Index
It is a family of small viruses, which are icosahedral and with very diverse genomes of single-stranded positive-stranded RNA.
Characteristics of all members of the family are three b-barrel-folding capsid proteins, processing of polyproteins by virus-encoded cysteine proteinase, and replication by RNA-dependent RNA polymerase with YGDD sequence motif.
The family comprises 35 genera containing 80 species, but many viruses are currently awaiting classification.
Picornaviruses can cause subclinical infections in humans and animals, or illnesses ranging from mild febrile illness to severe heart, liver, and central nervous system disease.
What is a picornavirus?
A picornavirus is a virus belonging to the Picornaviridae family. Picornaviruses are positive strand RNA viruses not enveloped with an icosahedral capsid.
Genomic RNA is unusual in that it has a protein at the 5 ‘end that is used as a primer for RNA polymerase transcription.
The name is derived from pico, which means small, and RNA, which refers to the ribonucleic acid genome, so “pico-rna-virus” literally means small RNA virus. Picornaviruses are separated into several genera and include many important human and animal pathogens.
The diseases they cause are varied, ranging from acute “common cold” diseases, to polio, to chronic infections of livestock. Additional species that do not belong to any of the recognized genera continue to be described.
Picornaviridae virus family:
- Ampivirus.
- Aftovirus.
- Aquamavirus.
- Avihepatovirus.
- Avisivirus.
- Cardiovirus.
- Cosavirus.
- Dicipivirus.
- Enterovirus.
- Erbovirus.
- Gallivirus.
- Harkavirus.
- Hepatovirus.
- Hunnivirus.
- Kobuvirus.
- Kunsagivirus.
- Limnipivirus.
- Megrivirus.
- mischivirus.
- Mosavirus.
- Oscivirus.
- Parechovirus.
- Passivirus.
- Passerivirus.
- Potamipivirus.
- Rabovirus.
- Rosavirus.
- Sakobuvirus.
- Salivirus.
- Sapelovirus.
- Senecavirus.
- Sicinivirus.
- Teschovirus.
- Torchivirus.
- Tremovirus.
Morphology of a virion
Virions consist of a capsid, without an envelope, that surrounds a core of ssRNA. Available crystal structures indicate that the particles have a diameter of 30-32 nm.
Electron micrographs do not reveal projections on the virions of most picornaviruses, the virus particle appears as an almost featureless sphere; however, kobuviruses display a surface structure that is different from small round-structured viruses (astroviruses and caliciviruses).
The capsid is made up of 60 identical units (protomers). Picornaviruses with four capsid proteins have three surface proteins, 1B, 1C and 1D, of 24-41 kDa, and one internal protein, 1A of 5.5-13.5 kDa; however, many picornaviruses have three capsid proteins since 1AB (VP0) remains uncleaved.
The total protomer is 80–97 kDa. Proteins 1A, 1B, 1C, and 1D are also often referred to as VP4, VP2, VP3, and VP1, respectively.
Proteins 1B, 1C, 1D, and uncleaved 1AB each possess a core structure comprising an eight-stranded b-sandwich (“b-barrel”).
The capsid protein (CP) sequences in many genera reveal similarities to those of the “rhv-like” superfamily of proteins, and may contain a conserved “inhibitor-binding site” which, in the case of some rhinos and enteroviruses, Active antivirals have been shown to bind.
The B barrels are packed together in the capsid with T = 1, pseudo T = 3, icosahedral symmetry.
These structural characteristics are shared by all members of the Picornaviral order with resolved atomic structures.
An example is the cricket paralysis virus (Dicistroviridae), infectious flacherie virus (Iflaviridae), and the comoviruses (cowpea mosaic virus, bean pod mottle virus, and red clover speckle virus).
The genders differ in the outer loops that interconnect the strands b. These loops account for the differences in the relief of the surface of each gender and in the thickness of the capsid wall. Assembly occurs through pentameric intermediates (pentamer: five protomers).
The proteins within each pentamer are held together by an internal network made up of the N ends of the three main PCs, the C ends found on the outer surface of the capsid.
