Mouse adaptation of influenza B virus increases replication in the upper respiratory tract and results in droplet transmissibility in ferrets.

Eun-Ha Kim,Eun-Ji Choi,Se Mi Kim,Hyeok-Il Kwon,Young-Ki Choi,Su-Jin Park,Min-Suk Song,Young-Il Kim,Philippe Noriel Q Pascua

doi:10.1038/srep15940

Abstract

To investigate the molecular changes that allow influenza B viruses to adapt to new mammalian hosts, influenza B/Florida/04/2006 was serially passaged in BALB/c mice until highly virulent. The viral factors underlying this transition were then investigated in mice and ferrets. Five viruses, including the wild-type virus (P0), three intermediate viruses (P5, P9, and P12), and a lethal mouse-adapted virus (P17 (MA)), harbored one to five amino acid substitutions in the hemagglutinin, M, NP, and PA segments suggesting that these mutations enhance virulence. The P17 (MA) virus replicated significantly more efficiently than the P0 virus both in vitro and in vivo (P < 0.0001), and was highly virulent (MLD50: 105.25TCID50) while the P0, P5, and P9 viruses did not kill any infected mice (MLD50 > 106.0TCID50). Furthermore, the P17 (MA) virus grew to greater titers in the ferret upper respiratory tract compared with the P0 and intermediate viruses, and only the P17 (MA) virus was transmissible between ferrets via both direct and aerosol contact. To our knowledge, this is the first study to demonstrate ferret-to-ferret transmission of influenza B virus and to delineate factors that may affect its transmission.

Highlights

Mouse-adapted — G T — S N I current vaccine strategies is the production of a quadrivalent influenza vaccine (QIV) that includes both influenza B virus lineages[7]
We provide insight into the mammalian adaptation of influenza B viruses through molecular modifications that increase pathogenicity
To generate the mouse-adapted (MA) influenza B strain, B/Florida/04/06 was serially passaged in the lungs every three dpi until high virulence with 100% mortality was observed in BALB/c mice

Summary

Introduction

Mouse-adapted — G T — S N I current vaccine strategies is the production of a quadrivalent influenza vaccine (QIV) that includes both influenza B virus lineages[7]. The limited known host range of the influenza B virus and the paucity of available animal models have precluded investigation of influenza B pathogenicity and transmission factors, as well as the evaluation of antiviral compounds and vaccine efficacies in animals. Mice have been considered a good mammalian model for investigating pathogenic mechanisms and host range determinants of influenza viruses[11]. In this regard, mouse adaptation via serial passage in the lungs has often been used to study influenza A virulence factors in mice[12,13,14,15,16]. Our results suggest that mutations in multiple genes encoding different viral proteins are associated with the growth and virulence of influenza B viruses

Methods

Results

Conclusion