Figure 4.

A working hypothesis for how JE, an acute inflammatory CNS disease, is caused by a mosquito-borne JEV infection. The infection begins with the bite of an infected mosquito that injects the virus from the salivary glands into the host’s skin, the dermis, where the virus presumably infects mononuclear phagocytes. From the dermis, the infected cells and cell-free virions may migrate through lymph and blood vessels to peripheral lymphoid organs, where the virus probably replicates in mononuclear leukocytes. Following viral amplification in peripheral lymphoid organs, JEV can spread into many other organs through the vascular system. In brains, JEV may cross the BBB to enter the brain parenchyma, where the virus replicates almost exclusively in neurons, causing neuronal death and activating glial cells. The activated glial cells then release numerous inflammatory mediators involved in various neuropathologic events, such as bystander neuronal death, neurogenesis impairment, BBB breakdown, and leukocyte infiltration. These neuropathologic events cause the worsening of both neurodegeneration and neuroinflammation.