The virus infects the epithelial cells of the midgut of the mosquito and spreads through the circulation to the salivary glands where it sets up a persistent infection. The virus enters a new host when the mosquito regurgitates virus-containing saliva into the victim's bloodstream. It replicates in the capillary endothelial cells, macrophages, monocytes, liver, spleen, or lymphatic tissue. This phase of the disease caused by VEEV is much more serious than that caused by WEEV or EEEV as lymphoid necrosis and blood lymphopenia can be severe. A secondary viremia follows the replication in the reticuloendothelial system and allows infection of the target cells in the brain.
Damage is due both to cell death following infection and to inflammation.
The disease occurs only in months when mosquitoes are active.