A carbohydrate-binding protein from the edible Lablab #beans effectively blocks the infections of #influenza viruses and #SARS-CoV-2 (Cell Rep., abstract)

[Source: Cell Reports, full page: (LINK). Abstract, edited.]

A carbohydrate-binding protein from the edible Lablab beans effectively blocks the infections of influenza viruses and SARS-CoV-2

Yo-Min Liu, Md. Shahed-Al-Mahmud, Xiaorui Chen, Ting-Hua Chen, Kuo-Shiang Liao, Jennifer M. Lo, Yi-Min Wu, Meng-Chiao Ho, Chung-Yi Wu, Chi-Huey Wong, Jia-Tsrong Jan, Che Ma

Open Access | Published: July 24, 2020 | DOI: https://doi.org/10.1016/j.celrep.2020.108016

 

Highlights

  • FRIL is a plant lectin with potent anti-influenza and anti-SARS-CoV-2 activity.
  • FRIL preferentially binds to complex type N-glycans on viral glycoproteins.
  • FRIL inhibits influenza virus entry by sequestering virions in late endosomes.
  • Intranasal administration of FRIL protects against lethal H1N1 challenge in mice.

 

Summary

The influenza virus hemagglutinin (HA) and coronavirus spike (S) protein mediate virus entry. HA and S proteins are heavily glycosylated, making them potential targets for carbohydrate binding agents such as lectins. Here we show that the lectin FRIL, isolated from hyacinth beans (Lablab purpureus), has anti-influenza and anti-SARS-CoV-2 activity. FRIL can neutralize 11 representative human and avian influenza strains at low nanomolar concentrations, and intranasal administration of FRIL is protective against lethal H1N1 infection in mice. FRIL binds preferentially to complex type N-glycans, and neutralizes viruses that possess complex type N-glycans on their envelopes. As a homotetramer, FRIL is capable of aggregating influenza particles through multivalent binding and trapping influenza virions in cytoplasmic late endosomes, preventing their nuclear entry. Remarkably, FRIL also effectively neutralizes SARS-CoV-2, preventing viral protein production and cytopathic effect in host cells. These findings suggest potential application of FRIL for prevention and/or treatment of influenza and COVID-19.

Accepted: July 17, 2020 – Received in revised form: June 9, 2020 – Received: March 3, 2020

Publication stage In Press Accepted Manuscript

Identification DOI: https://doi.org/10.1016/j.celrep.2020.108016

Copyright © 2020

Keywords: SARS-CoV-2; COVID-19; Influenza A; Antivirals.

——

Single-cell #sequencing of peripheral #blood #mononuclear cells reveals distinct immune response landscapes of #COVID19 and #influenza patients (Immunity, abstract)

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

Single-cell sequencing of peripheral blood mononuclear cells reveals distinct immune response landscapes of COVID-19 and influenza patients

Linnan Zhu, Penghui Yang, Yingze Zhao, Zhenkun Zhuang, Zhifeng Wang, Rui Song, Jie Zhang, Chuanyu Liu, Qianqian Gao, Qumiao Xu, Xiaoyu Wei, Hai-Xi Sun, Beiwei Ye, Yanan Wu, Ning Zhang, Guanglin Lei, Linxiang Yu, Jin Yan, Guanghao Diao, Fanping Meng, Changqing Bai, Panyong Mao, Yeya Yu, Mingyue Wang, Yue Yuan, Qiuting Deng, Ziyi Li, Yunting Huang, Guohai Hu, Yang Liu, Xiaoqian Wang, Ziqian Xu, Peipei Liu, Yuhai Bi, Yi Shi, Shaogeng Zhang, Zhihai Chen, Jian Wang, Xun Xu, Guizhen Wu, Fusheng Wang ∗, George F. Gao ∗, Longqi Liu ∗, William J. Liu  ∗

Published: July 19, 2020 | DOI: https://doi.org/10.1016/j.immuni.2020.07.009

 

Highlights

  • We generated a single-cell atlas of PBMCs in both COVID-19 and influenza patients.
  • Plasma cells increase significantly in both COVID-19 and influenza patients.
  • COVID-19 is featured with XAF1-, TNF- and FAS-induced T cell apoptosis.
  • Distinct pathways activate in COVID-19 (STAT1/IRF3) vs. influenza (STAT3/NFκB) patients.

