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Reviews in Medical Virology Jan 2017Saffold virus (SAFV) is an emerging human cardiovirus that has been shown to be ubiquitous. Initial studies of SAFV focused on respiratory and gastrointestinal... (Review)
Review
Saffold virus (SAFV) is an emerging human cardiovirus that has been shown to be ubiquitous. Initial studies of SAFV focused on respiratory and gastrointestinal infection; however, it has also recently been associated with diverse clinical symptoms including the endocrine, cardiovascular, and neurological systems. Given the systemic nature of SAFV, and its high prevalence, understanding its pathogenicity and clinical impact is of utmost importance. This comprehensive review highlights and discusses recent developments in epidemiology, human pathogenicity, animal, and molecular studies related to SAFV. It also provides detailed insights into the neuropathogenicity of SAFV. We argue that human studies have been confounded by coinfections and therefore require support from robust molecular and animal research. Thereby, we aim to provide foresight into further research to better understand this emerging virus.
Topics: Animals; Cardiovirus Infections; Communicable Diseases, Emerging; Disease Models, Animal; Humans; Prevalence; Theilovirus
PubMed: 27723176
DOI: 10.1002/rmv.1908 -
Bioscience Reports Jan 2022Cardioviruses are single-stranded RNA viruses of the family Picornaviridae. In addition to being the first example of internal ribosome entry site (IRES) utilization,... (Review)
Review
Cardioviruses are single-stranded RNA viruses of the family Picornaviridae. In addition to being the first example of internal ribosome entry site (IRES) utilization, cardioviruses also employ a series of alternative translation strategies, such as Stop-Go translation and programmed ribosome frameshifting. Here, we focus on cardiovirus 2A protein, which is not only a primary virulence factor, but also exerts crucial regulatory functions during translation, including activation of viral ribosome frameshifting and inhibition of host cap-dependent translation. Only recently, biochemical and structural studies have allowed us to close the gaps in our knowledge of how cardiovirus 2A is able to act in diverse translation-related processes as a novel RNA-binding protein. This review will summarize these findings, which ultimately may lead to the discovery of other RNA-mediated gene expression strategies across a broad range of RNA viruses.
Topics: Cardiovirus; Internal Ribosome Entry Sites; Viral Proteins
PubMed: 35022657
DOI: 10.1042/BSR20210406 -
Infection, Genetics and Evolution :... Sep 2022Recently a growing number of novel cardioviruses have been frequently discovered, which boosts interest in the search for the genetic diversity of cardioviruses....
Recently a growing number of novel cardioviruses have been frequently discovered, which boosts interest in the search for the genetic diversity of cardioviruses. However, wild-marmot cardioviruses have been rarely reported. Here, a novel cardiovirus (tentatively named HHMCDV) was identified in fecal samples from wild Himalayan marmots in Qinghai Tibetan Plateau, China, by viral metagenomics analysis. 3 out of 99 fecal samples from Himalayan marmots were positive for HHMCDV, with the viral loads ranging from 2.7 × 10 to 1.3 × 10 gene copies/g. The complete genomic sequence of HHMCDV was 8108 nucleotides in length, with the typical cardiovirus genome organization and motifs. Coincidentally, while the data was analyzing, one marmot cardiovirus HT7 partial sequence was available in the Genbank, showing 95.1%, 95.6% and 96.0% amino acid (aa) identity in P1, P2 and P3, respectively. However, sequence analysis revealed that HHMCDV and HT7 are more closely related to species Cardiovirus F strain with 65.7%, 61.9-65.6%, 58.9-59.7%, 71.1-71.7%, 69.1-69.4% and 71.4-72.2% aa identity in polyprotein, P1, P2, P3, 2C and 3CD proteins, respectively. Phylogenetic analysis of P1, P2, P3 and 3CD aa sequences indicated that HHMCDV and HT7 clustered tightly and formed a distinct cluster in the Cardiovirus genus. Based on these data, we propose that HHMCDV and HT7 should be two different members of a potential novel species within the genus Cardiovirus. Further studies are needed to investigate the epidemiology and potential pathogenicity of the virus in Himalayan marmots.