Physicochemical and physical properties
The molecular weight of picornavirus virions ranges from 8 x 10 6 – 9 x 10 6 with a sedimentation rate (S 20w) of 140-165S (for empty particles S 20w is 70-80S). Its floating density in CsCl is 1.33-1.45 g cm -3, depending on the gender.
Some species are unstable below pH 7; many are less stable at low ionic strength than at high ionic strength. Virions are insensitive to ether, chloroform, or non-ionic detergents.
Viruses are inactivated by light when grown with or in the presence of photodynamic dyes such as neutral red or proflavin. Thermal stability varies with viruses as does stabilization by divalent cations.
Nucleic acid
Virions contain one molecule of positive sense ssRNA, 6.7-10.1 kb in size, and possessing a single long ORF; Canine picodicistroviruses (Dicipivirus genus), however, display two ORFs, the translation of each is driven by a separate internal ribosomal entry site (IRES).
A poly tail, of heterogeneous length, is located after the 3′-terminal heteropolymeric sequence. A small protein, VPg (c. 2.2 to 3.9 kDa), is covalently attached to the 5 ′ end.
The untranslated regions (UTRs) at both ends contain regions of secondary structure that are essential for genome function.
The long 5′-UTR (500-1500 nt) includes a 5′-terminal domain involved in replication (eg, poliovirus “clover leaf virus”) and an IRES of 220-450 nt upstream of the translation start site.
Most picornaviral IRES elements can be assigned to one of several types (I to V, IGR-IRES), according to their secondary structure. Between the 5′-terminal domain and the IRES there may be one or more, pseudo-knots.
A poly tract is found in the 5′-UTR of foot-and-mouth disease viruses, encephalomyocarditis viruses, and possibly porcine teschoviruses. The 3′-UTR, which can also contain a pseudoknot, ranges from 25 to nearly 800 nt in length.
Protein
In addition to the major PCs, 1A, 1B, 1C, and 1D, and 3B (VPg), described above, small amounts of 1AB (VP0) are commonly seen in place of one or more copies of 1A and 1B.
Protein 1A is small in hepatoviruses, and 1AB is not cleaved between members of Ampivirus, Aquamavirus, Avihepatovirus, Avisivirus, Gallivirus, Kobuvirus, Kunsagivirus, Limnipivirus, Mnipivirus, Sicinivirus-genus Virus Viruses, and a number of unclassified picornaviruses.
Orthologous proteins 1B, 1C, 1D, 2C, 3C and 3D are conserved in all picornaviruses and can be used for sequence alignments between viruses, whereas 1A, 2A, 2B, 3A and 3B are highly divergent between members of different genera picornavirus.
The viral proteinases are as follows: 3C pro, a chymotrypsin-like cysteine protease encoded by all picornaviruses, performs the majority of cleavages; 2A pro related to 3C pro is responsible for some cleavages in enteroviruses, and possibly sapeloviruses and raboviruses.
The L protein leader is a papain-related cysteine protease that is released from polyprotein in afhoviruses, erboviruses, and possibly mosaviruses.
Also, the 2A of aftoviruses, aquamaviruses, avihepatoviruses, avisiviruses, cardioviruses, cosaviruses, erboviruses, hunniviruses, kunsagiviruses, limnipiviruses, mischiviruses, mosaviruses, members of the Parechovirus B, C and D species, passiviruses, potamipiviruses, rosaviruses, teschonecaviruses.
Lipids
Some picornaviruses carry a sphingosine-like molecule (“pocket factor”) in a cavity (“pocket”) located within 1D.
Protein 1A, when present, generally has a myristic acid molecule covalently attached to the amino terminal glycine. No myristoylation signal is found in the N-terminal VP4 and VP0 sequence of avihepatovirus, dicipivirus, kobuvirus, parechovirus, and tremovirus.
Carbohydrates
None of the viral proteins are glycosylated.
