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Could SARS-CoV-2/COVID-19 simply fade away?
Abstract
Since its emergence in Wuhan, China, on November 2019, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been progressively invading every corner of the world. As of today (April 30), it is responsible for more than 3.2 million confirmed cases and more than 220 thousand deaths in 186 countries (1). SARS-CoV-2 belongs to the enveloped, positive-sense, single-stranded RNA (+ssRNA) Coronaviridae family of viruses, which includes at least 49 different species (2). Coronaviruses are known to infect both birds and mammals, usually producing either respiratory or gastrointestinal diseases (3). Two previous highly pathogenic outbreaks of coronavirus infections have occurred during the last decades: severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak which started in China in 2003 (4), and Middle East Respiratory Syndrome coronavirus (MERS-CoV), first identified in Saudi Arabia in 2012 (5). Both of those had a fast expansion and a relatively high case fatality rate (CFR), but after being subject to crucial public health, interventions to control their dissemination. Before a vaccine could be developed, both diseases tended to fade away.
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Purpose of Review: In this review, we discuss the current implications of the changing genomic epidemiology of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), etiological agent of the Coronavirus Disease 2019 (COVID-19) and its potential relationship with the change of clinical manifestations in patients with confirmed infection.
Recent Findings: Over the course of the current pandemic, the virus has been found more diverse in new countries. Simultaneously, also new clinical manifestations are observed, particularly more prominent gastrointestinal and neurological findings.
Summary: SARS-CoV-2/COVID-19 is changing not only its epidemiology, but also its genomic diversity and clinical manifestations, both aspects coupled, needs to be considered in the study of this ongoing pandemic.
Over the course of three months (December 2019-March 2020) the pandemic of the Coronavirus Disease 2019 (COVID-19) (1), caused by a zoonotic virus (2), the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has raised multiple concerns and triggered an unprecedented and deep impact across multiple areas of biomedical research, especially the disciplines of molecular biology, virology with particular emphasis on molecular epidemiology, and comparative genomics (3).
According the International Association of Epidemiology, molecular epidemiology is defined as the application of epidemiologic principles to study the molecular, biochemical, cellular and genetic mechanisms that underlie the pathophysiology, etiology and prevention of human diseases and related outcomes, as well as their early detection, treatment, or prognosis.
From an instrumental viewpoint, the use in epidemiological research of molecular and cell biology techniques as well as the integration of genetics and systems biology into the interdisciplinary “omics” approach has revolutionized translational research and greatly contributed to the discovery of novel biomarkers allowing tracing systems through genome navigation, the so called genomic epidemiology. Molecular epidemiology is making valuable contributions to biomedical, clinical, and population sciences with exceptional impact on the role of gene-environment interactions, etiology of diseases and the complex drivers of disease progression by generating sound evidence about the underlying biological mechanisms and by providing knowledge with to potential primary prevention strategies (4).
Advances in sequencing technology has blossomed into a new era of genomic epidemiology, where traditional molecular diagnostics and genotyping methods are being enhanced and even replaced by novel throughput genomics-based methods to aid in the epidemiologic investigations of communicable diseases. The ability to analyze and compare entire pathogen genomes has allowed for unprecedented resolution into how and why infectious diseases spread. As these genomics-based methods continue to improve in speed, cost, and accuracy, they will be increasingly adopted to inform and guide infection control and public health practices (5).
The present outbreak of a coronavirus-associated acute respiratory disease called coronavirus disease 19 (COVID-19) is the third documented spillover of an animal coronavirus to humans in only two decades that has resulted in a major epidemic. The Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses, which is responsible for developing the classification of viruses and taxon nomenclature of the family Coronaviridae, has assessed the placement of the human pathogen, tentatively named 2019-nCoV, within the Coronaviridae. Based on phylogeny, taxonomy and established practice, the CSG recognizes this virus as forming a sister clade to the prototype human and bat severe acute respiratory syndrome coronaviruses (SARS-CoVs) of the species Severe acute respiratory syndrome-related coronavirus, and designates it as SARS-CoV-2. In order to facilitate communication, the CSG proposes to use the following naming convention for individual isolates: SARS-CoV-2/host/location/isolate/date. While the full spectrum of clinical manifestations associated with SARS-CoV-2 infections in humans remains to be determined, the independent zoonotic transmission of SARS-CoV and SARS-CoV-2 highlights the need for studying viruses at the species level to complement research focused on individual pathogenic viruses of immediate significance. This will improve our understanding of virus–host interactions in an ever-changing environment and enhance our preparedness for future outbreaks.
Sixty-one SARS coronavirus genomic sequences derived from the early,
middle, and late phases of the severe acute respiratory syndrome (SARS)
epidemic were analyzed together with two viral sequences from palm
civets. Genotypes characteristic of each phase were discovered, and the
earliest genotypes were similar to the animal SARS-like coronaviruses.
Major deletions were observed in the Orf8 region of the genome, both at
the start and the end of the epidemic. The neutral mutation rate of the
viral genome was constant but the amino acid substitution rate of the
coding sequences slowed during the course of the epidemic. The spike
protein showed the strongest initial responses to positive selection
pressures, followed by subsequent purifying selection and eventual
stabilization.
A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.
Background
The H1N1 influenza A virus has been circulating in the human population for over 95 years, first manifesting itself in the pandemic of 1917–1918. Initial mortality was extremely high, but dropped exponentially over time. Influenza viruses have high mutation rates, and H1N1 has undergone significant genetic changes since 1918. The exact nature of H1N1 mutation accumulation over time has not been fully explored.
Methods
We have made a comprehensive historical analysis of mutational changes within H1N1 by examining over 4100 fully-sequenced H1N1 genomes. This has allowed us to examine the genetic changes arising within H1N1 from 1918 to the present.
