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.
Highlights
H9N2 subtype avian influenza virus was first isolated in turkeys in the U.S in 1966 [1]
The mice infected with VK627 or rTsE627K showed the greatest signs of illness, such as ruffled fur and severe morbidity (24.1% and 23.6% weight loss at day 7) (Fig.1A)
To determine viral replication in the lungs, lungs from three mice infected with 104 PFU of each virus per group were collected on day 1, 3, 5 and 7 p.i. and viral load in supernatant of lungs homogenizer was quantified in MDCK cells by plaque assay (Fig. 1B)
Summary
H9N2 subtype avian influenza virus was first isolated in turkeys in the U.S in 1966 [1]. Since 1998, H9N2 viruses have been isolated in pigs and humans in Hong Kong and Mainland China, and the infected displayed an influenza-like illness [2]. These findings indicate the H9N2 avian influenza virus takes on rapid evolution [2]. Evidence shows H9N2 avianhuman reassortant virus has enhanced replication and efficient transmission in ferrets [6]. Following adaptation in the ferret, a reassortant virus carrying the surface proteins of an avian H9N2 in a human H3N2 backbone could transmit efficiently via respiratory droplets, creating a clinical infection similar to human influenza infections [7]. In 2010, Hye-Ryoung Kim’s research results showed that three H9N2 reassortant viruses generated from the H5N2 viruses of domestic ducks without pre-adaptation were recovered at high titers in chickens [8]
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