#Cytoplasm and Beyond: The Dynamic Innate Immune Sensing of #Influenza A Virus by RIG-I (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Cytoplasm and Beyond: The Dynamic Innate Immune Sensing of Influenza A Virus by RIG-I

GuanQun Liu, Yan Zhou

DOI: 10.1128/JVI.02299-18

 

ABSTRACT

Innate immune sensing of influenza A virus (IAV) requires RIG-I, a fundamental cytoplasmic RNA sensor. How RIG-I’s cytoplasmic localization reconciles with the nuclear replication nature of IAV is poorly understood. Recent findings provide advanced insights into the spatiotemporal RIG-I sensing of IAV and highlight the contribution of various RNA ligands to RIG-I activation. Understanding a compartment-specific RIG-I sensing paradigm would facilitate the identification of the full spectrum of physiological RIG-I ligands produced during IAV infection.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A.

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#H5N8 and #H7N9 packaging signals constrain #HA #reassortment with a seasonal #H3N2 #influenza A virus (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

H5N8 and H7N9 packaging signals constrain HA reassortment with a seasonal H3N2 influenza A virus

Maria C. White, Hui Tao, John Steel, and Anice C. Lowen

PNAS published ahead of print February 13, 2019 / DOI: https://doi.org/10.1073/pnas.1818494116

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 17, 2019 (received for review October 26, 2018)

 

Significance

Influenza A viruses (IAV) can exchange genetic material in coinfected cells in a process termed reassortment. The last three IAV pandemic strains arose from reassortment events involving human and nonhuman IAVs. Because introduction of the hemagglutinin (HA) gene from a nonhuman virus is required for a pandemic, we addressed the compatibility of human and avian IAV. We show that sequence differences between human and avian HA genes limit the potential for reassortment. However, human IAV still incorporated heterologous HA genes at a low level in coinfected animals. This observed low level of incorporation could become significant if reassortant viruses had a fitness advantage within the host, such as resistance to preexisting immunity, and highlights the continued need for IAV surveillance.

 

Abstract

Influenza A virus (IAV) has a segmented genome, which (i) allows for exchange of gene segments in coinfected cells, termed reassortment, and (ii) necessitates a selective packaging mechanism to ensure incorporation of a complete set of segments into virus particles. Packaging signals serve as segment identifiers and enable segment-specific packaging. We have previously shown that packaging signals limit reassortment between heterologous IAV strains in a segment-dependent manner. Here, we evaluated the extent to which packaging signals prevent reassortment events that would raise concern for pandemic emergence. Specifically, we tested the compatibility of hemagglutinin (HA) packaging signals from H5N8 and H7N9 avian IAVs with a human seasonal H3N2 IAV. By evaluating reassortment outcomes, we demonstrate that HA segments carrying H5 or H7 packaging signals are significantly disfavored for incorporation into a human H3N2 virus in both cell culture and a guinea pig model. However, incorporation of the heterologous HAs was not excluded fully, and variants with heterologous HA packaging signals were detected at low levels in vivo, including in naïve contact animals. This work indicates that the likelihood of reassortment between human seasonal IAV and avian IAV is reduced by divergence in the RNA packaging signals of the HA segment. These findings offer important insight into the molecular mechanisms governing IAV emergence and inform efforts to estimate the risks posed by H7N9 and H5N8 subtype avian IAVs.

influenza A virus – reassortment – packaging – zoonosis – antigenic shift

Keywords: Influenza A; Pandemic Influenza; Seasonal Influenza; Avian Influenza; Reassortant strain; H3N2; H5N8; H7N9; Animal models.

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#AZT acts as an anti- #influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/ #H1N1 RNA dependent RNA #polymerase (J Comput Aided Mol Des., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Comput Aided Mol Des. 2019 Feb 9. doi: 10.1007/s10822-019-00189-w. [Epub ahead of print]

AZT acts as an anti-influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/H1N1 RNA dependent RNA polymerase.

Pagadala NS1,2,3,4.

