+1 is the day after that. A higher rate of SARS-CoV-2 infections compared with SARS-CoV infections may be at least partially explained by a higher affinity of spike protein for ACE2.13 The sequence divergence in both the receptor-binding domain and cleavage domains in the spike protein between SARS-CoV-2 and the bat virus highlight how only a few changes are needed to adapt an animal virus to humans.7,12,13,16.