Adjustment of receptor-binding and neuraminidase substrate specificties in avian–human reassortant influenza viruses

Shtyrya, Yulia; Mochalova, L. V.; Voznova, Galina; Руднева, И. А.; Шилов, А. А.; Каверин, Н. В.; Bovin, Nicolai V.

doi:10.1007/s10719-008-9169-x

Cited by 32 publications

(35 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Segment-specific regulation is particularly important for the HA and NA genes, because balancing the relative activity levels of these two molecules is key to maintaining optimal fitness across different host contexts (20,21,29). Previously described mechanisms of NA regulation in response to selective pressure entail cis-acting mutations that modulate NA activity in cells or virions (22,(30)(31)(32). NA activity on virions also can be influenced in trans by M1 and the viral polymerase proteins PB2 and PB1, although the specific mechanisms involved are uncertain (33,34).…”

Section: Discussionmentioning

confidence: 99%

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Brooke

Ince

Wei

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The influenza A virus (IAV) genome is divided into eight distinct RNA segments believed to be copackaged into virions with nearly perfect efficiency. Here, we describe a mutation in IAV nucleoprotein (NP) that enhances replication and transmission in guinea pigs while selectively reducing neuraminidase (NA) gene segment packaging into virions. We show that incomplete IAV particles lacking gene segments contribute to the propagation of the viral population through multiplicity reactivation under conditions of widespread coinfection, which we demonstrate commonly occurs in the upper respiratory tract of guinea pigs. NP also dramatically altered the functional balance of the viral glycoproteins on particles by selectively decreasing NA expression. Our findings reveal novel functions for NP in selective control of IAV gene packaging and balancing glycoprotein expression and suggest a role for incomplete gene packaging during host adaptation and transmission.influenza virus | genome segmentation | genome packaging | nucleoprotein | host adaptation S easonal influenza A virus (IAV) remains a major public health threat, causing tens of thousands of deaths each year in the United States alone (1). Morbidity and mortality rates can increase dramatically when a zoonotic strain adapts to circulate in humans, triggering a pandemic. The continuing toll exerted by IAV stems from its remarkable adaptability, which enables it to move between widely divergent host species and also evade herd immunity within each species. Defining the specific mechanisms that mediate IAV adaptation is essential to improving anti-IAV vaccines, therapeutics, and pandemic surveillance.The IAV genome consists of eight negative-sense RNA segments, each of which is required for productive infection. Genome segmentation complements the high mutation rate of IAV by facilitating reassortment, which can maximize positive intergenic epistasis (2-5) and allow selective elimination of segments with deleterious mutations (6, 7). Although reassortment is the most obvious and best-characterized benefit of segmentation, there are likely additional evolutionary advantages.Genome segmentation imposes the substantial constraint of maintaining a gene-packaging mechanism to produce fully infectious virions (8). For IAV, it is widely believed that a single copy of each segment is packaged into progeny virions with nearly perfect efficiency, resulting in an equimolar ratio of the segments at the population level (9-12). Confounding this model, we recently demonstrated that most IAV virions fail to express one or more gene products (13). This finding raises the possibility that in some circumstances incomplete influenza gene packaging is evolutionarily neutral and possibly even advantageous (14).The viral glycoproteins HA and neuraminidase (NA) are encoded by separate genome segments. HA attaches IAV to terminal sialic acid residues on the host cell surface, enabling viral entry. By hydrolyzing sialic acids, NA detaches budding virions and neutralizes HA-inhibiting glyco...

show abstract

Section: Discussionmentioning

confidence: 99%

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Brooke

Ince

Wei

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Substrate specificity of influenza virus NA. The fluorescent assay for studying the substrate specificity of NA was described previously (48,52,53). Purified influenza virus (3 l; 1 to 20 HAU) was added to a microtube containing 0.7 nmol of a BODIPY-labeled sialyloligosaccharide in 4 l of 0.1 M Na-acetate buffer (pH 5.0).…”

Section: Methodsmentioning

confidence: 99%

Alterations in Hemagglutinin Receptor-Binding Specificity Accompany the Emergence of Highly Pathogenic Avian Influenza Viruses

