Mutated influenza A virus exhibiting reduced susceptibility to baloxavir marboxil from an experimentally infected horse.
Abstract: Baloxavir marboxil (BXM), an inhibitor of the cap-dependent endonuclease of the influenza virus polymerase acidic protein (PA), exerts an antiviral effect against influenza A virus. It has been available in Japan since March 2018. This study evaluated the antiviral efficacy of BXM against equine influenza A virus (EIV) by an experimental challenge study using horses. Six horses were experimentally inoculated with EIV, and BXM was administered to the three horses at 2 days post inoculation. Horses treated with BXM showed milder clinical signs than horses without treatment and shed less virus. These results suggest that BXM is effective against EIV. The PA gene of viruses present in the nasopharyngeal swabs collected from horses treated with BXM was sequenced. Two mutations have been detected in viruses recovered from horses treated with BXM. These mutations were the substitution of isoleucine with threonine at position 38 (PA-I38T) and that of asparagine with aspartic acid at position 675 in PA (PA-N675D). A mutated virus with PA-I38T was less susceptible to BXM than viruses with PA-N675D or without mutation. A PA-I38T mutation has also been detected in viruses recovered from humans treated with BXM and is responsible for the reduction in susceptibility to BXM. This suggests that we should not unthinkingly use BXM for the treatment of EI. BXM is likely to easily induce resistance in influenza A viruses, not only in humans but also in horses.
Publication Date: 2019-09-19 PubMed ID: 31526451DOI: 10.1099/jgv.0.001325Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The researchers studied the efficacy of an antiviral drug, Baloxavir Marboxil (BXM), against equine influenza A virus (EIV) in horses, finding that it mitigates the virus’s severity but could also provoke drug resistance.
Evaluating BXM’s Antiviral Efficacy
- The researchers conducted an experimental challenge study using BXM, an inhibitor of the cap-dependent endonuclease of the influenza virus polymerase acidic protein (PA), to examine its antiviral effect on equine influenza A virus (EIV) in horses.
- In the study, six horses were experimentally inoculated with EIV, out of which three were administered BXM at 2 days post their inoculation.
- The observed results showed that horses which received the BXM treatment presented milder clinical signs of the virus than those without the treatment and also shed less of the virus.
Impact of BXM on Virus Mutations
- The research further involved gene sequencing. The Polymerase Acidic (PA) gene of viruses present in the nasopharyngeal swabs collected from the BXM-treated horses was sequenced.
- Two mutations were discovered in the viruses recovered from the BXM-treated horses – a substitution of isoleucine with threonine at position 38 (PA-I38T) and a substitution of asparagine with aspartic acid at position 675 in PA (PA-N675D).
- The mutated PA-I38T virus was less susceptible to BXM than the PA-N675D virus or other viruses without mutation. This potentially implies that the BXM treatment can induce resistance in the EIV, thereby reducing its susceptibility.
Implications for BXM Treatment
- A PA-I38T mutation was also noted in viruses derived from humans who had received BXM treatment, which is associated with reduced susceptibility of the virus to the same drug.
- In effect, this study raises a caution against the indiscriminate use of BXM for treating equine influenza, due to the potential elicitation of resistance in both human and equine influenza A viruses.
Cite This Article
APA
Nemoto M, Tamura N, Bannai H, Tsujimura K, Kokado H, Ohta M, Yamanaka T.
(2019).
Mutated influenza A virus exhibiting reduced susceptibility to baloxavir marboxil from an experimentally infected horse.
J Gen Virol, 100(11), 1471-1477.
https://doi.org/10.1099/jgv.0.001325 Publication
Researcher Affiliations
- Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.
- Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.
- Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.
- Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.
- Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.
- Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.
- Equine Research Institute, Japan Racing Association, Shimotsuke, Tochigi, Japan.
MeSH Terms
- Amino Acid Substitution
- Animals
- Antiviral Agents / pharmacology
- Antiviral Agents / therapeutic use
- Dibenzothiepins
- Drug Resistance, Viral
- Horse Diseases / drug therapy
- Horse Diseases / pathology
- Horse Diseases / virology
- Horses
- Influenza A Virus, H3N8 Subtype / drug effects
- Influenza A Virus, H3N8 Subtype / isolation & purification
- Japan
- Morpholines
- Mutation, Missense
- Nasopharynx / virology
- Orthomyxoviridae Infections / drug therapy
- Orthomyxoviridae Infections / pathology
- Orthomyxoviridae Infections / veterinary
- Orthomyxoviridae Infections / virology
- Oxazines / pharmacology
- Oxazines / therapeutic use
- Pyridines / pharmacology
- Pyridines / therapeutic use
- Pyridones
- RNA-Dependent RNA Polymerase / genetics
- Sequence Analysis, DNA
- Thiepins / pharmacology
- Thiepins / therapeutic use
- Treatment Outcome
- Triazines / pharmacology
- Triazines / therapeutic use
- Viral Proteins / genetics
Citations
This article has been cited 4 times.- Nemoto M, Reedy SE, Yano T, Suzuki K, Fukuda S, Garvey M, Kambayashi Y, Bannai H, Tsujimura K, Yamanaka T, Cullinane A, Chambers TM. Antigenic comparison of H3N8 equine influenza viruses belonging to Florida sublineage clade 1 between vaccine strains and North American strains isolated in 2021-2022. Arch Virol 2023 Feb 19;168(3):94.
- Caceres CJ, Seibert B, Cargnin Faccin F, Cardenas-Garcia S, Rajao DS, Perez DR. Influenza antivirals and animal models. FEBS Open Bio 2022 Jun;12(6):1142-1165.
- Yue K, Lu S, Yang T, Mi J, He S, Ma H, He Y, Yang Z, Huang Y, Song L, Ren Z, Ren L, Xu J. Lactiplantibacillus plantarum GUANKE Alleviates Intestinal Barrier Damage Caused by Influenza Infection in Mice. Probiotics Antimicrob Proteins 2025 Jul 16;.
- Taniguchi K, Noshi T, Omoto S, Sato A, Shishido T, Matsuno K, Okamatsu M, Krauss S, Webby RJ, Sakoda Y, Kida H. The impact of PA/I38 substitutions and PA polymorphisms on the susceptibility of zoonotic influenza A viruses to baloxavir. Arch Virol 2024 Jan 12;169(2):29.
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