Differential Viral-Host Immune Interactions Associated with Oseltamivir-Resistant H275Y and Wild-Type H1N1 A(pdm09)
Beatriz Vidaña1,2, Pamela Martínez-Orellana2,3, Jaime M Martorell4
1Bristol Veterinary School, Faculty of Health Sciences, University of Bristol, Langford, Bristol BS40 5DU, UK.
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.
Insights
Oseltamivir-resistant influenza A (H1N1) viruses show reduced fitness and milder disease in ferrets compared to wild-type strains. This is linked to an early, protective host immune response involving type I interferon and RIG-I genes.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Oseltamivir is a key influenza A virus (IAV) therapy.
- Oseltamivir resistance (OR) mutations, like H275Y, can emerge but may impact viral fitness.
- OR H1N1 viruses have shown population-level spread.
Purpose of the Study:
- To compare the fitness of two OR H1N1 strains (R6, R7) with a wild-type (F) strain in vitro and in mice.
- To select an OR strain for comparative fitness studies in ferrets.
- To investigate viral kinetics and host immune responses in ferrets infected with OR vs. wild-type IAV.
Main Methods:
- In vitro and in vivo (mice) fitness assessments of OR (R6, R7) and wild-type (F) H1N1 strains.
- Fitness comparison of selected OR strain (R6) and wild-type (F) strain in ferrets.
- Analysis of clinical signs, lung histopathology, viral load, and host immune gene expression (Type I IFN, RIG-I) in infected ferrets.
Main Results:
- OR strain R6 exhibited greater replication and pathogenicity than R7 in vitro and in mice.
- Ferrets infected with wild-type F virus showed more severe disease than those infected with OR R6.
- OR R6 infection induced earlier expression of protective Type I IFN and RIG-I genes, correlating with milder disease.
Conclusions:
- Oseltamivir-resistant H1N1 virus (R6) demonstrates reduced fitness and pathogenicity compared to wild-type virus in ferrets.
- Early viral-host immune interactions, specifically enhanced Type I IFN and RIG-I responses, contribute to milder disease in OR-infected ferrets.
- These findings highlight the importance of host immune responses in modulating influenza-associated lung pathology.
More Related Videos
04:47A Method to Assess Fc-mediated Effector Functions Induced by Influenza Hemagglutinin Specific Antibodies
Published on: February 23, 2018
09:07Using Zebrafish Models of Human Influenza A Virus Infections to Screen Antiviral Drugs and Characterize Host Immune Cell Responses
Published on: January 20, 2017
Related Concept Videos
01:29Immune Response Against Viral Pathogens
NK Cells
NK cells are a crucial part of our innate immune system, acting as the first line of defense against viral infections. These cells can recognize and kill infected cells without prior exposure to the virus, effectively slowing down the spread of infection. Additionally, NK cells produce proinflammatory...
00:57Viral Recombination