A Single Amino Acid Substitution in the Hemagglutinin of H3N2 Subtype Influenza A Viruses Is Associated with Resistance to the Long Pentraxin PTX3 and Enhanced Virulence in Mice
Abstract:The long pentraxin, pentraxin 3 (PTX3), can play beneficial or detrimental roles during infection and disease by modulating various aspects of the immune system. There is growing evidence to suggest that PTX3 can mediate antiviral activity in vitro and in vivo. Previous studies demonstrated that PTX3 and the short pentraxin serum amyloid P express sialic acids that are recognized by the hemagglutinin (HA) glycoprotein of certain influenza A viruses (IAV), resulting in virus neutralization and anti-IAV activity… Show more
“…Avian-strains prefer binding to NeuAc-α-2,3-Gal, whereas human-strains prefer binding to NeuAc-α-2,6-Gal (81–84). Minor changes to the protein sequence correlate with a switch in sialic-acid binding preferences leading to changes in receptor specificities and altered susceptibility toward antibodies and lectins (17, 85–87). …”
Section: Resultsmentioning
confidence: 99%
“…The activity of this lectin depends on the presence of high mannose N -glycans on viral HA; IAV strains lacking glycosylation on the HA head region resist neutralization by SP-D. These include the pandemic strains of H1N1 1918 and 2009, the H3N2 of 1968 and the H2N2 of 1957 (17–19). Thus, the pathogenicity of pandemic IAV correlates with ability to escape neutralization by SP-D (15, 18, 20).…”
Despite sustained biomedical research effort, influenza A virus remains an imminent threat to the world population and a major healthcare burden. The challenge in developing vaccines against influenza is the ability of the virus to mutate rapidly in response to selective immune pressure. Hemagglutinin is the predominant surface glycoprotein and the primary determinant of antigenicity, virulence and zoonotic potential. Mutations leading to changes in the number of HA glycosylation sites are often reported. Such genetic sequencing studies predict at best the disruption or creation of sequons for N-linked glycosylation; they do not reflect actual phenotypic changes in HA structure. Therefore, combined analysis of glycan micro and macro-heterogeneity and bioassays will better define the relationships among glycosylation, viral bioactivity and evolution. We present a study that integrates proteomics, glycomics and glycoproteomics of HA before and after adaptation to innate immune system pressure. We combined this information with glycan array and immune lectin binding data to correlate the phenotypic changes with biological activity. Underprocessed glycoforms predominated at the glycosylation sites found to be involved in viral evolution in response to selection pressures and interactions with innate immune-lectins. To understand the structural basis for site-specific glycan microheterogeneity at these sites, we performed structural modeling and molecular dynamics simulations. We observed that the presence of immature, high-mannose type glycans at a particular site correlated with reduced accessibility to glycan remodeling enzymes. Further, the high mannose glycans at sites implicated in immune lectin recognition were predicted to be capable of forming trimeric interactions with the immune-lectin surfactant protein-D.
“…Avian-strains prefer binding to NeuAc-α-2,3-Gal, whereas human-strains prefer binding to NeuAc-α-2,6-Gal (81–84). Minor changes to the protein sequence correlate with a switch in sialic-acid binding preferences leading to changes in receptor specificities and altered susceptibility toward antibodies and lectins (17, 85–87). …”
Section: Resultsmentioning
confidence: 99%
“…The activity of this lectin depends on the presence of high mannose N -glycans on viral HA; IAV strains lacking glycosylation on the HA head region resist neutralization by SP-D. These include the pandemic strains of H1N1 1918 and 2009, the H3N2 of 1968 and the H2N2 of 1957 (17–19). Thus, the pathogenicity of pandemic IAV correlates with ability to escape neutralization by SP-D (15, 18, 20).…”
Despite sustained biomedical research effort, influenza A virus remains an imminent threat to the world population and a major healthcare burden. The challenge in developing vaccines against influenza is the ability of the virus to mutate rapidly in response to selective immune pressure. Hemagglutinin is the predominant surface glycoprotein and the primary determinant of antigenicity, virulence and zoonotic potential. Mutations leading to changes in the number of HA glycosylation sites are often reported. Such genetic sequencing studies predict at best the disruption or creation of sequons for N-linked glycosylation; they do not reflect actual phenotypic changes in HA structure. Therefore, combined analysis of glycan micro and macro-heterogeneity and bioassays will better define the relationships among glycosylation, viral bioactivity and evolution. We present a study that integrates proteomics, glycomics and glycoproteomics of HA before and after adaptation to innate immune system pressure. We combined this information with glycan array and immune lectin binding data to correlate the phenotypic changes with biological activity. Underprocessed glycoforms predominated at the glycosylation sites found to be involved in viral evolution in response to selection pressures and interactions with innate immune-lectins. To understand the structural basis for site-specific glycan microheterogeneity at these sites, we performed structural modeling and molecular dynamics simulations. We observed that the presence of immature, high-mannose type glycans at a particular site correlated with reduced accessibility to glycan remodeling enzymes. Further, the high mannose glycans at sites implicated in immune lectin recognition were predicted to be capable of forming trimeric interactions with the immune-lectin surfactant protein-D.
“…Furthermore, the amino acid substitution described for UL18 gene may as well suggest an important protein structure modification that could potentially result in the viral capsid being more resistant to the host immune system. As has been shown before, even a single amino acid substitution can be the cause of viral drug resistance and enhanced virulence [54][55][56]. Even though its positioning in the protein structure is based only on computational modelling and the validity of its importance is subject to different conditions, such as the amino acid being at least moderately exposed instead of buried, it is worth noting it as a target for future deeper analysis with laboratory experimental techniques.…”
Section: Amino Acid Variation In the Turks And Caicos Populationmentioning
Background: Fibropapillomatosis (FP) is a neoplastic disease characterized by cutaneous tumours that has been documented to infect all sea turtle species. Chelonid fibropapilloma-associated herpesvirus (CFPHV) is believed to be the aetiological agent of FP, based principally on consistent PCR-based detection of herpesvirus DNA sequences from FP tumours. We used a recently described PCR-based assay that targets 3 conserved CFPHV genes, to survey 208 green turtles (Chelonia mydas). This included both FP tumour exhibiting and clinically healthy individuals. An additional 129 globally distributed clinically healthy individual sea turtles; representing four other species were also screened.
“…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 glycoproteins and is required for the spread of IAV within and between hosts (15)(16)(17)(18). Because the specificity of HA and NA for different sialic acid linkages and contexts can vary substantially, functional alignment between the yin-yang activities of HA and NA represents a major determinant of host adaptation, transmissibility, and immune escape (19)(20)(21)(22)(23).…”
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...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.