Genome organization and replication
Virion RNA is infectious (Colter et al., 1957, Alexander et al., 1958) and serves as both the genome and the viral mRNA. The initiation of protein synthesis is stimulated by IRES.
Translation of the single ORF produces the polyprotein precursor (216-277 kDa) to structural proteins (derived from the P1 region of the genome) and non-structural proteins (from the P2 and P3 regions) In many viruses, P1 is preceded by a leader protein (L).
In dicipiviruses, ORF1 encodes the precursor of the structural proteins (corresponding to the P1 region), while ORF2 encodes the precursor of the functional protein (regions P2 and P3).
The polyprotein is cleaved into functional proteins by virus-encoded proteinases. Intermediates are indicated by letter combinations (eg, 3CD, the uncleaved precursor of 3C and 3D). Picornaviruses exhibit a modular organization of the genome.
Certain genetic elements of the 5′- and 3′-UTR and gene regions are believed to have been exchanged between the genera.
There may be one or more genetic regions that code for various 2A proteins.
Beside 2A pro and afftovirus-like naftp 2A, 2A may have H-box / NC sequence motifs [avihepatovirus, avisivirus, gallivirus, kobuvirus, megrivirus, parechovirus, paserivirus, potamipivirus, sakobuvirus, saliviruses, sicinivirus, tremovirus and various unclassified picornaviruses (Hughes and Stanway, 2000).
There may also be a similarity with the guanine binding domain of the AIG1 type, an NTPase P-loop with the GxxGxGKS motif (avihepatovirus, avisivirus); its role in virus replication is unclear.
The regions of genes 2B and 3A vary greatly between genders, although functionally they can be homologous.
Some intermediates are stable and serve different functions than their cleavage products (eg, cleavage of poliovirus P1 by 3CD pro, not 3C pro). Where it occurs, the cleavage of 1AB, which accompanies RNA encapsidation, is thought to be autocatalytic, but the precise mechanism is unknown.
A typical picornavirus genome layout can be represented by the following:
- VPg + 5’UTR [1A-1B-1C-1D / 2A-2B-2C / 3A-3B-3C-3D] 3’UTR-poli (A).
Where “[” and “]” define the extent of the polyprotein coding region, “/” represents primary divisions and “-” represents final divisions.
When a particular polypeptide is present only in some members of the genus, it may be shown in parentheses.
This scheme can also be used to indicate some protein functions or amino acid motifs where they differ between viruses (eg, 2A pro or 2A npgp or 2A H-box / NC or 2A NTPase).
There may be multiple copies of a particular genomic region in the picornavirus genome, including repeated copies of a particular region (eg, three 3Bs in the FMD virus genome).
They can also be different types of a particular region (for example, two different 2A motifs in the Ljungan virus of the genus Parechovirus) and three different 2A motifs in the genome of the duck hepatitis A virus of the genus Avihepatovirus).
Viral RNA replication occurs in close association with reorganized cytoplasmic membranous structures.
These complexes called replication organelles contain proteins derived from the entire 2BC-P3 region of the polyprotein, including polymerase (3D pol, an enzyme that lengthens the RNA chain), and 2C (an ATPase that contains a sequence motif nucleotide binding).
The 3C pro component of poliovirus and coxsackievirus has been shown to be required to bind to the 5′-terminal RNA cloverleaf.
The small protein encoded by the virus, VPg, acts as a transcription primer for the synthesis of both positive and negative strand RNA.
Prior to transcription, two uridine residues covalently bind to the conserved tyrosine at position 3 in VPg to form VPgpUpU OH through a template mechanism involving a cis-acting replication element (cre) and 3D polymerase. of the virus.
Cre is a loop of the stem that contains the sequence “AAAC” in the loop and is found in various places in the genome depending on the species / genus of virus. Many compounds have been described that specifically inhibit replication.
Mutants resistant to, or dependent on, drugs have been reported. Genetic recombination, complementation, and phenotypic mixing occur.
Defective particles, containing deletions in PCs or Ls, have been produced experimentally but have not been observed in wild-type virus populations.
