Secreted NS1 activates murine macrophages and PBMC through TLR4 signaling, elevating mRNA levels of TNF-α, IL-6, IFN-β, IL-1β, and IL-12, thus behaving as a viral toxin analogous to LPS. NS1 colocalizes with TLR4 in PBMC. The use of TLR4 antagonist protects mice from vascular leak in a model of infection. Here, IL1B is linked to infection.