 

SUMMARY

COVID-19 is a severe infectious disease that is a current global health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19 and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients, and XAF1-, TNF- and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) vs. IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of IL6R and IL6ST expression in COVID-19 patients, but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased pro-inflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.

Accepted: July 14, 2020 – Received in revised form: June 7, 2020 – Received: April 29, 2020

Publication stage In Press Accepted Manuscript

Identification DOI: https://doi.org/10.1016/j.immuni.2020.07.009

Copyright © 2020 Published by Elsevier Inc.

Keywords: SARS-CoV-2; COVID-19; Influenza A; Immunology.

——

#Epidemiology and #Genotypic #Diversity of #EA #Avian-Like #H1N1 #Swine #Influenza Viruses in #China (Virol Sin., abstract)

[Source: Virologica Sinica, full page: (LINK). Abstract, edited.]

Epidemiology and Genotypic Diversity of Eurasian Avian-Like H1N1 Swine Influenza Viruses in China

Zhaomin Feng, Wenfei Zhu, Lei Yang, Jia Liu, Lijuan Zhou, Dayan Wang & Yuelong Shu

Virologica Sinica (2020)

 

Abstract

Eurasian avian-like H1N1 (EA H1N1) swine influenza virus (SIV) outside European countries was first detected in Hong Kong Special Administrative Region (Hong Kong, SAR) of China in 2001. Afterwards, EA H1N1 SIVs have become predominant in pig population in this country. However, the epidemiology and genotypic diversity of EA H1N1 SIVs in China are still unknown. Here, we collected the EA H1N1 SIVs sequences from China between 2001 and 2018 and analyzed the epidemic and phylogenic features, and key molecular markers of these EA H1N1 SIVs. Our results showed that EA H1N1 SIVs distributed in nineteen provinces/municipalities of China. After a long-time evolution and transmission, EA H1N1 SIVs were continuously reassorted with other co-circulated influenza viruses, including 2009 pandemic H1N1 (A(H1N1)pdm09), and triple reassortment H1N2 (TR H1N2) influenza viruses, generated 11 genotypes. Genotype 3 and 5, both of which were the reassortments among EA H1N1, A(H1N1)pdm09 and TR H1N2 viruses with different origins of M genes, have become predominant in pig population. Furthermore, key molecular signatures were identified in EA H1N1 SIVs. Our study has drawn a genotypic diversity image of EA H1N1 viruses, and could help to evaluate the potential risk of EA H1N1 for pandemic preparedness and response.

Keywords: Avian Influenza; Swine Influenza; Influenza A; Reassortant strain; Pigs; H1N1; H1N2; H1N1pdm09; China.

——

Prevalent #Eurasian #avian-like #H1N1 #swine #influenza virus with #H1N1pdm09 viral #genes facilitating #human 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.]

Prevalent Eurasian avian-like H1N1 swine influenza virus with 2009 pandemic viral genes facilitating human infection

Honglei Sun, Yihong Xiao,  Jiyu Liu, Dayan Wang, Fangtao Li, Chenxi Wang, Chong Li, Junda Zhu, Jingwei Song, Haoran Sun,  Zhimin Jiang, Litao Liu, Xin Zhang, Kai Wei, Dongjun Hou, Juan Pu, Yipeng Sun, Qi Tong, Yuhai Bi, Kin-Chow Chang, Sidang Liu,  George F. Gao, and Jinhua Liu

PNAS first published June 29, 2020 https://doi.org/10.1073/pnas.1921186117

Contributed by George F. Gao, April 28, 2020 (sent for review December 9, 2019; reviewed by Ian H. Brown and Xiu-Feng Henry Wan)

 

Significance

Pigs are intermediate hosts for the generation of pandemic influenza virus. Thus, systematic surveillance of influenza viruses in pigs is a key measure for prewarning the emergence of the next pandemic influenza. Here, we identified a reassortant EA H1N1 virus possessing pdm/09 and TR-derived internal genes, termed as G4 genotype, which has become predominant in swine populations since 2016. Similar to pdm/09 virus, G4 viruses have all the essential hallmarks of a candidate pandemic virus. Of concern is that swine workers show elevated seroprevalence for G4 virus. Controlling the prevailing G4 EA H1N1 viruses in pigs and close monitoring in human populations, especially the workers in swine industry, should be urgently implemented.

