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Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.
Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold, while more lethal varieties can cause SARS, MERS and COVID-19, which is causing the ongoing pandemic. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis.
Severe-acute-respiratory-syndrome–related coronavirus is a species of virus consisting of many known strains. Two strains of the virus have caused outbreaks of severe respiratory diseases in humans: severe acute respiratory syndrome coronavirus 1, which caused the 2002–2004 outbreak of severe acute respiratory syndrome (SARS), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is causing the ongoing pandemic of COVID-19. There are hundreds of other strains of SARSr-CoV, which are only known to infect non-human mammal species: bats are a major reservoir of many strains of SARSr-CoV; several strains have been identified in Himalayan palm civets, which were likely ancestors of SARS-CoV-1.
Coronaviridae is a family of enveloped, positive-strand RNA viruses which infect amphibians, birds, and mammals. The group includes the subfamilies Letovirinae and Orthocoronavirinae; the members of the latter are known as coronaviruses.
Murine coronavirus (M-CoV) is a virus in the genus Betacoronavirus that infects mice. Belonging to the subgenus Embecovirus, murine coronavirus strains are enterotropic or polytropic. Enterotropic strains include mouse hepatitis virus (MHV) strains D, Y, RI, and DVIM, whereas polytropic strains, such as JHM and A59, primarily cause hepatitis, enteritis, and encephalitis. Murine coronavirus is an important pathogen in the laboratory mouse and the laboratory rat. It is the most studied coronavirus in animals other than humans, and has been used as an animal disease model for many virological and clinical studies.
ORF7a is a gene found in coronaviruses of the Betacoronavirus genus. It expresses the Betacoronavirus NS7A protein, a type I transmembrane protein with an immunoglobulin-like protein domain. It was first discovered in SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS). The homolog in SARS-CoV-2, the virus that causes COVID-19, has about 85% sequence identity to the SARS-CoV protein.
Susan R. Weiss is an American microbiologist who is a Professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania. She holds vice chair positions for the Department of Microbiology and for Faculty Development. Her research considers the biology of coronaviruses, including SARS, MERS and SARS-CoV-2. As of March 2020, Weiss serves as Co-Director of the University of Pennsylvania/Penn Medicine Center for Research on Coronavirus and Other Emerging Pathogens.
Karen Louise Mossman is a Canadian virologist who is a professor of Pathology and Molecular Medicine at McMaster University. Mossman looks to understand how viruses get around the defence mechanisms of cells. She was part of a team of Canadian researchers who first isolated SARS-CoV-2.
ORF3b is a gene found in coronaviruses of the subgenus Sarbecovirus, encoding a short non-structural protein. It is present in both SARS-CoV and SARS-CoV-2, though the protein product has very different lengths in the two viruses. The encoded protein is significantly shorter in SARS-CoV-2, at only 22 amino acid residues compared to 153–155 in SARS-CoV. Both the longer SARS-CoV and shorter SARS-CoV-2 proteins have been reported as interferon antagonists. It is unclear whether the SARS-CoV-2 gene expresses a functional protein.
ORF3d is a gene found in SARS-CoV-2 and at least one closely related coronavirus found in pangolins, though it is not found in other closely related viruses within the Sarbecovirus subgenus. It is 57 codons long and encodes a novel 57 amino acid residue protein of unknown function. At least two isoforms have been described, of which the shorter 33-residue form, ORF3d-2, may be more highly expressed, or even the only form expressed. It is reported to be antigenic and antibodies to the ORF3d protein occur in patients recovered from COVID-19. There is no homolog in the genome of the otherwise closely related SARS-CoV.
The envelope (E) protein is the smallest and least well-characterized of the four major structural proteins found in coronavirus virions. It is an integral membrane protein less than 110 amino acid residues long; in SARS-CoV-2, the causative agent of Covid-19, the E protein is 75 residues long. Although it is not necessarily essential for viral replication, absence of the E protein may produce abnormally assembled viral capsids or reduced replication. E is a multifunctional protein and, in addition to its role as a structural protein in the viral capsid, it is thought to be involved in viral assembly, likely functions as a viroporin, and is involved in viral pathogenesis.
The membrane (M) protein is an integral membrane protein that is the most abundant of the four major structural proteins found in coronaviruses. The M protein organizes the assembly of coronavirus virions through protein-protein interactions with other M protein molecules as well as with the other three structural proteins, the envelope (E), spike (S), and nucleocapsid (N) proteins.
