Autophagy is highly targeted among host comparative proteomes during infection with different virulent RABV strains.

Ling Li,Changchun Tu,Pengfei Hou,Xianzhu Xia,Yongkun Zhao,Qian Li,Hongli Jin,Tiecheng Wang,Lina Wang,Na Feng,Cuicui Jiao,Yuwei Gao,Pei Huang,Jianzhong Wang,Hang Chi,Nan Li,Hualei Wang,Wenzhao Sun ,Cuiling Wang ,Guang‐Wan Hu ,Zongjie Cao ,Xiaodong Zheng

doi:10.18632/oncotarget.15184

Abstract

Rabies virus (RABV) is a neurotropic virus that causes serious disease in humans and animals worldwide. It has been reported that different RABV strains can result in divergent prognoses in animal model. To identify host factors that affect different infection processes, a kinetic analysis of host proteome alterations in mouse brains infected with different virulent RABV strains was performed using isobaric tags for a relative and absolute quantification (iTRAQ)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics approach, and this analysis identified 147 differentially expressed proteins (DEPs) between the pathogenic challenge virus standard (CVS)-11 strain and the attenuated SRV9 strain. Bioinformatics analyses of these DEPs revealed that autophagy and several pathways associated with autophagy, such as mammalian target of rapamycin (mTOR) signaling, p70S6K signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress and superoxide radical degradation, were dysregulated. Validation of the proteomic data showed that attenuated SRV9 induced more autophagosome accumulation than CVS-11 in an in vitro model. Our findings provide new insights into the pathogenesis of RABV and encourage further studies on this topic.

Highlights

Rabies is a public health threat worldwide, and the pathogen, rabies virus (RABV), has high neurotropism and belongs to the genus Lyssavirus in the family Rhabdoviridae [1,2,3]
To confirm whether the mice were successfully infected with Rabies virus (RABV) and to determine which time points were suitable for the proteomics analysis, the genomic RNA and virus titers in the mouse brains were detected at 1, 4, and 7 dpi
At 7 dpi, a higher viral load and higher levels of genomic RNA were observed in the challenge virus standard (CVS)-11-infected group, but no virus and only traces of genomic RNA were detected in the attenuated SRV9 group, indicating that attenuated RABV was almost cleared from the central neural system (CNS) at this time point

Summary

Introduction

Rabies is a public health threat worldwide, and the pathogen, rabies virus (RABV), has high neurotropism and belongs to the genus Lyssavirus in the family Rhabdoviridae [1,2,3]. Fu et al analyzed gene expression profiles and showed that attenuated RABV triggers an extensive inflammatory response in mouse brains, whereas pathogenic RABV scarcely induces this response [7]. These authors demonstrated different immune responses after wild-type (wt) RABV and attenuated RABV infection and revealed a single divergent mechanism through which attenuated RABV triggers a high level of virus-neutralizing antibodies (VNA) in both serum and cerebrospinal fluid (CSF) after intrathecal (IT) infection, whereas wt RABV does not elicit VNA, and all infected dogs succumbed to rabies [14]

Objectives

Methods

Results

Conclusion