Topics: Animals; Cardiovirus; Feces; Genome, Viral; Marmota; Phylogeny
PubMed: 35932998
DOI: 10.1016/j.meegid.2022.105347 -
Virulence Jul 2012The encephalomyocarditis virus (EMCV) is a small non-enveloped single-strand RNA virus, the causative agent of not only myocarditis and encephalitis, but also... (Review)
Review
The encephalomyocarditis virus (EMCV) is a small non-enveloped single-strand RNA virus, the causative agent of not only myocarditis and encephalitis, but also neurological diseases, reproductive disorders and diabetes in many mammalian species. EMCV pathogenesis appears to be viral strain- and host-specific, and a better understanding of EMCV virulence factors is increasingly required. Indeed, EMCV is often used as a model for diabetes and viral myocarditis, and is also widely used in immunology as a double-stranded RNA stimulus in the study of Toll-like as well as cytosolic receptors. However, EMCV virulence and properties have often been neglected. Moreover, EMCV is able to infect humans albeit with a low morbidity. Progress on xenografts, such as pig heart transplantation in humans, has raised safety concerns that need to be explored. In this review we will highlight the biology of EMCV and all known and potential virulence factors.
Topics: Animals; Cardiovirus Infections; Encephalomyocarditis virus; Host-Pathogen Interactions; Humans; Mammals; Models, Biological; Viral Proteins; Virulence; Virulence Factors
PubMed: 22722247
DOI: 10.4161/viru.20573 -
PLoS Pathogens Aug 2021Long polycytidine (polyC) tracts varying in length from 50 to 400 nucleotides were first described in the 5'-noncoding region (NCR) of genomes of picornaviruses... (Review)
Review
Long polycytidine (polyC) tracts varying in length from 50 to 400 nucleotides were first described in the 5'-noncoding region (NCR) of genomes of picornaviruses belonging to the Cardio- and Aphthovirus genera over 50 years ago, but the molecular basis of their function is still unknown. Truncation or complete deletion of the polyC tracts in picornaviruses compromises virulence and pathogenicity but do not affect replicative fitness in vitro, suggesting a role as "viral security" RNA element. The evidence available suggests that the presence of a long polyC tract is required for replication in immune cells, which impacts viral distribution and targeting, and, consequently, pathogenic progression. Viral attenuation achieved by reduction of the polyC tract length has been successfully used for vaccine strategies. Further elucidation of the role of the polyC tract in viral replication cycle and its connection with replication in immune cells has the potential to expand the arsenal of tools in the fight against cancer in oncolytic virotherapy (OV). Here, we review the published data on the biological significance and mechanisms of action of the polyC tract in viral pathogenesis in Cardio- and Aphthoviruses.
Topics: Animals; Aphthovirus; Cardiovirus; Humans; Oncolytic Virotherapy; Poly C; Virus Replication
PubMed: 34347852
DOI: 10.1371/journal.ppat.1009739 -
Virology Journal Mar 2018Cardioviruses cause severe illnesses in rodents and humans. In recent years, novel cardioviruses have been frequently found, which promoted further studies of the...
Cardioviruses cause severe illnesses in rodents and humans. In recent years, novel cardioviruses have been frequently found, which promoted further studies of the genetic diversity of cardioviruses. Using viral metagenomics, we genetically characterized a novel cardiovirus (named SX1) from wild rat feces. The genomic structure of SX1 shared similar features with those of the Theiler's murine encephalomyelitis viruses, including a leader protein, four structural proteins and seven non-structural proteins. Phylogenetic analysis based on both structural proteins and non-structural proteins coding regions showed that SX1 was formed into a separate branch, being located between the branches of Theiler's murine encephalomyelitis viruses and Thera viruses. Variable resides presented in the Ser/Thr rich domain of L protein, VP1 loops, and VP2 puffs distinguished SX1 from Theiler's murine encephalomyelitis viruses, suggesting the different antigenicity and pathogenicity of SX1.