Heider

Mochalova

Harder

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Highly pathogenic avian influenza viruses (HPAIVs) of hemagglutinin H5 and H7 subtypes emerge after introduction of lowpathogenic avian influenza viruses (LPAIVs) from wild birds into poultry flocks, followed by subsequent circulation and evolution. The acquisition of multiple basic amino acids at the endoproteolytical cleavage site of the hemagglutinin (HA) is a molecular indicator for high pathogenicity, at least for infections of gallinaceous poultry. Apart from the well-studied significance of the multibasic HA cleavage site, there is only limited knowledge on other alterations in the HA and neuraminidase (NA) molecules associated with changes in tropism during the emergence of HPAIVs from LPAIVs. We hypothesized that changes in tropism may require alterations of the sialyloligosaccharide specificities of HA and NA. To test this hypothesis, we compared a number of LPAIVs and HPAIVs for their HA-mediated binding and NA-mediated desialylation of a set of synthetic receptor analogs, namely, ␣2-3-sialylated oligosaccharides. NA substrate specificity correlated with structural groups of NAs and did not correlate with pathogenic potential of the virus. In contrast, all HPAIVs differed from LPAIVs by a higher HA receptor-binding affinity toward the trisaccharides Neu5Ac␣2-3Gal␤1-4GlcNAc␤ (3=SLN) and Neu5Ac␣2-3Gal␤1-3GlcNAc␤ (SiaLe c ) and by the ability to discriminate between the nonfucosylated and fucosylated sialyloligosaccharides 3=SLN and Neu5Ac␣2-3Gal␤1-4(Fuc␣1-3)GlcNAc␤ (SiaLe x ), respectively. These results suggest that alteration of the receptor-binding specificity accompanies emergence of the HPAIVs from their low-pathogenic precursors. A vian influenza is a highly contagious infection with influenza A viruses, with a worldwide occurrence in aquatic wild bird populations which represent the major natural hosts of these viruses. Influenza A viruses are classified into subtypes according to their surface glycoproteins: 18 hemagglutinin (HA) and 11 neuraminidase (NA) antigenic subtypes have been identified (1, 2, 3). Avian influenza viruses (AIVs) are subdivided into groups of high and low pathogenicity. The presence of multiple basic amino acids at the endoproteolytical cleavage site of the HA is a molecular indicator for high pathogenicity, at least for infections of gallinaceous poultry (4,5,6,7,8). Influenza viruses of HA subtypes H5, H7, and H9 are commonly identified in terrestrial gallinaceous poultry (9, 10). Only low-pathogenic AIVs (LPAIVs) of subtypes H5 and H7 naturally evolve into highly pathogenic AIVs (HPAIVs), which cause severe infections with high rates of mortality in poultry (11,12,13,14) and can also be transmitted from birds to humans (15,16,17,18).The two viral glycoproteins, HA and NA, expressed on the surface of influenza virions play an important role in determining the pathogenic properties of the virus. Influenza virus infection is initiated by interactions between the viral HA and sialic acid-containing oligosaccharides on target cells. The NA cleaves off the terminal si...

show abstract

“…Due to their opposing functions, the HA and NA proteins encoded by a given influenza virus are required to be in balance to achieve high viral fitness (37). A loss of HA/NA balance can occur through (i) reassortment involving either, but not both, of these genes (38); (ii) infection of a new tissue or host species, where sialic acids on cells or mucins may differ in type and distribution (39); (iii) a change in HA affinity/avidity due to the acquisition of antibody escape mutations (37,(40)(41)(42); or (iv) the presence of pharmaceutical neuraminidase inhibitors in the host (43). In each of these cases, studies have demonstrated that selective pressure on the virus can result in realignment of HA and NA functions such that viral attachment and release are not compromised.…”

mentioning

confidence: 99%

The M Segment of the 2009 Pandemic Influenza Virus Confers Increased Neuraminidase Activity, Filamentous Morphology, and Efficient Contact Transmissibility to A/Puerto Rico/8/1934-Based Reassortant Viruses

Campbell

Danzy

Kyriakis

et al. 2014

J Virol

103

117

View full text Add to dashboard Cite

To aid in understanding how the M segment might affect transmission, we evaluated neuraminidase activity and virion morphology of reassortant viruses. Transmission was found to correlate with higher neuraminidase activity and a more filamentous morphology. Importantly, we found that introduction of the pandemic M segment alone resulted in an increase in the neuraminidase activity of two pairs of otherwise isogenic PR8-based viruses. Thus, our data demonstrate the surprising result that functions encoded by the influenza A virus M segment impact neuraminidase activity and, perhaps through this mechanism, have a potent effect on transmissibility. IMPORTANCEOur work uncovers a previously unappreciated mechanism through which the influenza A virus M segment can alter the receptor-destroying activity of an influenza virus. Concomitant with changes to neuraminidase activity, the M segment impacts the morphology of the influenza A virion and transmissibility of the virus in the guinea pig model. We suggest that changes in NA activity underlie the ability of the influenza M segment to influence virus transmissibility. Furthermore, we show that coadapted M, NA, and HA segments are required to provide optimal transmissibility to an influenza virus. The M-NA functional interaction we describe appears to underlie the prominent role of the 2009 pandemic M segment in supporting efficient transmission and may be a highly important means by which influenza A viruses restore HA/NA balance following reassortment or transfer to new host environments.

show abstract

Adjustment of receptor-binding and neuraminidase substrate specificties in avian–human reassortant influenza viruses

Cited by 32 publications

References 28 publications

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Influenza A virus nucleoprotein selectively decreases neuraminidase gene-segment packaging while enhancing viral fitness and transmissibility

Alterations in Hemagglutinin Receptor-Binding Specificity Accompany the Emergence of Highly Pathogenic Avian Influenza Viruses

The M Segment of the 2009 Pandemic Influenza Virus Confers Increased Neuraminidase Activity, Filamentous Morphology, and Efficient Contact Transmissibility to A/Puerto Rico/8/1934-Based Reassortant Viruses

Contact Info

Product

Resources

About