Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne alphavirus that can cause a potentially lethal encephalomyelitis in humans and equids. There is currently no licensed vaccine available for use in humans. Efforts to understand the host requirements for successfully controlling VEEV infection have been limited by the extreme lethality of the virus in small animal models. Here we describe the use of the V3533 mutant of VEEV as a model for successful control of VEEV infection. Following peripheral inoculation of a mouse, V3533 behaves similarly to lethal strains of VEEV. Rapid replication of V3533 in secondary lymphoid organs results in the development of a serum viremia, followed by viral invasion of the central nervous system (CNS). The infection is short-lived, however, as the development of an adaptive immune response results in clearance of infectious virus from all tissues by day 8 post-infection. Using this model we identified previously unappreciated roles for complement activation and T cells in promoting recovery from VEEV infection. Complement activation within the first 24 hours of infection enhanced serum clearance and delayed viral invasion of the CNS, preventing the development of overt encephalomyelitis. This effect was independent of anti-VEEV antibody induction or inflammatory cell recruitment. In addition, we showed that T cells, particularly CD4+ T cells, were capable of controlling V3533 infection in the CNS and facilitating recovery from severe encephalomyelitis in the absence of antibody. Together, these results provide a starting point for future efforts to identify the requirements of a protective host response to VEEV infection
