Dr. Emil Ionita
Dr. Ion Cantacuzino Institute
Part one
Rezumat:
Aceasta lucrare este o trecere in revista a datelor din literatura de specialitate asupra biologiei moleculare a virusurilor gripale –ARN negative unicatenare invelite in capsida virala apartinand familiei Orthomyxoviride. Sunt cunoscute 3 tipuri de virusuri gripale: A, B si C conform cu diferenta antigenica dintre nucleoproteinele lor (NP) si proteinele matriceale(M). Sunt discutate particularitatile de structura virala si de ciclu celular ca si mecanismele de transcriere si replicare virala.
Abstract
This is a review of the literature data on the molecular biology of influenza viruses single stranded,negative –sense,enveloped RNA viruses which belong to Orthomyxoviridae family.There are known three types of influenza viruses namely A,B and C according to the antigenic difference between their nucleoproteins (NP) and matrix proteins (M).
Are discussed particularities of viral structure and life cycle as well as molecular mechanisms of transcription and replication.
Introduction
According to the antigenic difference between their nucleoproteins(NP) and matrix proteins (M),there are known three types of influenza viruses: A, B and C.
Influenza A and B virus share more structural similarity and both possess 8 RNA genome segments (PB2, PB1, PA, HA, NP, NA, M, NS), while influenza C virus only contains 7 (PB2, PB1, P3, HEF, NP, M, NS). According to the antigenic properties, type A virus can be classified into 16 HA subtypes and 9 NA subtypes, whereas type B and C virus genes have no such subtype classification.
From phylogenetic analysis based on HA2/HEF gene , type B and C viruses form the most closely related groups, such that all type A virus HA genes diverged after they separated from type B virus[1].
Within each type of influenza virus, the segmented genome structure, can readly change
genetic information by “reassortment” during co-infection of the same host cell.
The reasortment however, between different subtypes has not been reported, suggesting a form of “speciation” by genetic divergence[2].
Even all three types of influenza viruses can naturally infect human, only type
A virus has a wide range of animal host species, including birds, swine, horses and other
mammals [3];
As far as the identification of influenza B and C viruses in animal hosts this is sporadic [4]. Surprisingly, all of the HA and NA subtypes are found in wild aquatic birds (orders Anseriformes and Charadriiformes), indicating they are the nature reservoir of influenza A viruses. Along the migration routes (including northern breeding area, southern wintering area and many stopover sites during migration) of these reservoir species, influenza A viruses can be transmitted to other avian species, creating selfsustaining epidemics, and occasionally to some mammal species like humans, which may result in major pandemics.
Particularities of Viral structure and life cycle of Influenza virusA,B,and C
The main characteristics of Influenza viruses are: a) The prominent projections of
glycoprotein(s) (HA and NA for type A and B viruses, HEF for type C virus) in the lipid membrane envelope, which is derived from the viral-producing cells, and b) A segmented genome comprising the single-stranded negative sense RNA segments that are
encapsidated in a virally encoded nucleoprotein (NP) [5].
According to Mellema et al[6]]Influenza A and B viruses share very similar structures that make them virtually indistinguishable by electron microscopy . As a function of the viral strain and passage history, the virions may exhibit a variety of shapes, ranging from spherical particles about 100nm in diameter to elongated filament forms often in excess of 300 nm in length[5]. The viral envelope contains 3 proteins (HA, NA and M2) in type A virus and 4 proteins (HA, NA, BM2 and NB) in type B virus. Beneath the envelope lie the matrix proteins, M1, which bridge the inner core components (RNPs and NEP/NS2) and the membrane proteins, playing a vital role in assembly and budding process.
The RNP (ribonucleoprotein) complex consists of the viral RNA segments,coated by the nucleoprotein (NP) and bound to the polymerase complex, consisting three polymerase proteins (PB1 [polymerase basic 1], PB2 [polymerase basic 2], and PA[polymerase acid]). However, NS1, the nonstructural protein, is not incorporated into the virion. It has multiple functions and plays an important role in evading the host’s innate immune response by acting as the “IFN antagonist”.
Concerning Influenza C virions ,it has been found that they exhibit a structure distinct from type A and B viruses and they can form unusually long (500 μm)cordlike structures on the surface of infected cell. In addition, type C virus has only one glycoprotein, the hemagglutinin-esterase-fusion (HEF) protein, which combines the hemagglutinin, receptor-destroying, and fusion activities [5].
The molecular stages of infecting host
Attachment influenza viruses is initiated by the attachment of viral particle to its target cell through interaction between its hemagglutinin(HA) spikes on the viral envelope and sialic acid receptors on the host cell surface.
Sialic acids are nine-carbon acidic monosaccharides commonly found at the termini of
many glycoconjugates therefore ubiquitous in many cell types and animal species
On binding at the cell surface, the virus is internalized by receptor-mediated endocytosis. The low pH in the endosome triggers fusion of the viral and endosomal membranes, releasing the viral RNPs into the cytoplasm. Viral RNPs are imported into the nucleus, where they serve as the template for transcription. New proteins are synthesized from viral mRNA. The viral genome (vRNA) is replicated through a positive-sense intermediate (cRNA). Newly synthesized viral RNPs are exported from the nucleus to the assembly site at the apical plasma membrane, where virus particles bud and are released .
[7]. However, HAs of influenza viruses from different host species often suggest host specificity due to their preference on binding sialic acid through either α2,3 or α2,6 linkage [8]. Specifically, human influenza viruses preferentially bind to sialic acid bearing a α2,6 linkage (SAα2,6Gal), whereas avian influenza viruses mostly bind to sialic acid with a α2,3 linkage [9].