 

Abstract

Pigs are considered as important hosts or “mixing vessels” for the generation of pandemic influenza viruses. Systematic surveillance of influenza viruses in pigs is essential for early warning and preparedness for the next potential pandemic. Here, we report on an influenza virus surveillance of pigs from 2011 to 2018 in China, and identify a recently emerged genotype 4 (G4) reassortant Eurasian avian-like (EA) H1N1 virus, which bears 2009 pandemic (pdm/09) and triple-reassortant (TR)-derived internal genes and has been predominant in swine populations since 2016. Similar to pdm/09 virus, G4 viruses bind to human-type receptors, produce much higher progeny virus in human airway epithelial cells, and show efficient infectivity and aerosol transmission in ferrets. Moreover, low antigenic cross-reactivity of human influenza vaccine strains with G4 reassortant EA H1N1 virus indicates that preexisting population immunity does not provide protection against G4 viruses. Further serological surveillance among occupational exposure population showed that 10.4% (35/338) of swine workers were positive for G4 EA H1N1 virus, especially for participants 18 y to 35 y old, who had 20.5% (9/44) seropositive rates, indicating that the predominant G4 EA H1N1 virus has acquired increased human infectivity. Such infectivity greatly enhances the opportunity for virus adaptation in humans and raises concerns for the possible generation of pandemic viruses.

swine influenza – Eurasian avian-like H1N1 virus – 2009 pandemic H1N1 virus – reassortant – pandemic potential

 

Footnotes

1 H.S., Y.X., and J.L. contributed equally to this work.

2 To whom correspondence may be addressed. Email: gaof@im.ac.cn or ljh@cau.edu.cn.

Author contributions: Honglei Sun, Y.X., S.L., G.F.G., and Jinhua Liu designed research; Honglei Sun, Y.X., Jiyu Liu, F.L., C.L., J.Z., J.S., Haoran Sun, Z.J., L.L., X.Z., K.W., D.H., and Q.T. performed research; Honglei Sun, Jiyu Liu, D.W., C.W., J.P., Y.B., and Jinhua Liu analyzed data; and Honglei Sun, J.P., Y.S., K.-C.C., G.F.G., and Jinhua Liu wrote the paper.

Reviewers: I.H.B., Animal and Plant Health Agency; and X.-F.H.W., University of Missouri.

The authors declare no competing interest.

Data deposition: The sequences generated in this study have been deposited in the GenBank database (accession nos. are listed in SI Appendix, Table S3).

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1921186117/-/DCSupplemental.

Published under the PNAS license.

Keywords: Influenza A; Reassortant strain; Avian Influenza; Swine Influenza; Pigs; Human; China; H1N1; H1N1pdm09.

—–

#Neuraminidase #antigenic #drift of #H3N2 clade 3c.2a viruses alters virus #replication, enzymatic activity and inhibitory #antibody binding (PLOS Pathog., abstract)

[Source: PLOS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS |  PEER-REVIEWED | RESEARCH ARTICLE

Neuraminidase antigenic drift of H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding

Harrison Powell, Andrew Pekosz

Published: June 29, 2020 | DOI: https://doi.org/10.1371/journal.ppat.1008411 | This is an uncorrected proof.

 

