IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain.

Anurag R Mishra,Siddappa N Byrareddy,Debasis Nayak

doi:10.3390/vaccines8020326

Anurag R Mishra, Siddappa N Byrareddy + Show 1 more

Open Access

https://doi.org/10.3390/vaccines8020326

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Abstract

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.

Highlights

The central nervous system (CNS) is equipped with a dynamic immunological response mechanism to deal with invading infection and injuries [1,2]
Specialized innate sentinels such as astrocytes and microglia can initiate a robust innate immune response during injury and infection [3,4,5]. These cells are equipped with innate sensing mechanisms to detect injury and invading pathogens, which in turn pave the pathway for an innate immune response marked by local cytokine secretion
At the global gene expression level, to our surprise, surprise, we noticed a significant increase in the number of gene expression in the absence of IFN-I

Summary

Introduction

The central nervous system (CNS) is equipped with a dynamic immunological response mechanism to deal with invading infection and injuries [1,2]. Specialized innate sentinels such as astrocytes and microglia can initiate a robust innate immune response during injury and infection [3,4,5] These cells are equipped with innate sensing mechanisms (e.g., pattern recognition) to detect injury and invading pathogens, which in turn pave the pathway for an innate immune response marked by local cytokine secretion. This often leads to the recruitment of peripheral immune cells to the injury site. In normal physiological conditions, immune cell migration to the CNS is tightly regulated by the blood–brain barrier (BBB) [6] and blood–cerebral spinal fluid (CSF) barrier. A sizeable number of neurotropic viruses can get access to the CNS [8] via (a) inflammation-induced breakdown of BBB, (b) viral spread through

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