Abstract
The innate immune response to West Nile virus (WNV) infection involves recognition through toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), leading to establishment of an antiviral state. MiRNAs (miRNAs) have been shown to be reliable biomarkers of TLR activation. Here, we sought to evaluate the contribution of TLR3 and miRNAs to the host response to WNV infection. We first analyzed HEK293-NULL and HEK293-TLR3 cells for changes in the innate immune response to infection. The presence of TLR3 did not seem to affect WNV load, infectivity or phosphorylation of IRF3. Analysis of experimentally validated NFκB-responsive genes revealed a WNV-induced signature largely independent of TLR3. Since miRNAs are involved in viral pathogenesis and the innate response to infection, we sought to identify changes in miRNA expression upon infection in the presence or absence of TLR3. MiRNA profiling revealed 70 miRNAs induced following WNV infection in a TLR3-independent manner. Further analysis of predicted gene targets of WNV signature miRNAs revealed genes highly associated with pathways regulating cell death, viral pathogenesis and immune cell trafficking.
Highlights
West Nile Virus (WNV) is a mosquito-borne neurotropic flavivirus, and closely related to Yellow Fever Virus (YFV) and Dengue virus (DENV)
HEK293-TLR3 cells ectopically express only TLR3 and HEK293-Null cells have very little to no expression of any of the known toll-like receptors (TLRs)
Minimal residual activity of TLR3 has been reported in HEK293-Nulls
Summary
West Nile Virus (WNV) is a mosquito-borne neurotropic flavivirus, and closely related to Yellow Fever Virus (YFV) and Dengue virus (DENV). The genomic RNA is translated into a single polyprotein, and during viral RNA synthesis dsRNA intermediates are generated in the cytoplasm. WNV is transmitted by mosquitoes and is an emerging pathogen, especially in the Americas, with 5,674 and 2,469 reported cases of WNV in the United States in 2012 and 2013, respectively. WNV infection is asymptomatic, in a small percentage of patients WNV infection can lead to fatal encephalitis, in the elderly, transplant recipients and other immune-compromised hosts including patients infected with HIV. This suggests a pivotal role for the immune response in determining systemic WNV pathogenesis [5]
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