Results
We document multiple extinction events, including the previously known extinction of the human H1N1 lineage in the 1950s, and an apparent second extinction of the human H1N1 lineage in 2009. These extinctions appear to be due to a continuous accumulation of mutations. At the time of its disappearance in 2009, the human H1N1 lineage had accumulated over 1400 point mutations (more than 10% of the genome), including approximately 330 non-synonymous changes (7.4% of all codons). The accumulation of both point mutations and non-synonymous amino acid changes occurred at constant rates (μ = 14.4 and 2.4 new mutations/year, respectively), and mutations accumulated uniformly across the entire influenza genome. We observed a continuous erosion over time of codon-specificity in H1N1, including a shift away from host (human, swine, and bird [duck]) codon preference patterns.
Conclusions
While there have been numerous adaptations within the H1N1 genome, most of the genetic changes we document here appear to be non-adaptive, and much of the change appears to be degenerative. We suggest H1N1 has been undergoing natural genetic attenuation, and that significant attenuation may even occur during a single pandemic. This process may play a role in natural pandemic cessation and has apparently contributed to the exponential decline in mortality rates over time, as seen in all major human influenza strains. These findings may be relevant to the development of strategies for managing influenza pandemics and strain evolution.
Ribavirin, an antiviral drug discovered in 1972, is interesting and important for three reasons: (a) it exhibits antiviral activity against a broad range of RNA viruses; (b) it is currently used clinically to treat hepatitis C virus infections, respiratory syncytial virus infections, and Lassa fever virus infections; and (c) ribavirin's mechanism of action has remained unclear for many years. Here we recount the history of ribavirin and review recent reports regarding ribavirin's mechanism of action, including our studies demonstrating that ribavirin is an RNA virus mutagen and ribavirin's primary antiviral mechanism of action against a model RNA virus is via lethal mutagenesis of the RNA virus genomes. Implications for the development of improved versions of ribavirin and for the development of novel antiviral drugs are discussed.
In less than two months, an emerging threat entirely and radically changed the life of the population in Latin America.1 From February 25, 2020, when the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19), was firstly confirmed in Brazil, proceeding as an imported case from Italy, up to April 17, 2020, more than 81,000 cases have been reported in the Latin America and Caribbean region.2 More than 63,000 of them in South America, and more than 28,000 just in Brazil.3
COVID-19 endanger a broad spectrum of disease, going from asymptomatic cases that may recover with no specific interventions, up to complicated severe, life-threatening and even fatal disease, that may lead to unknown non-acute consequences, still to be better defined.1,2 In such a complex clinical scenario, the epidemiological situation of Brazil and most countries in Latin America before February 25, 2020, was already intricate, with overlapping epidemics of multiple vector-borne diseases, including especially dengue and yellow fever, but also, still struggling with long-term consequences, and endemicity, of 2014-2016 epidemics of chikungunya and Zika.1,4
Sadly, also the last years' vaccine coverages in multiple countries of Latin America, but also some areas of individual nations, have significantly decrease, allowing the imminent menace of imported cases and spreading with local transmission of this once not reported old diseases, such as is especially the case of measles, that in fact, due to forced migration from Venezuela arrived especially to Roraima and Amazonas to lead to thousands of cases in the region.4
If this is not enough, the political scenario is not friendly for evidence-based decisions. The high-rank stakeholders have not broadly followed the recommendations of the World Health Organization before or after the arrival of COVID-19 to the new world. Once world-recognized for the efforts in the fight against major infectious threats, such as HIV, tuberculosis, and malaria, Brazil is going facing now a challenge in the control of these infectious diseases but also confronting now one of the major epidemics in the history of the country with the pandemic COVID-19.1
Over the past weeks the spread of the Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [1], has been steady in Asia and other regions in the world. Latin America was an exception until February 25, 2020, when the Brazilian Ministry of Health, confirmed the first case.
This first case was a Brazilian man, 61 years-old, who traveled from February 9 to 20, 2020, to Lombardy, northern Italy, where a significant outbreak is ongoing. He arrived home on February 21, 2020, and was attended at the Hospital Albert Einstein in São Paulo, Brazil. At this institution, an initial real-time RT-PCR was positive for SARS-CoV-2 and then confirmed by the National Reference Laboratory at the Instituto Adolfo Lutz using the real-time RT-PCR protocol developed by the Institute of Virology at Charité in Berlin, Germany [2]. The established protocol also included now, as part of the Sao Paulo State Health Secretary, to include metagenomics and immunohistochemistry with PCR, as part of the response plan to COVID-19 outbreak in the city [3]. The patient presented with fever, dry cough, sore throat, and coryza. So far, as of February 27, the patient is well, with mild signs. He received standard precautionary care, and in the meantime, he is isolated at home [4]. Local health authorities are carrying out the identification and tracing of contacts at home, at the hospital, and on the flight. For now, other cases are under investigation in São Paulo, and other cities in Latin America. In addition to the Sao Paulo State Health Secretary, the Brazilian Society for Infectious Diseases have developed technical recommendations [4].
Human coronaviruses (HCoVs), including SARS-CoV and MERS-CoV, are zoonotic pathogens that originated in wild animals. HCoVs have large genomes that encode a fixed array of structural and nonstructural components, as well as a variety of accessory proteins that differ in number and sequence even among closely related CoVs. Thus, in addition to recombination and mutation, HCoV genomes evolve through gene gains and losses. In this review we summarize recent findings on the molecular evolution of HCoV genomes, with special attention to recombination and adaptive events that generated new viral species and contributed to host shifts and to HCoV emergence.
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