A Single E627K Mutation in the PB2 Protein of H9N2 Avian Influenza Virus Increases Virulence by Inducing Higher Glucocorticoids (GCs) Level

Abstract

While repeated infection of humans and enhanced replication and transmission in mice has attracted more attention to it, the pathogenesis of H9N2 virus was less known in mice. PB2 residue 627 as the virulent determinant of H5N1 virus is associated with systemic infection and impaired TCR activation, but the impact of this position in H9N2 virus on the host immune response has not been evaluated. In this study, we quantified the cellular immune response to infection in the mouse lung and demonstrate that VK627 and rTsE627K infection caused a significant reduction in the numbers of T cells and inflammatory cells (Macrophage, Neutrophils, Dendritic cells) compared to mice infected with rVK627E and TsE627. Further, we discovered (i) a high level of thymocyte apoptosis resulted in impaired T cell development, which led to the reduced amount of mature T cells into lung, and (ii) the reduced inflammatory cells entering into lung was attributed to the diminished levels in pro-inflammatory cytokines and chemokines. Thereafter, we recognized that higher GCs level in plasma induced by VK627 and rTsE627K infection was associated with the increased apoptosis in thymus and the reduced pro-inflammatory cytokines and chemokines levels in lung. These data demonstrated that VK627 and rTsE627K infection contributing to higher GCs level would decrease the magnitude of antiviral response in lung, which may be offered as a novel mechanism of enhanced pathogenicity for H9N2 AIV.

A Combination of HA and PA Mutations Enhances Virulence in a Mouse-Adapted H6N6 Influenza A Virus

“…The rGDK6 and rGDK6-MA viruses showed pathogenicity levels similar to their wild-type forms. As previous studies demonstrated (28)(29)(30), the PB2(E627K) substitution enhances pathogenicity in mammals, and this was observed PFU of virus died ( Fig. 3B and C).…”

Pathogenicity of the Novel A/H7N9 Influenza Virus in Mice

“…It is likely that PB2-E627K contributes to mammalian host adaptation and pathogenicity of Sh2/H7N9. An E627K substitution in the PB2 gene has been identified in many human virus isolates, and a number of studies have shown that this mutation is associated with increased virulence of avian influenza viruses for mammals (6–11). Although some of the recent H7N9 human isolates still retain 627E, the occurrence of the PB2-D701N mutation in these viruses may compensate as the mammalian host adaptation mutation in these viruses (12, 13).…”

NK-cells are involved in thymic atrophy induced by influenza A virus infection

“…Trypanosoma cruzi, Plasmodium chaubi) and fungal infections (exemplified by experimental infections with Paracoccidioides brasiliensis and Histoplasma capsulatum) (Savino, 2006). To date, several mechanisms have been implicated in influenza virus infection-induced thymic atrophy, such as interference with T-lymphocyte development, increased levels of glucocorticoids and elevated IFN-c production by innate CD8 + T-cells (Liu et al, 2014;Tian et al, 2012;Vogel et al, 2010).…”