Antigenicidad
Serotypes are classified, according to gender, by cross protection, neutralization of infectivity, complement fixation, specific ELISA using a capture or immunodiffusion format.
Some serotypes can be identified by inhibition of hemagglutination.
Serotypes have been determined for most members of the enteroviruses, afftoviruses, cardiovascular, erboviruses, and teschoviruses, but are increasingly being replaced by genotypes (commonly referred to as “types”) in clinical or diagnostic practice.
The genera are not antigenically related when investigated.
biology
Most picornaviruses for which natural hosts have been identified are specific to one or very few host species [exceptions are foot-and-mouth disease virus (foot-and-mouth disease virus) and encephalomyocarditis virus (EMCV)] .
Members of most species can be grown in cell culture. Resistant host cells (eg, mouse cells in the case of primate-specific polioviruses) can often be infected (by a single round) by transfection with infectious naked RNA.
Transmission is horizontal, mainly by the fecal-oral, fomite or airborne route. Transmission by arthropod vectors is not known, although EMCV has been isolated from mosquitoes and ticks and poliovirus from flies; therefore, mechanical transmission may be possible.
The infection is generally cytolytic, but persistent infections are common with some species and reported with others.
Cells infected with poliovirus undergo extensive vacuolation as the membranes reorganize into viral replication complexes.
Infection may be accompanied by rapid inhibition of cap-dependent translation of cellular mRNAs (poliovirus 2A pro and Aphthovirus L pro are powerful inhibitors), mRNA synthesis, and the cellular secretory pathway (poliovirus 2B have been implicated and 3A).
Gender demarcation criteria
A picornavirus species is a class of phylogenetically related viruses that are normally expected to share (i) a significant degree of amino acid identity of the P1, 2C, 3C, and 3D proteins, (ii) monophyly in phylogenetic trees, (iii) essentially identical genomic maps.
And finally (iv) a significant degree of compatibility in proteolytic processing, replication, encapsidation and genetic recombination.
Members of a genus would normally be expected to have homologous IRES structures and proteins; their sequences are grouped on the same branch in phylogenetic trees (monophyly).
Members of all known picornavirus genera differ in (i) genomic maps showing distinctive features compared to their closest relatives.
Then (ii) significant divergence (number of differences per site between sequences) of orthologous proteins that exceed 66% P1 cap and 64% 2C hel, 3C pro, and 3D pol [these values are based on current sequence data and may vary with additional data available in the future].
It is then manifested, (iii) lack of detectable homology of proteins L (if present), 2B, 3A, 3B. If these rules do not apply, a new species or genus can be proposed.
The Picornaviridae Study Group recommends that strain designations include information on host species, specific laboratory identification number, country of sampling, year of sampling, for example, / ABC1234 / USA / 2015 stamp.
When proposing a new species of picornavirus, a preferred virus name must be provided.
Derivation of names
Picorna: an acronym for p V igilanciadella, insensitivity to ether, c oxsackievirus, or rphan virus, r hinovirus, r ibo nucleic un cid; also, from the prefix »peak» which designates a very small unit of measurement (equivalent to 10 -12) and RNA to designate very small RNA viruses.
Phylogenetic relationships
Viruses of each genus of picornavirus are phylogenetically distinct from members of other genera in those regions of the genome that are orthologous, ie, P1 cap, 2C hel, 3C pro, and 3D pol.
The divergence between members of a genus can be as high as 67% for the P1 polyprotein and 64% for the 2C, 3C and 3D proteins. The divergence between members of different genders is usually greater.
Similarity with other taxa
The presence of 1-3 domains with detectable similarity to the characteristic folding rhv-like superfamily (“barrel-b”) in capsid proteins is common to most members of the order Picornavirales.
Likewise, in all members of Picornavirales there is also present a “replication block” comprising an RNA-helicase domain (P-loop NTPase), a peptidase C-proteinase and an RNA-dependent RNA polymerase 1 (RT-like la superfamily) and many unclassified itch-like viruses.
