Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets

Masaki Imai; Makoto Yamashita; Yuko Sakai-Tagawa; Kiyoko Iwatsuki-Horimoto; Maki Kiso; Jurika Murakami; Atsuhiro Yasuhara; Kosuke Takada; Mutsumi Ito; Noriko Nakajima; Kenta Takahashi; Tiago J S Lopes; Jayeeta Dutta; Zenab Khan; Divya Kriti; Harm van Bakel; Akifumi Tokita; Haruhisa Hagiwara; Naomi Izumida; Haruo Kuroki; Tamon Nishino; Noriyuki Wada; Michiko Koga; Eisuke Adachi; Daisuke Jubishi; Hideki Hasegawa; Yoshihiro Kawaoka

doi:10.1038/s41564-019-0609-0

Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets

Nat Microbiol. 2020 Jan;5(1):27-33. doi: 10.1038/s41564-019-0609-0. Epub 2019 Nov 25.

Authors

Masaki Imai^#¹, Makoto Yamashita^#², Yuko Sakai-Tagawa^#², Kiyoko Iwatsuki-Horimoto^#², Maki Kiso², Jurika Murakami², Atsuhiro Yasuhara², Kosuke Takada², Mutsumi Ito², Noriko Nakajima³, Kenta Takahashi³, Tiago J S Lopes^{2

4}, Jayeeta Dutta⁵, Zenab Khan⁵, Divya Kriti⁵, Harm van Bakel⁵, Akifumi Tokita^{6

7}, Haruhisa Hagiwara^{7

8}, Naomi Izumida^{7

9}, Haruo Kuroki¹⁰, Tamon Nishino^{7

11}, Noriyuki Wada^{7

12}, Michiko Koga¹³, Eisuke Adachi¹⁴, Daisuke Jubishi^{2

15}, Hideki Hasegawa^{3

16}, Yoshihiro Kawaoka^{17

18

19}

Affiliations

¹ Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [email protected].
² Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
³ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
⁴ Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Clinic Bambini, Tokyo, Japan.
⁷ Members of the Tokyo Pediatric Association Public Health Committee, Tokyo, Japan.
⁸ Hagiwara Clinic, Tokyo, Japan.
⁹ Akebonocho Clinic, Tokyo, Japan.
¹⁰ Sotobo Children's Clinic, Chiba, Japan.
¹¹ Alpaca Kids Ent Clinic, Tokyo, Japan.
¹² Wada Pediatric Clinic, Tokyo, Japan.
¹³ Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
¹⁴ Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan.
¹⁵ Nezu Clinic, Tokyo, Japan.
¹⁶ Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
¹⁷ Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [email protected].
¹⁸ Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA. [email protected].
¹⁹ Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. [email protected].

^# Contributed equally.

PMID: 31768027
DOI: 10.1038/s41564-019-0609-0

Abstract

Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein-a mutation that confers reduced susceptibility to baloxavir marboxil-from patients before and after treatment with baloxavir marboxil in Japan. These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology*
Cricetinae
Dibenzothiepins
Drug Resistance, Viral*
Ferrets
Humans
Influenza A virus / drug effects*
Influenza A virus / isolation & purification
Influenza A virus / pathogenicity*
Influenza A virus / physiology
Influenza, Human / transmission*
Influenza, Human / virology*
Japan
Mice
Morpholines
Nasal Lavage Fluid / virology
Orthomyxoviridae Infections / transmission
Orthomyxoviridae Infections / virology
Oxazines / pharmacology*
Pyridines / pharmacology*
Pyridones
RNA-Dependent RNA Polymerase / genetics
Thiepins / pharmacology*
Triazines / pharmacology*
Viral Proteins / genetics
Virulence
Virus Replication

Substances

Antiviral Agents
Dibenzothiepins
Morpholines
Oxazines
PA protein, influenza viruses
Pyridines
Pyridones
Thiepins
Triazines
Viral Proteins
baloxavir
RNA-Dependent RNA Polymerase

Grants and funding

HHSN272201400008C/AI/NIAID NIH HHS/United States