Influenza virus hemagglutinin cleavage into HA
            <sub>1</sub>
            , HA
            <sub>2</sub>
            : No laughing matter

Taubenberger, Jeffery K.

doi:10.1073/pnas.95.17.9713

Cited by 50 publications

(45 citation statements)

References 20 publications

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“…As a class I viral fusion protein, HA plays an important role for viral entry by binding to the host receptor, sialylated glycans on endothelial cells in the respiratory tract, and facilitating membrane fusion in the low pH environment of the endosomal compartments after cell entry via endocytosis. During virus replication, the uncleaved precursor of the HA, namely HA0, is synthesized and is then cleaved by cellular proteases into two subunits HA1 and HA2, to produce the fully functional form of the protein [23]. Although this cleavage is usually catalyzed by trypsin-like serine endoproteases [24, 25], HAs from highly pathogenic H5 and H7 subtypes that contain a polybasic cleavage site can also be cleaved by the ubiquitous protease furin [26–28].…”

Section: Introductionmentioning

confidence: 99%

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Wilson

2017

Journal of Molecular Biology

148

174

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Influenza virus evolves rapidly to constantly escape from natural immunity. Most humoral immune responses to influenza virus target the hemagglutinin glycoprotein (HA), which is the major antigen on the surface of the virus. The HA is comprised of a globular head domain for receptor binding and a stem domain for membrane fusion. The major antigenic sites of HA are located in the globular head subdomain, which is highly tolerant of amino-acid substitutions and continual addition of glycosylation sites. Nonetheless, the evolution of the receptor-binding site (RBS) and the stem region on HA is severely constrained by their functional roles in engaging the host receptor and in mediating membrane fusion, respectively. Here, we review how broadly neutralizing antibodies (bnAbs) exploit these evolutionary constraints to protect against diverse influenza strains. We also discuss the emerging role of other epitopes that are conserved only in subsets of viruses. This rapidly increasing knowledge of the evolutionary biology, immunology, structural biology, and virology of influenza virus is invaluable for development and design of more universal influenza vaccines as well as novel therapeutics.

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Section: Introductionmentioning

confidence: 99%

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Wilson

2017

Journal of Molecular Biology

148

174

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“…In their natural hosts, these viruses cause asymptomatic infection of the gastrointestinal and respiratory tracts; however, in land-based poultry, mild respiratory symptoms may be present. In its more severe form, highly pathogenic (HP) avian IAVs cause systemic disease with high mortality and spread to numerous organs of the respiratory, digestive, and ner-vous systems (8,11,12). A difference in core body temperature between humans and avian species is a known factor in limiting interspecies transmission, as avian IAVs that have adapted to replication at 41°C demonstrate decreased polymerase activity at temperatures of 33 to 37°C, typical of the human respiratory tract (13)(14)(15)(16).…”

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confidence: 99%

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Kasloff

Pizzuto

Silic-Benussi

et al. 2014

J Virol

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Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3-and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCEDespite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These results suggest that slightly pathogenic IAVs may prove to be effective for oncolytic virotherapy of PDA and provide grounds for further studies to develop specific and targeted viruses, with the aim of testing their efficacy in clinical contexts.

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“…Recent studies regarding this pandemic have revealed that most deaths occurred among young adults, a group in which the influenza-related mortality rate is usually very low, and pathology sections from these cases often exhibited massive alveolar haemorrhage and pulmonary oedema [5][6][7]. In these cases, the majority of sections showed acute lobular pneumonia with massive neutrophil infiltration, suggesting death by acute bacterial pneumonia, one of the most common sequelae of the pandemic.…”

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confidence: 99%

Immunokinetics in severe pneumonia due to influenza virus and bacteria coinfection in mice

Seki¹,

Yanagihara²,

Higashiyama³

et al. 2004

Eur Respir J

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Coinfections of bacteria and influenza are a major cause of excessive mortality during influenza epidemics. However, the mechanism of the synergy between influenza virus and bacteria are poorly understood.In this study, mice were inoculated with influenza virus, followed 2 days later by inoculation with Streptococcus pneumoniae. The kinetics of viral titres, bacterial numbers and the immune response (cytokine and chemokine production) were also analysed.Short-term survival correlated with pathological changes in the lungs of infected mice. Influenza virus or S. pneumoniae infection alone induced moderate pneumonia; however, severe bronchopneumonia with massive haemorrhage in coinfected mice, which caused death of these mice y2 days after inoculation with S. pneumoniae, was noted. Intrapulmonary levels of inflammatory cytokines/chemokines, type-1 T-helper cell cytokines and Toll-like receptors, and the related mitogen-activated protein kinase signalling molecules (phosphorylated extracellular signal-regulated kinase -1 and -2, p38 and c-Jun N-terminal kinase), were increased in coinfected mice.These results suggest that immune mediators, including cytokines and chemokines, through Toll-like receptors/mitogen-activated protein kinase pathways, play important roles in the pathology of coinfection caused by influenza virus and Streptococcus pneumoniae.

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Influenza virus hemagglutinin cleavage into HA ₁ , HA ₂ : No laughing matter

Cited by 50 publications

References 20 publications

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Immunokinetics in severe pneumonia due to influenza virus and bacteria coinfection in mice

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Influenza virus hemagglutinin cleavage into HA 1 , HA 2 : No laughing matter

Cited by 50 publications

References 20 publications

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

A Perspective on the Structural and Functional Constraints for Immune Evasion: Insights from Influenza Virus

Oncolytic Activity of Avian Influenza Virus in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Immunokinetics in severe pneumonia due to influenza virus and bacteria coinfection in mice

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Influenza virus hemagglutinin cleavage into HA ₁ , HA ₂ : No laughing matter