Author information: 1 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 2 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 3 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 4 Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, T6G 2E1, Canada. nattu251@gmail.com.

 

Abstract

To develop potent drugs that inhibit the activity of influenza virus RNA dependent RNA polymerase (RdRp), a set of compounds favipiravir, T-705, T-1105 and T-1106, ribavirin, ribavirin triphosphate viramidine, 2FdGTP (2′-deoxy-2′-fluoroguanosine triphosphate) and AZT-TP (3′-Azido-3′-deoxy-thymidine-5′-triphosphate) were docked with a homology model of IAV RdRp from the A/PR/8/34/H1N1 strain. These compounds bind to four pockets A-D of the IAV RdRp with different mechanism of action. In addition, AZT-TP also binds to the PB1 catalytic site near to the tip of the priming loop with a highest ΔG of - 16.7 Kcal/mol exhibiting an IC50 of 1.12 µM in an in vitro enzyme transcription assay. This shows that AZT-TP mainly prevents the incorporation of incoming nucleotide involved in initiation of vRNA replication. Conversely, 2FdGTP used as a positive control binds to pocket-B at the end of tunnel-II with a highest ΔG of - 16.3 Kcal/mol inhibiting chain termination with a similar IC50 of 1.12 µM. Overall, our computational results in correlation with experimental studies gives information for the first time about the binding modes of the known influenza antiviral compounds in different models of vRNA replication by IAV RdRp. This in turn gives new structural insights for the development of new therapeutics exhibiting high specificity to the PB1 catalytic site of influenza A viruses.

KEYWORDS: Catalytic site; Docking; Nucleotide triphosphates; RNA dependent RNA polymerase

PMID: 30739239 DOI: 10.1007/s10822-019-00189-w

Keywords: Influenza A; H1N1; Antivirals; AZT; Ribavirin; Favipiravir.

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#Influenza virus #polymerase #inhibitors in #clinical development (Curr Opin Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Curr Opin Infect Dis. 2019 Feb 4. doi: 10.1097/QCO.0000000000000532. [Epub ahead of print]

Influenza virus polymerase inhibitors in clinical development.

Hayden FG1, Shindo N2.

Author information: 1 Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA. 2 Health Emergencies Program, World Health Organization, Geneva, Switzerland.

 

Abstract

PURPOSE OF REVIEW:

We review antivirals inhibiting subunits of the influenza polymerase complex that are advancing in clinical development.

RECENT FINDINGS:

Favipiravir, pimodivir, and baloxavir are inhibitory in preclinical models for influenza A viruses, including pandemic threat viruses and those resistant to currently approved antivirals, and two (favipiravir and baloxavir) also inhibit influenza B viruses. All are orally administered, although the dosing regimens vary. The polymerase basic protein 1 transcriptase inhibitor favipiravir has shown inconsistent clinical effects in uncomplicated influenza, and is teratogenic effects in multiple species, contraindicating its use in pregnancy. The polymerase basic protein 2 cap-binding inhibitor pimodivir displays antiviral effects alone and in combination with oseltamivir in uncomplicated influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Single doses of the polymerase acidic protein cap-dependent endonuclease inhibitor baloxavir are effective in alleviating symptoms and rapidly inhibiting viral replication in otherwise healthy and higher risk patients with acute influenza, although variants with reduced susceptibility emerge frequently during monotherapy. Combinations of newer polymerase inhibitors with neuraminidase inhibitors show synergy in preclinical models and are currently undergoing clinical testing in hospitalized patients.

SUMMARY:

These new polymerase inhibitors promise to add to the clinical management options and overall control strategies for influenza virus infections.

PMID: 30724789 DOI: 10.1097/QCO.0000000000000532

Keywords: Antivirals; Drugs Resistance; Influenza A; Pandemic Influenza; Favipiravir; Pimodivir; Baloxavir.