Capsid proteins and replication block proteins show varying degrees of similarity. The presence of a small genome-linked protein that is also the replication primer is also common to many small positive-stranded RNA viruses.
An organization of the genome with a single open reading frame and a region of the gene encoding CP at the 5 ‘end and the region of the gene encoding the replication block proteins at the 3’ end is common to members of Picornaviridae and Iflaviridae.
Pathogenicity
Picornaviruses are a diverse group of human viral pathogens that together constitute the most common causes of human infections in the developed world.
Within the picornavirus family there are three known groups of human pathogens: human rhinoviruses (HRV), enteroviruses (EV) (including polioviruses, coxsackieviruses, and echoviruses), and hepatoviruses (including hepatitis A).
HRVs include more than 100 serotypes in two main groups based on their cell receptors. The main risk factor for HRV infection appears to be contact with young children.
Diseases that are caused by pichornaviridae
Members of the pichornaviridae can cause a variety of significant and very different diseases, including paralysis, hand, foot, and mouth disease, the common cold, myocarditis, and hepatitis , among others.
Symptoms
Most symptomatic EV infections in the United States are characterized by mild EV illnesses associated with fever and constitutional symptoms, with or without rashes.
These diseases are of clinical importance because they can mimic other diseases such as bacterial sepsis, other exanthematic viral diseases, and herpes simplex infections.
A recent review of respiratory diseases associated with VE found that 46% of cases presented with upper respiratory infections, 13% with respiratory distress / apnea , 13% with pneumonia , 12% with otitis media, and fewer cases of bronchiolitis, wheezing, croup , and pharyngotonsillitis.
Diagnosis
New developments in the rapid diagnosis and therapy of these infections promise to significantly reduce the burden of disease and associated costs for affected individuals and for society.
Diagnosis depends primarily on isolating and typing the virus from a throat swab or stool sample. Analysis of viral RNA in CSF (by RT-PCR) can be a quick and reliable way to define a Picornavirus as the cause of meningitis.
The value of serological testing is controversial. There is a complement fixation test based on a cocktail of anti-Picornavirus antibodies, but this test lacks sensitivity.
The diagnosis depends on a documented seroconversion or a titer of more than 80. Antibodies can be detected by a neutralization technique based on a limited number of serotypes, that is, those most frequently found in human infections (Coxsackie A7, A9 , A16 and B1 to B6).
Neutralizing antibodies persist long after the resolution of the infection and, furthermore, can be stimulated by other, not necessarily related, antigens.
Seroconversion is good evidence, but the mere detection of high titers of one or more antibodies is by no means conclusive and should be interpreted in the context of the nature of the symptoms and when they first appeared.
Treatment
Currently, there are few treatments for many of the viruses in Picornaviridae. For rhinoviruses, there are no approved treatments, although ruprintrivir appears promising in clinical trials, and pyridazinyl oxime ethers may be helpful.
Poliovirus treatments are needed to complement the World Health Organization’s polio eradication plan to treat infections caused by the reversion of the attenuated vaccine virus and to complement the control of vaccine coverage in communities. endemic areas of polio.
However, no promising compounds have been developed for the treatment of poliovirus due to the efficacy of the vaccines in use.
Broad spectrum inhibitors developed for other picornaviruses may be useful for poliovirus infections.
Coxsackievirus infections in children and infants are being treated with pleconaril with some efficacy to reduce mortality and improve recovery, although treatment is often on a compassionate use basis.
There are no therapies for echovirus infections.
Very little drug discovery research is being done to develop inhibitors of echovirus infections, probably due to the broad-spectrum inhibition of capsid-binding agents and protease inhibitors discovered for the treatment of other picornaviruses.
For example, pyridazinyl oxime ethers are inhibitors of most echoviruses. Treatments for enterovirus infections are also limited, although in a small clinical trial, milrinone appeared to reduce mortality and improve recovery from EV-induced pulmonary edema71.
Therefore, these results strongly emphasize the need for the development of potent and non-toxic compounds for the treatment of picornavirus infections.