Abstract

In the 2014–2015 influenza season a novel neuraminidase (NA) genotype was detected in global human influenza A surveillance. This novel genotype encoded an N-linked glycosylation site at position 245–247 in the NA protein from clade 3c.2a H3N2 viruses. In the years following the 2014–2015 season, this novel NA glycosylation genotype quickly dominated the human H3N2 population of viruses. To assess the effect this novel N-linked glycan has on virus fitness and antibody binding, recombinant viruses with (NA Gly+) or without (NA Gly-) the 245 NA glycan were created. Viruses with the 245 NA Gly+ genotype grew to a significantly lower infectious virus titer on primary, differentiated human nasal epithelial cells (hNEC) compared to viruses with the 245 NA Gly- genotype, but growth was similar on immortalized cells. The 245 NA Gly+ blocked human and rabbit monoclonal antibodies that target the enzymatic site from binding to their epitope. Additionally, viruses with the 245 NA Gly+ genotype had significantly lower enzymatic activity compared to viruses with the 245 NA Gly- genotype. Human monoclonal antibodies that target residues near the 245 NA glycan were less effective at inhibiting NA enzymatic activity and virus replication of viruses encoding an NA Gly+ protein compared to ones encoding NA Gly- protein. Additionally, a recombinant H6N2 virus with the 245 NA Gly+ protein was more resistant to enzymatic inhibition from convalescent serum from H3N2-infected humans compared to viruses with the 245 NA Gly- genotype. Finally, the 245 NA Gly+ protected from NA antibody mediated virus neutralization. These results suggest that while the 245 NA Gly+ decreases virus replication in hNECs and decreases enzymatic activity, the 245 NA glycan blocks the binding of monoclonal and human serum NA specific antibodies that would otherwise inhibit enzymatic activity and virus replication.

 

Author summary

Influenza virus infects millions of people worldwide and leads to thousands of deaths and millions in economic loss each year. During the 2014/2015 season circulating human H3N2 viruses acquired a novel mutation in the neuraminidase (NA) protein. This mutation has since fixed in human H3N2 viruses. This mutation at position 245 through 247 in the amino acid sequence of NA encoded an N-linked glycosylation. Here, we studied how this N-linked glycan impacts virus fitness and protein function. We found that this N-linked glycan on the NA protein decreased viral replication fitness on human nasal epithelial cells (hNEC) but not immortalized Madin-Darby Canine Kidney (MDCK) cells. We also determined this glycan decreases NA enzymatic activity, enzyme kinetics and affinity for substrate. Furthermore, we show that this N-linked glycan at position 245 blocks some NA specific inhibitory antibodies from binding to the protein, inhibiting enzymatic activity, and inhibiting viral replication. Finally, we showed that viruses with the novel 245 N-linked glycan are more resistant to convalescent human serum antibody mediated enzymatic inhibition. While this 245 N-linked Glycan decreases viral replication and enzymatic activity, the 245 N-linked glycan protects the virus from certain NA specific inhibitory antibodies. Our study provides new insight into the function of this dominant H3N2 NA mutation and how it impacts antigenicity and fitness of circulating H3N2 viruses.

___

Citation: Powell H, Pekosz A (2020) Neuraminidase antigenic drift of H3N2 clade 3c.2a viruses alters virus replication, enzymatic activity and inhibitory antibody binding. PLoS Pathog 16(6): e1008411. https://doi.org/10.1371/journal.ppat.1008411

Editor: Anice C. Lowen, Emory University School of Medicine, UNITED STATES

Received: February 13, 2020; Accepted: May 11, 2020; Published: June 29, 2020

Copyright: © 2020 Powell, Pekosz. 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: All relevant data are within the manuscript.

Funding: The work was supported by CEIRS HHSN272201400007C and T32 AI007417 (HP). 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.

Keywords: Seasonal Influenza; Influenza A; H3N2; Viral pathogenesis.

——

#Influenza #H1N1pdm09 virus exhibiting reduced #susceptibility to #baloxavir due to a PA E23K #substitution detected from a #child without baloxavir #treatment (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 20 June 2020, 104828 | In Press, Journal Pre-proof | Short Communication

Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment

Emi Takashita 1, Takashi Abe 2, Hiroko Morita 1, Shiho Nagata 1, Seiichiro Fujisaki 1, Hideka Miura 1, Masayuki Shirakura 1, Noriko Kishida 1, Kazuya Nakamura 1, Tomoko Kuwahara 1, KeikoMitamura 3, Masataka Ichikawa 4, Masahiko Yamazaki 5, Shinji Watanabe 1, Hideki Hasegawa 1, The Influenza Virus Surveillance Group of Japan,  Rika Komagome 6, Asami Ohnishi 7, Rika Tsutsui 8, Masaki Takahashi 9, MieSasaki 10, Shiho Tamura 11, Chihiro Shibata 12, Kenichi Komabayashi 13, Nozomi Saito 14, Aoi Saito 15, Fuminori Mizukoshi 16, Akira Wakatsuki 17, Hiroyuki Tsukagoshi 18, Noriko Suzuki 19, Yuka Uno 20, Noriko Oitate 21, Wakako Nishikawa  22, Mami Nagashima 23, Sumi Watanabe 24, Chiharu Kawakami 25, Hideaki Shimizu 26, Hazime Amano 27, Satoko Kanazawa 28, Kaori Watanabe 29, Kazunari Yamamoto 30, Tetsuya Yoneda 31, Sachiko Nakamura 32, Kaori Sato 33, Masayuki Oonuma 34, Michiko Takeuchi 35, ErinaTanaka 36, Masahiro Nishioka 37, Yusuke Sato 38, Yukiko Sakai 39, Takaharu Maehata 40, Toshihiko Furuta 41, Yoshihiro Yasui 42, Takuya Yano 43, Asa Tanino 44, Sachi Hirata 45, Akiko Nagasao 46, Satoshi Hiroi 47, Hideyuki Kubo 47, Fumika Okayama 48, Tomohiro Oshibe 49, Ai Mori 50, Ryutaro Murayama 51, Shoko Chiba 52, Yuki Matsui 53, Yuko Kiguchi 54, Koji Takeuchi 55, Tetsuo Mita 56, Kayoko Nomiya 57, Yukie Shimazu 58, Yoshiki Fujii 59, Shoichi Toda 60, Yumiko Kawakami 61, Yukari Terajima 62, Mayumi Yamashita 63, Tomiyo Takahashi 64, Yuki Ashizuka 65, Chinami Wasano 66, Takashi Kimura 67, Sanae Moroishi 68, Miho Urakawa 69, Takashi Sakai 70, Kaori Nishizawa 71, Toru Hayashi 72, Yu Matsuura 73, Yuka Hamada 74, Yumani Kuba 75

