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

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.

In silico and in vitro studies reveal complement system drives coagulation cascade in SARS-CoV-2 pathogenesis

“…This could exacerbate pathogenesis of lung parenchymal cells, diminish oxygen uptake, and cause rapid thrombotic events and intravascular coagulation, which could result in multiorgan failure including central nervous system complications and death. [54] …”

Type I interferon shapes brain distribution and tropism of tick-borne flavivirus

“…Single cell or snRNAseq is a useful tool to study the transcriptional response in specific cell types upon infection or inflammation. In contrast to bulk RNA sequencing or microarray analysis of tissue 56,57 , where the combined response of all cells is measured, we show that in WT mice, the response to infection was highly cell-type specific and that the identified upregulated pathways showed a balance between pro-and anti-inflammatory signaling. While scRNA sequencing of Rabies virus infected WT mice showed a very strong pro-inflammatory response 58 , we detected a relatively low number of DEGs after LGTV infection in WT mice.…”

“…Even though we detected a similar viral load in cerebral cortex of WT and Ifnar –/– mice, the transcriptional profiles were markedly different, and a large number of DEGs were upregulated independently of IFNAR signaling. This IFN-I-independent immune response has also been observed for vesicular stomatitis virus (VSV) 56 . In this case, IFNγ in combination with TNFα and IRF1 compensate for the loss of IFN-I response 56 .…”

“…This IFN-I-independent immune response has also been observed for vesicular stomatitis virus (VSV) 56 . In this case, IFNγ in combination with TNFα and IRF1 compensate for the loss of IFN-I response 56 . We observed a large overlap between cell types among the upregulated genes in Ifnar –/– mice, and these were mainly related to IFN signaling and antigen presentation.…”

Development and scale-up of rVSV-SARS-CoV-2 vaccine process using single use bioreactor

“…Although Vero cells lack the ability to produce IFN [5] , there might be other IFN-independent innate immune pathways that lactate is modulating. It has been shown that VSV infection modulates many genes even in the absence of IFN signaling [21] . It is plausible that with its role in both cell metabolism and innate immune signaling, increased initial levels of lactate in bioreactors without MX have “primed” the cells for a favorable viral replication environment.…”