This is correspondent to the fact that sialic acid with a α2,6 linkage is predominating in
human tracheal epithelial cells [10], whereas the α2,3 linkage is more common in duck gut epithelium[11] . Crucially, the viral host specificity is not absolute, as both the sialic acids linkages (α2,3 linkage and α2,6 linkage) can be found in human and avian cells, although with differential expression by cell type and location[12]. This may explain the low infectivity of avian influenza virus on human as sialic acids with α2,3 linkage mostly
present in the lower respiratory tract [13].
Occasionally, when viruses are passaged in a particular host they can adapt to that host
by accumulating mutations at the receptor-binding sites in HA. Specifically, a single
mutation (D190E) can trigger the change of binding specificity of a 1918 influenza strain
from α2,6 linkage to α2,3 linkage [14]. Therefore, the reverse mutation (E190D) in HA gene might be responsible for the adaptation of 1918 Spanish influenza from avian to human.
Membrane Fusion and Uncoating
After the interaction of influenza HA protein and sialic acid, the virus is internalized to a host cell endosome mainly through a clathrin-dependent receptor mediated endocytosis [15].
The low pH in endosome triggers conformational change in the HA thus exposes the ‘fusion peptide’, leading to the merging of virus envelope with the endosomal membrane thus releasing the vRNPs into the host cell cytoplasm (reviewed in [16].
The conformation change requires the cleavage of HA0 precursor protein into two
subunits, HA1 and HA2. Consequently, the precursor cleavability is correlated with the
pathogenicity of influenza infection [17]For example, most of HAs can only be cleaved by protease localized in respiratory and intestine organs, resulting in mild localized infections.
However, the cleavage sites of HAs in highly pathogenic avian influenza contain an insertion of multiple basic amino acids (RERRRKKR), which can be cleaved by ubiquitous protease such as furin in a wild range of organs, resulting in lethal
systemic infection [18]. In other cases, absence of acarbohydrate side chain [19] normally located 14 Å membrane distal to the cleavage site can also influence the accessibility of the site to proteases, thus increasing pathogenicity.
The successful uncoating of influenza virion also needs the dissociation of viral
matrix and the vRNPs before membrane fusion. The low pH environment of endosome
activates the proton-channel function of M2 proteins located in the viral envelope,
allowing the influx of protons from the endosome into the virus particle[20].
The internal acidification thus disrupts the internal protein-protein interactions and
dissociates the matrix protein from viral nucleoprotein, allowing the release of the vRNPs
into the cytoplasm. Blocking the ion channel activity of M2 protein by anti-viral drugs
Amantadine and Rimantadine (the adamantanes) can inhibit the viral replication [21].
Transcription and Replication
Once liberated from the virion, the vRNPs are actively transported to the nucleus
using the cellular nucleus import machinery, mediated by the nuclear localization signal
(NLS) located at the extreme N-terminus of NP[22]. All of the vRNA syntheses including viral transcription, replication and the assembling of vRNPs occur in nucleus. The viral RNA-dependent RNA polymerase uses the negative sense vRNA as template to synthesize both viral mRNAs, which are translated in the cytoplasm, and positive-sense antigenomes, the template for negative-sense RNA segment synthesis.
The transcription of viral genome is initiated using primers containing cap-1structure derived from host premature mRNAs by a “cap-snatching” mechanism, in which the cap structure is first recognized by PB2 and the capped oligonucleotide is then cleaved by PB1 [23].
The mRNA chain elongation will then proceeduntil reaching the polyadenalytion signal, consisting of a track of 5 – 7 U residues approximately 17 nucleotides from the 5’ end of vRNA. The stuttering and slipping of polymerase on these poly(U) stretch lead to the non-templated addition of a poly(A) tail that is 150nt long [24]. The primary transcripts of M and NS will then be spliced using cellular machinery to produce M1/M2 and NS1/NS2 mRNAs. These matured viral mRNAs will be exported to the cytoplasm and translated just as the host mRNA.
In contrast to transcription, the syntheses of cRNA occur via a primerindependent
mechanism and generate full-length products of vRNAs. The switch from mRNA to cRNA synthesis is proposed depending on the availability of soluble NP proteins, as the newly synthesized cRNAs and vRNAs are both encapsidated. Similarly,the newly synthesized PB2, PB1 and PA will also be imported into nucleus for the assembly of vRNPs, while M1 and NS2 proteins will associate the export of vRNPs to assemble the progeny viral particles [25].
Budding and Release
Followed the synthesis, HA, NA and M2 are processed in the endoplasmic reticulum and Golgi apparatus, and subsequently directed to the assembly site on the apical plasma membrane via their apical signal[26]. The apical budding facilitates the dissemination of progeny virions and thus related to the cell tropism. The HA and NA preferentially concentrate into patches correspondent to lipid raft, which is the key factor for the efficient budding [27]. These regions of plasma membrane form the new virion membrane and they envelop the matrix proteins layer,which interacts with both the cytoplasmic tail of glycoproteins and vRNPs therefore bridging the information between envelope and inner virion. M1 protein is also responsible for recruiting the host factors required for the late stage of budding, making itself a crucial factor in the budding process [28].
Due to the binding of sialic acid-containing receptors by HA proteins, the newly formed
progeny virions are initially aggregated at the host cell membrane. The successful
release of the infectious progeny virions requires the enzymatic activity of NA proteins,
which remove the sialic acid on the cell surface (Palese & Compans 1976). NA protein
is also suggested to provide an important role at cell entry by mucus degradation hence
allowing the access of virus to epithelium cells in the respiratory tract [29].
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