The nucleocapsid (N) protein is a protein that packages the positive-sense RNA genome of coronaviruses to form ribonucleoprotein structures enclosed within the viral capsid. The N protein is the most highly expressed of the four major coronavirus structural proteins. In addition to its interactions with RNA, N forms protein-protein interactions with the coronavirus membrane protein (M) during the process of viral assembly. N also has additional functions in manipulating the cell cycle of the host cell. The N protein is highly immunogenic and antibodies to N are found in patients recovered from SARS and COVID-19.
ORF3a is a gene found in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It encodes an accessory protein about 275 amino acid residues long, which is thought to function as a viroporin. It is the largest accessory protein and was the first of the SARS-CoV accessory proteins to be described.
ORF7b is a gene found in coronaviruses of the genus Betacoronavirus, which expresses the accessory protein Betacoronavirus NS7b protein. It is a short, highly hydrophobic transmembrane protein of unknown function.
ORF8 is a gene that encodes a viral accessory protein, Betacoronavirus NS8 protein, in coronaviruses of the subgenus Sarbecovirus. It is one of the least well conserved and most variable parts of the genome. In some viruses, a deletion splits the region into two smaller open reading frames, called ORF8a and ORF8b - a feature present in many SARS-CoV viral isolates from later in the SARS epidemic, as well as in some bat coronaviruses. For this reason the full-length gene and its protein are sometimes called ORF8ab. The full-length gene, exemplified in SARS-CoV-2, encodes a protein with an immunoglobulin domain of unknown function, possibly involving interactions with the host immune system. It is similar in structure to the ORF7a protein, suggesting it may have originated through gene duplication.
ORF9b is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is an overlapping gene whose open reading frame is entirely contained within the N gene, which encodes coronavirus nucleocapsid protein. The encoded protein is 97 amino acid residues long in SARS-CoV and 98 in SARS-CoV-2, in both cases forming a protein dimer.
ORF10 is an open reading frame (ORF) found in the genome of the SARS-CoV-2 coronavirus. It is 38 codons long. It is not conserved in all Sarbecoviruses. In studies prompted by the COVID-19 pandemic, ORF10 attracted research interest as one of two viral accessory protein genes not conserved between SARS-CoV and SARS-CoV-2 and was initially described as a protein-coding gene likely under positive selection. However, although it is sometimes included in lists of SARS-CoV-2 accessory genes, experimental and bioinformatics evidence suggests ORF10 is likely not a functional protein-coding gene.
ORF1ab refers collectively to two open reading frames (ORFs), ORF1a and ORF1b, that are conserved in the genomes of nidoviruses, a group of viruses that includes coronaviruses. The genes express large polyproteins that undergo proteolysis to form several nonstructural proteins with various functions in the viral life cycle, including proteases and the components of the replicase-transcriptase complex (RTC). Together the two ORFs are sometimes referred to as the replicase gene. They are related by a programmed ribosomal frameshift that allows the ribosome to continue translating past the stop codon at the end of ORF1a, in a -1 reading frame. The resulting polyproteins are known as pp1a and pp1ab.
The nidoviral papain-like protease is a papain-like protease protein domain encoded in the genomes of nidoviruses. It is expressed as part of a large polyprotein from the ORF1a gene and has cysteine protease enzymatic activity responsible for proteolytic cleavage of some of the N-terminal viral nonstructural proteins within the polyprotein. A second protease also encoded by ORF1a, called the 3C-like protease or main protease, is responsible for the majority of further cleavages. Coronaviruses have one or two papain-like protease domains; in SARS-CoV and SARS-CoV-2, one PLPro domain is located in coronavirus nonstructural protein 3 (nsp3). Arteriviruses have two to three PLP domains. In addition to their protease activity, PLP domains function as deubiquitinating enzymes (DUBs) that can cleave the isopeptide bond found in ubiquitin chains. They are also "deISGylating" enzymes that remove the ubiquitin-like domain interferon-stimulated gene 15 (ISG15) from cellular proteins. These activities are likely responsible for antagonizing the activity of the host innate immune system. Because they are essential for viral replication, papain-like protease domains are considered drug targets for the development of antiviral drugs against human pathogens such as MERS-CoV, SARS-CoV, and SARS-CoV-2.
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