Differential viral-host immune interactions associated with oseltamivir-resistant H275Y and wild-type H1N1 A(pdm09) Influenza virus pathogenicity

B. Vidaña, Pamela Analia Martinez Orellana, Jaime Miguel Martorell Monserrat, Massimiliano Baratelli, Jorge Martínez, Lourdes Migura Garcia, Lorena Córdoba, Mónica Pérez, Inmaculada Casas, Francisco Pozo, Lorenzo Fraile, Natalia Majo Masferrer, María José Montoya

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Oseltamivir is a common therapy against influenza A virus (IAV) infections. The acquisition of oseltamivir resistance (OR) mutations, such as H275Y, hampers viral fitness. However, OR H1N1 viruses have demonstrated the ability to spread throughout different populations. The objective of this work was to compare the fitness of two strains of OR (R6 and R7) containing the H275Y mutation, and a wild-type (F) pandemic influenza A (H1N1) 2009 (pdm09) virus both in vitro and in vivo in mice and to select one OR strain for a comparison with F in ferrets. R6 showed faster replication and pathogenicity than R7 in vitro and in mice. Subsequently, R6 was selected for the fitness comparison with the F strain in ferrets. Ferrets infected with the F virus showed more severe clinical signs, histopathological lung lesions, and viral quantification when compared to OR R6-infected animals. More importantly, differential viral kinetics correlated with differential pro-inflammatory host immune responses in the lungs of infected ferrets, where OR-infected animals developed a protective higher expression of type I IFN and Retinoid acid Inducible Gene I (RIG-I) genes early after infection, resulting in the development of milder disease. These results suggest the presence of early specific viral-host immune interactions relevant in the development of influenza-associated lung pathology.

Original languageEnglish
Article number794
Number of pages20
JournalViruses
Volume12
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

Keywords

  • A(H1N1)PDM09
  • A-VIRUS
  • ANTIVIRAL RESISTANCE
  • EVOLUTION
  • FITNESS
  • IDENTIFICATION
  • IN-VITRO
  • MUTATIONS
  • RESPONSES
  • TRANSMISSION
  • immunopathology
  • influenza
  • oseltamivir
  • pneumonia
  • resistance

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