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High #ambient #temperature dampens adaptive immune #responses to #influenza A virus #infection (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

High ambient temperature dampens adaptive immune responses to influenza A virus infection

Miyu Moriyama and Takeshi Ichinohe

PNAS published ahead of print February 4, 2019 / DOI: https://doi.org/10.1073/pnas.1815029116

Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved December 26, 2018 (received for review August 31, 2018)

 

Significance

Although half of the world’s population could face severe food crisis as a result of global warming by the end of this century, the effects of environmental temperature and host nutritional status in host defense to viral infection in vivo are less clear. Here, we demonstrated that exposure of mice to the high ambient temperature of 36 °C reduced their food intake and impaired adaptive immune responses to influenza virus infection. In addition, we found that administration of glucose or dietary short-chain fatty acids restored influenza virus-specific adaptive immune responses in high heat-exposed mice. Our results imply possible public health problems and concerns that outside temperature and host nutritional status may be critical determinants of viral pathogenesis or vaccine efficacy.

 

Abstract

Although climate change may expand the geographical distribution of several vector-borne diseases, the effects of environmental temperature in host defense to viral infection in vivo are unknown. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C impaired adaptive immune responses against infection with viral pathogens, influenza, Zika, and severe fever with thrombocytopenia syndrome phlebovirus. Following influenza virus infection, the high heat-exposed mice failed to stimulate inflammasome-dependent cytokine secretion and respiratory dendritic cell migration to lymph nodes. Although commensal microbiota composition remained intact, the high heat-exposed mice decreased their food intake and increased autophagy in lung tissue. Induction of autophagy in room temperature-exposed mice severely impaired virus-specific CD8 T cells and antibody responses following respiratory influenza virus infection. In addition, we found that administration of glucose or dietary short-chain fatty acids restored influenza virus-specific adaptive immune responses in high heat-exposed mice. These findings uncover an unexpected mechanism by which ambient temperature and nutritional status control virus-specific adaptive immune responses.

global warming – vector-borne diseases – immunity to viral infection – autophagy – inflammasomes

 

Footnotes

1 To whom correspondence should be addressed. Email: ichinohe@ims.u-tokyo.ac.jp.

Author contributions: M.M. and T.I. designed research; M.M. and T.I. performed research; M.M. and T.I. analyzed data; and T.I. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1815029116/-/DCSupplemental.

Published under the PNAS license.

Keywords: Influenza A; Climate Change; Global Warming.

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Potent anti- #influenza #H7 human #monoclonal #antibody induces separation of #hemagglutinin receptor-binding head domains (PLoS Biology, abstract)

[Source: PLoS Biology, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains

Hannah L. Turner , Jesper Pallesen , Shanshan Lang, Sandhya Bangaru, Sarah Urata, Sheng Li, Christopher A. Cottrell, Charles A. Bowman, James E. Crowe Jr., Ian A. Wilson, Andrew B. Ward

Published: February 4, 2019 / DOI: https://doi.org/10.1371/journal.pbio.3000139 / This is an uncorrected proof.

 

Abstract

Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the prefusion conformation. The “breathing” of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.

 

Author summary

Influenza viruses cause severe respiratory infections on a global scale annually. Vaccine efforts are hampered by the virus’s naturally high mutation rate, which results in wide variation between influenza strains of the antigens that are produced and recognized by antibodies, particularly in the surface glycoprotein hemagglutinin (HA). However, broadly neutralizing antibodies (bnAbs) are a class of antibodies that develop during natural infections that are capable of inhibiting infection across multiple strains. In this study, we structurally characterized one such bnAb, H7.5, which targets a unique semioccluded yet highly conserved region on the HA head. We showed, using both negative-stain and high-resolution cryo-electron microscopy (cryoEM), that after a short incubation, H7.5 fragment antigen binding (Fab) induces HA to fall apart, effectively preventing infection. We found that H7.5 binds to an epitope only accessible through transient “breathing” of the HA head, and this observation provides insight into the conformational transitions necessary for viral fusion as well as key information about a unique vaccine target.