6 Hokkaido Institute of Public Health; 7 Sapporo City Institute of Public Health; 8 Aomori Prefectural Public Health and Environment Center; 9 Iwate Prefectural Research Institute for Environmental Sciences and Public Health; 10 Miyagi Prefectural Institute of Public Health and Environment; 11 Sendai City Institute of Public Health; 12 Akita Prefectural Research Center for Public Health and Environment; 13 Yamagata Prefectural Institute of Public Health; 14 Fukushima Prefectural Institute of Public Health; 15 Ibaraki Prefectural Institute of Public Health; 16 Tochigi Prefectural Institute of Public Health and Environmental Sciences; 17 Utsunomiya City Institute of Public Health and Environment Science; 18 Gunma Prefectural Institute of Public Health and Environmental Sciences; 19 Saitama Institute of Public Health; 20 Saitama City Institute of Health Science and Research;  21 Chiba Prefectural Institute of Public Health; 22 Chiba City Institute of Health and Environment; 23 Tokyo Metropolitan Institute of Public Health; 24 Kanagawa Prefectural Institute of Public Health; 25 Yokohama City Institute of Public Health; 26 Kawasaki City Institute of Public Health; 27 Yokosuka Institute of Public Health; 28 Sagamihara City Institute of Public Health; 29 Niigata Prefectural Institute of Public Health and Environmental Sciences; 30 Niigata City Institute of Public Health and Environment; 31 Toyama Institute of Health; 32 Ishikawa Prefectural Institute of Public Health and Environmental Science; 33 Fukui Prefectural Institute of Public Health and Environmental Science; 34 Yamanashi Institute for Public Health; 35 Nagano Environmental Conservation Research Institute; 36 Nagano City Health Center; 37
Gifu Prefectural Research Institute for Health and Environmental Sciences; 38 Gifu Municipal Institute of Public Health; 39 Shizuoka Institute of Environment and Hygiene; 40 Shizuoka City Institute of Environmental Sciences and Public Health; 41 Hamamatsu City Health Environment Research Center; 42 Aichi Prefectural Institute of Public Health; 43 Mie Prefecture Health and Environment Research Institute; 44 Shiga Prefectural Institute of Public Health; 45 Kyoto Prefectural Institute of Public Health and Environment; 46 Kyoto City Institute of Health and Environmental Sciences; 47 Osaka Institute of Public Health; 48 Sakai City Institute of Public Health; 49 Hyogo Prefectural Institute of Public Health Science; 50 Kobe Institute of Health; 51 Amagasaki City Institute of Public Health; 52 Nara Prefecture Institute of Health; 53 Wakayama Prefectural Research Center of Environment and Public Health; 54 Wakayama City Institute of Public Health; 55 Tottori Prefectural Institute of Public Health and Environmental Science; 56 Shimane Prefectural Institute of Public Health and Environmental Science; 57 Okayama Prefectural Institute for Environmental Science and Public Health; 58 Hiroshima Prefectural Technology Research Institute; 59 Hiroshima City Institute of Public Health; 60 Yamaguchi Prefectural Institute of Public Health and Environment; 61 Tokushima Prefectural Public Health, Pharmaceutical and Environmental Sciences Center; 62 Kagawa Prefectural Research Institute for Environmental Sciences and Public Health; 63 Ehime Prefecture Institute of Public Health and Environmental Science; 64 Kochi Public Health and Environmental Science Research Institute; 65 Fukuoka Institute of Health and Environmental Sciences; 66 Fukuoka City Institute of Health and Environment; 67 Kitakyushu City Institute of Health and Environmental Sciences; 68 Saga Prefectural Institute of Public Health and Pharmaceutical Research; 69 Nagasaki Prefectural Institute for Environment Research and Public Health; 70 Kumamoto Prefectural Institute of Public-Health and Environmental Science; 71 Kumamoto City Environmental Research Center; 72 Oita Prefectural Institute of Health and Environment; 73 Miyazaki Prefectural Institute for Public Health and Environment; 74 Kagoshima Prefectural Institute for Environmental Research and Public Health; 75 Okinawa Prefectural Institute of Health and Environment; 1 Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan; 2 Abe Children’s Clinic, Minowa 2-15-22, Kohoku, Yokohama, Kanagawa, 223-0051, Japan; 3 Eiju General Hospital, Higashi Ueno 2-23-16, Taito, Tokyo, 110-8645, Japan; 4 Ichikawa Children’s Clinic, Higashi Odake 1544-3, Isehara, Kanagawa, 259-1133, Japan; 5 Zama Children’s Clinic, Tatsuno Dai 2-20-24, Zama, Kanagawa, 252-0023, Japan

Received 18 February 2020, Revised 14 May 2020, Accepted 28 May 2020, Available online 20 June 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104828

 

Highlights

  • Influenza A(H1N1)pdm09 virus carrying a PA E23K substitution was detected.
  • The PA E23K mutant virus showed reduced baloxavir susceptibility.
  • The PA E23K mutant virus was isolated from a child without baloxavir treatment.
  • Possible transmission of the PA E23K mutant virus among humans is suggested.
  • Baloxavir susceptibility monitoring of influenza viruses is essential.

 

Abstract

Human-to-human transmission of PA I38 mutant influenza A(H3N2) viruses with reduced baloxavir susceptibility has been reported in Japan. In December 2019, we detected a PA E23K mutant A(H1N1)pdm09 virus from a child without baloxavir treatment. The PA E23K mutant virus exhibited reduced baloxavir susceptibility but remained susceptible to neuraminidase inhibitors. Epidemiological data suggest possible transmission of this PA E23K mutant virus among humans, although its growth capability relative to that of the wild-type virus was reduced. Therefore, baloxavir susceptibility monitoring of influenza viruses is essential.

Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir; Oseltamivir; Pediatrics; Japan.

——

The #Antiviral Effects of #Baloxavir Marboxil Against #Influenza A Virus Infection in #Ferrets (Influenza Other Respir Viruses, abstract)

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

Influenza Other Respir Viruses. 2020 Jun 13. doi: 10.1111/irv.12760. Online ahead of print.