Topics: Animals; Animals, Wild; Cardiovirus; China; Feces; Genome, Viral; Metagenomics; Phylogeny; Rats; Sequence Alignment; Species Specificity; Viral Proteins
PubMed: 29587779
DOI: 10.1186/s12985-018-0968-9 -
Journal of Virology Feb 2012Although cardioviruses have been thought to mainly infect rodents, a novel human cardiovirus, designated Saffold virus (SAFV), was identified in 2007. SAFV is grouped... (Review)
Review
Although cardioviruses have been thought to mainly infect rodents, a novel human cardiovirus, designated Saffold virus (SAFV), was identified in 2007. SAFV is grouped with Theiler-like rat virus and Theiler's murine encephalomyelitis virus (TMEV) in the species Theilovirus of the genus Cardiovirus of the family Picornaviridae. Eight genotypes of SAFV have now been identified. SAFV has been isolated from nasal and stool specimens from infants presenting with respiratory and gastrointestinal symptoms as well as from children with nonpolio acute flaccid paralysis; however, the relationship of SAFV to this symptomatology remains unclear. Of note, the virus has also been isolated from the cerebrospinal fluid specimens of patients with aseptic meningitis. This finding is of interest since TMEV is known to cause a multiple sclerosis-like syndrome in mice. The involvement of SAFV in various diseases (e.g., respiratory illness, gastrointestinal illness, neurological diseases, and type I diabetes) is presently under investigation. In order to clarify the pathogenicity of SAFV, additional epidemiological studies are required. Furthermore, identification of the SAFV cellular receptor will help establish an animal model for SAFV infection and help clarify the pathogenesis of SAFV-related diseases. In addition, investigation of the tissue-specific expression of the receptor may facilitate development of a novel picornavirus vector, which could be a useful tool in gene therapy for humans. The study of viral factors involved in viral pathogenicity using a reverse genetics technique will also be important.
Topics: Animals; Cardiovirus; Cardiovirus Infections; Genome, Viral; Humans; Mice; Viral Proteins
PubMed: 22114344
DOI: 10.1128/JVI.06087-11 -
MBio Apr 2018Picornaviruses induce dramatic rearrangements of endomembranes in the cells that they infect to produce dedicated platforms for viral replication. These structures,...
Picornaviruses induce dramatic rearrangements of endomembranes in the cells that they infect to produce dedicated platforms for viral replication. These structures, termed replication organelles (ROs), have been well characterized for the genus of the However, it is unknown whether the diverse RO morphologies associated with enterovirus infection are conserved among other picornaviruses. Here, we use serial electron tomography at different stages of infection to assess the three-dimensional architecture of ROs induced by encephalomyocarditis virus (EMCV), a member of the genus of the family of picornaviruses that is distantly related. Ultrastructural analyses revealed connections between early single-membrane EMCV ROs and the endoplasmic reticulum (ER), establishing the ER as a likely donor organelle for their formation. These early single-membrane ROs appear to transform into double-membrane vesicles (DMVs) as infection progresses. Both single- and double-membrane structures were found to support viral RNA synthesis, and progeny viruses accumulated in close proximity, suggesting a spatial association between RNA synthesis and virus assembly. Further, we explored the role of phosphatidylinositol 4-phosphate (PI4P), a critical host factor for both enterovirus and cardiovirus replication that has been recently found to expedite enterovirus RO formation rather than being strictly required. By exploiting an EMCV escape mutant, we found that low-PI4P conditions could also be overcome for the formation of cardiovirus ROs. Collectively, our data show that despite differences in the membrane source, there are striking similarities in the biogenesis, morphology, and transformation of cardiovirus and enterovirus ROs, which may well extend to other picornaviruses. Like all positive-sense RNA viruses, picornaviruses induce the rearrangement of host cell membranes to form unique structures, or replication organelles (ROs), that support viral RNA synthesis. Here, we investigate the architecture and biogenesis of cardiovirus ROs and compare them with those induced by enteroviruses, members of the well-characterized picornavirus genus The origins and dynamic morphologies of cardiovirus ROs are revealed using electron tomography, which points to the endoplasmic reticulum as the donor organelle usurped to produce single-membrane tubules and vesicles that transform into double-membrane vesicles. We show that PI4P, a critical lipid for cardiovirus and enterovirus replication, is not strictly required for the formation of cardiovirus ROs, as functional ROs with typical morphologies are formed under phosphatidylinositol 4-kinase type III alpha (PI4KA) inhibition in cells infected with an escape mutant. Our data show that the transformation from single-membrane structures to double-membrane vesicles is a conserved feature of cardiovirus and enterovirus infections that likely extends to other picornavirus genera.