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Citation: Turner HL, Pallesen J, Lang S, Bangaru S, Urata S, Li S, et al. (2019) Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains. PLoS Biol 17(2): e3000139. https://doi.org/10.1371/journal.pbio.3000139

Academic Editor: James Conway, University of Pittsburgh, UNITED STATES

Received: September 28, 2018; Accepted: January 18, 2019; Published: February 4, 2019

Copyright: © 2019 Turner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The final coordinates for the H7.5 Fab structure have been deposited to the RCSB database with the accession code PDB 6BTJ. The nsEM map of H7 NY HA1/2 complexed with 3 H7.5 Fabs bound, and the cryo-EM maps of H7 NL HA1/2 with 3 H7.5 Fabs bound, the H7 NL HA1/2 with 2 H7.5 Fabs bound, and the H7 Sh2 HA1/2 with 3 H7.5 Fabs bound were deposited to the Electron Microscopy Databank with the accession codes EMD-9144, EMD-9143, EMD-9145 EMD-9142, respectively. The cryo-EM map and fitted coordinates for H7 NY HA with 3 H7.7 Fabs bound has been deposited to the RCSB database with accession numbers EMD-9139/PDB 6MLM.

Funding: National Institutes of Health grant U19 AI117905 and National Institutes Health contract HHSN272201400024C. Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIAID, DOE, or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: bnAb, broadly neutralizing antibody; CDRH3, complementary determining region heavy chain 3; cryoEM, cryo-electron microscopy; Fab, fragment antigen binding; FSC, Fourier shell correlation; HA, hemagglutinin; HDX-MS, hydrogen–deuterium exchange mass spectrometry; H-FR3, heavy-chain framework region 3; mAb, monoclonal antibody; NA, neuraminidase; nsEM, negative-stain electron microscopy; PDB, Protein Data Bank; RBS, receptor-binding site; smFRET, single molecule Forster resonance energy transfer

Keywords: Influenza A; H7; Monoclonal antibodies.

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Back to the Future for #Influenza #Preimmunity-Looking Back at Influenza Virus History to Infer the #Outcome of Future #Infections (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Jan 30;11(2). pii: E122. doi: 10.3390/v11020122.

Back to the Future for Influenza Preimmunity-Looking Back at Influenza Virus History to Infer the Outcome of Future Infections.

Francis ME1, King ML2, Kelvin AA3,4,5.

Author information: 1 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. M.Francis@dal.ca. 2 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. MorganKing@dal.ca.  3 Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. akelvin@dal.ca. 4 Department of Pediatrics, Division of Infectious Disease, Faculty of Medicine, Dalhousie University, Halifax, NS B3K 6R8, Canada. akelvin@dal.ca. 5 Canadian Centre for Vaccinology, IWK Health Centre, Halifax NS B3K 6R8, Canada. akelvin@dal.ca.

 

Abstract

The influenza virus-host interaction is a classic arms race. The recurrent and evolving nature of the influenza virus family allows a single host to be infected several times. Locked in co-evolution, recurrent influenza virus infection elicits continual refinement of the host immune system. Here we give historical context of circulating influenza viruses to understand how the individual immune history is mirrored by the history of influenza virus circulation. Original Antigenic Sin was first proposed as the negative influence of the host’s first influenza virus infection on the next and Imprinting modernizes Antigenic Sin incorporating both positive and negative outcomes. Building on imprinting, we refer to preimmunity as the continual refinement of the host immune system with each influenza virus infection. We discuss imprinting and the interplay of influenza virus homology, vaccination, and host age establishing preimmunity. We outline host signatures and outcomes of tandem infection according to the sequence of virus and classify these relationships as monosubtypic homologous, monosubtypic heterologous, heterosubtypic, or heterotypic sequential infections. Finally, the preimmunity knowledge gaps are highlighted for future investigation. Understanding the effects of antigenic variable recurrent influenza virus infection on immune refinement will advance vaccination strategies, as well as pandemic preparedness.

KEYWORDS: Spanish influenza; antigenic drift; antigenic shift; immune response; imprinting; influenza virus; original antigenic sin; orthomyxoviridae; pandemic; preimmunity

PMID: 30704019 DOI: 10.3390/v11020122

Keywords: Influenza A; Pandemic Influenza; Immunology.

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