The Antiviral Effects of Baloxavir Marboxil Against Influenza A Virus Infection in Ferrets

Mitsutaka Kitano 1, Takanobu Matsuzaki 1, Ryoko Oka 1, Kaoru Baba 2, Takahiro Noda 2, Yuki Yoshida 1, Kenji Sato 1, Kohei Kiyota 1, Tohru Mizutare 1, Ryu Yoshida 1, Akihiko Sato 1, Hiroshi Kamimori 1, Takao Shishido 1, Akira Naito 1

Affiliations: 1 Shionogi & Co., Ltd., Toyonaka, Japan. 2 Shionogi TechnoAdvance Research, Co., Ltd., Toyonaka, Japan.

PMID: 32533654 DOI: 10.1111/irv.12760

 

Abstract

Background:

Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients.

Objectives:

To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets.

Methods:

Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM.

Results:

The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4.

Conclusions:

The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission.

Keywords: baloxavir marboxil; ferrets; influenza A virus; pharmacodynamics; pharmacokinetics.

© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.

Keywords: Influenza A; Antivirals; Baloxavir; Oseltamivir; Animal models.

—–

Host-targeted #Nitazoxanide has a high barrier to #resistance but does not reduce the emergence or #proliferation of #oseltamivir-resistant #influenza viruses in vitro or in vivo when used in combination with oseltamivir (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 13 June 2020, 104851 | In Press, Journal Pre-proof | Research paper

Host-targeted Nitazoxanide has a high barrier to resistance but does not reduce the emergence or proliferation of oseltamivir-resistant influenza viruses in vitro or in vivo when used in combination with oseltamivir

Danielle Tilmanis 1, Paulina Koszalka 1, Ian G. Barr 1,3, Jean-Francois Rossignol 2, Edin Mifsud 1, Aeron C. Hurt 1,3

1 WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia; 2 Romark Laboratories, L.C., Tampa, Florida, USA; 3 The University of Melbourne, Department of Microbiology and Immunology, Parkville, Victoria, 3010, Australia

Received 1 January 2020, Revised 5 June 2020, Accepted 7 June 2020, Available online 13 June 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104851

 

Highlights

  • Serial passaging was used to determine the propensity for influenza viruses to develop resistance to tizoxanide.
  • Tizoxanide selective pressure up to 20 μM did not result in virus populations with altered drug susceptibility.
  • Host-targeted Nitazoxanide has a high barrier to antiviral resistance.
  • Tizoxanide/oseltamivir combination therapy did not prevent the emergence or selection of oseltamivir resistant virus.

 

Abstract

A major limitation of the currently available influenza antivirals is the potential development of drug resistance. The adamantanes, neuraminidase inhibitors, and more recently polymerase inhibitors, have all been associated with the emergence of viral resistance in preclinical, clinical studies or in clinical use. As a result, host-targeted drugs that act on cellular proteins or functions have become an attractive option for influenza treatment as they are less likely to select for resistance. Nitazoxanide (NTZ) is a host-targeted antiviral that is currently in Phase III clinical trials for the treatment of influenza. In this study, we investigated the propensity for circulating influenza viruses to develop resistance to nitazoxanide in vitro by serially passaging viruses under selective pressure. Phenotypic and genotypic analysis of viruses passaged ten times in the presence of up to 20 μM tizoxanide (TIZ; the active metabolite of nitazoxanide) showed that none had a significant change in TIZ susceptibility, and amino acid substitutions arising that were unique to TIZ passaged viruses, did not alter TIZ susceptibility.

Combination therapy, particularly utilising drugs with different mechanisms of action, is another option for combatting antiviral resistance, and while combination therapy has been shown to improve antiviral effects, the effect of reducing the emergence and selection of drug-resistant virus has been less widely investigated. Here we examined the use of TIZ in combination with oseltamivir, both in vitro and using the ferret model for influenza infection and found that the combination of the two drugs did not provide significant benefit in reducing the emergence or selection of oseltamivir-resistant virus.

These in vitro findings suggest that clinical use of NTZ may be significantly less likely to select for resistance in circulating influenza viruses compared to virus-targeted antivirals, and although the combination of NTZ with oseltamivir did not reduce the emergence of oseltamivir-resistant virus in vitro or in vivo, combination therapy with NTZ and other newer classes of influenza antiviral drugs should be considered due to NTZ’s higher host-based barrier to resistance.

View full text© 2020 Elsevier B.V. All rights reserved.

