A systems biology approach unravels the host response to West Nile virus infection in human dendritic cells

Abstract

Abstract West Nile virus (WNV) is a neurotropic Flavivirus and the leading cause of mosquito-borne encephalitis in the United States. Previous studies in mice have found that dendritic cells (DCs) are pivotal for viral control and programming of antiviral immunity in a RIG-I like receptor (RLR) and type I interferon (IFN) dependent manner. To gain a better understanding of human WNV infection, we evaluated infection of human monocyte DCs (moDCs). We found that moDCs support productive WNV infection and that stimulation of RLR and type I IFN signaling potently restricts viral replication. Most intriguingly, we observed significant variability in viral infection of moDCs generated from different donors, ranging from 6–56% of cells infected by 48 hours post infection. To define the antiviral landscape during WNV infection, we performed mRNA sequencing and found that, in contrast to RLR and type I IFN signaling, WNV infection partially triggers expression of antiviral defense response related genes. Despite strong induction of IFNβ during WNV infection, we observed minimal expression of cytokines that promote antiviral T cell immunity (IL-4, IL-12, IL-7, IL-15) and costimulatory molecules (CD80, CD86, CD40) at the transcriptional and protein level. Using weighted gene co-expression network analysis combined with cis-regulatory sequence analysis, we identified STAT5 as an important regulatory node downstream of RLR signaling. Most intriguingly, we found that STAT5 was not induced during WNV infection, suggesting that WNV dampens DC activation by preventing STAT5 activation. Further studies are underway to better understand how RLR signaling promotes STAT5 activation and to define the viral factors that regulate STAT5 activation.