Topics: Electron Microscope Tomography; Encephalomyocarditis virus; Endoplasmic Reticulum; HeLa Cells; Humans; Organelle Biogenesis; Organelles; Phosphatidylinositol Phosphates; Virus Replication
PubMed: 29666283
DOI: 10.1128/mBio.00420-18 -
Frontiers in Immunology 2023Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating... (Review)
Review
Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating disease in susceptible mice. TMEV infects dendritic cells, macrophages, B cells, and glial cells. The state of TLR activation in the host plays a critical role in initial viral replication and persistence. The further activation of TLRs enhances viral replication and persistence, leading to the pathogenicity of TMEV-induced demyelinating disease. Various cytokines are produced via TLRs, and MDA-5 signals linked with NF-κB activation following TMEV infection. In turn, these signals further amplify TMEV replication and the persistence of virus-infected cells. The signals further elevate cytokine production, promoting the development of Th17 responses and preventing cellular apoptosis, which enables viral persistence. Excessive levels of cytokines, particularly IL-6 and IL-1β, facilitate the generation of pathogenic Th17 immune responses to viral antigens and autoantigens, leading to TMEV-induced demyelinating disease. These cytokines, together with TLR2 may prematurely generate functionally deficient CD25-FoxP3+ CD4 T cells, which are subsequently converted to Th17 cells. Furthermore, IL-6 and IL-17 synergistically inhibit the apoptosis of virus-infected cells and the cytolytic function of CD8+ T lymphocytes, prolonging the survival of virus-infected cells. The inhibition of apoptosis leads to the persistent activation of NF-κB and TLRs, which continuously provides an environment of excessive cytokines and consequently promotes autoimmune responses. Persistent or repeated infections of other viruses such as COVID-19 may result in similar continuous TLR activation and cytokine production, leading to autoimmune diseases.
Topics: Mice; Animals; Theilovirus; Interleukin-6; Demyelinating Diseases; NF-kappa B; Virulence; COVID-19; Cytokines; Virus Replication
PubMed: 37153539
DOI: 10.3389/fimmu.2023.1167972 -
Advances in Virus Research 1991Theiler's murine encephalomyelitis virus belongs to the family of picornaviridae. Picornaviruses are small ( “pico”), phylogenetically related RNA viruses. Based on... (Review)
Review
Theiler's murine encephalomyelitis virus belongs to the family of picornaviridae. Picornaviruses are small ( “pico”), phylogenetically related RNA viruses. Based on different biochemical and biophysical characteristics picornaviruses are subdivided into four groups: enteroaphthovirus (foot-and-mouth disease virus), cardiovirus [encephalomyocarditis virus (EMCV), Mengo virus], and rhinovirus (human rhinovirus). Theiler's murine encephalomyelitis virus was originally classified among the picornaviridae as an enterovirus because of its biological similarities with poliovirus. Further comparison of the complete genome of TMEV BeAn 8386 strain identifies remarkable similarities at the level of nucleotides and predicted amino acids between BeAn and the cardioviruses EMCV and Mengo virus. Theiler's murine encephalomyelitis virus is a single-stranded nonenveloped RNA virus. The viral RNA is of positive sense, having the same polarity as mRNA. Viral mRNA lacks the cap structure found at the 5’ end of almost all eukaryotic mRNAs.
Topics: Animals; Enterovirus Infections; Maus Elberfeld virus; Mice
PubMed: 2038955
DOI: 10.1016/s0065-3527(08)60798-8