Keywords: Influenza A; Antivirals; Drugs Resistance; Nitazoxamide, Oseltamivir; Animal models.

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#Molecular Characterization and Three-Dimensional #Structures of #Avian #H8, #H11, #H14, #H15 and #Swine #H4 #Influenza Virus #Hemagglutinins (Heliyon, abstract)

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

Heliyon. 2020 Jun 6;6(6):e04068. doi: 10.1016/j.heliyon.2020.e04068. eCollection 2020 Jun.

Molecular Characterization and Three-Dimensional Structures of Avian H8, H11, H14, H15 and Swine H4 Influenza Virus Hemagglutinins

Hua Yang 1, Paul J Carney 1, Jessie C Chang 1, James Stevens 1

Affiliation: 1 Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.

PMID: 32529072 PMCID: PMC7281811 DOI: 10.1016/j.heliyon.2020.e04068

 

Abstract

Of the eighteen hemagglutinin (HA) subtypes (H1-H18) that have been identified in bats and aquatic birds, many HA subtypes have been structurally characterized. However, several subtypes (H8, H11 and H12) still require characterization. To better understand all of these HA subtypes at the molecular level, HA structures from an A(H4N6) (A/swine/Missouri/A01727926/2015), an A(H8N4) (A/turkey/Ontario/6118/1968), an A(H11N9) (A/duck/Memphis/546/1974), an A(H14N5) A/mallard/Gurjev/263/1982, and an A(H15N9) (A/wedge-tailed shearwater/Western Australia/2576/1979 were determined by X-ray crystallography at 2.2Å, 2.3Å, 2.8Å, 3.0Å and 2.5Å resolution, respectively. The interactions between these viruses and host receptors were studied utilizing glycan-binding analyses with their recombinant HA. The data show that all avian HAs retain their strict binding preference to avian receptors, whereas swine H4 has a weak human receptor binding. The molecular characterization and structural analyses of the HA from these zoonotic influenza viruses not only provide a deeper appreciation and understanding of the structure of all HA subtypes, but also re-iterate why continuous global surveillance is needed.

Keywords: A(H11N9); A(H14N5); A(H15N9); A(H4N6); A(H8N4); Avian; Biomolecules; Glycobiology; Hemagglutinin; Influenza virus; Microbiology; Proteins; Receptor binding; Swine; Viral protein; Virology.

Keywords: Influenza A; Avian Influenza; Swine Influenza; H8N4; H4N6; H11N9; H14N5; H15N9.

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Type III #interferons disrupt the #lung #epithelial #barrier upon viral recognition (Science, abstract)

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

Type III interferons disrupt the lung epithelial barrier upon viral recognition

Achille Broggi1,*, Sreya Ghosh1,*, Benedetta Sposito1,2,*, Roberto Spreafico3,†, Fabio Balzarini1,2, Antonino Lo Cascio1,2, Nicola Clementi4, Maria De Santis5, Nicasio Mancini4,6, Francesca Granucci2,7, Ivan Zanoni1,2,8,‡

1 Harvard Medical School, Boston Children’s Hospital, Division of Immunology, Boston, MA, USA. 2 Department of Biotechnology and Biosciences, University of Milano – Bicocca, Milan, Italy. 3 Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA. 4 Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy. 5 Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy.
6IRCCS San Raffaele Hospital, Milan, Italy. 7 INGM-National Institute of Molecular Genetics “Romeo ed Enrica Invernizzi” Milan, Italy. 8 Harvard Medical School, Boston Children’s Hospital, Division of Gastroenterology, Boston, MA, USA.

‡Corresponding author. Email: ivan.zanoni@childrens.harvard.edu

* These authors contributed equally to this work.

† Present address: Vir Biotechnology, San Francisco, CA, USA.

Science  11 Jun 2020: eabc3545 | DOI: 10.1126/science.abc3545

 

Abstract

Lower respiratory tract viral infections are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. Here, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report IFN-λ is present in the lower, but not upper, airways of COVID-19 patients. In mice, we demonstrate IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in the clinical practice against endemic viruses, such as influenza virus, as well as the emerging SARS-CoV-2 viral infection.

Keywords: SARS-CoV-2; COVID-19; Influenza A; Interferons.

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