Encephalitic Development in Alphaviral Infection

Viruses are currently the most common cause of encephalitis. With more than 20 viruses known to cause human encephalitis, arboviruses, arthropod-borne viruses, represent a significant number of emerging infectious diseases both in the United States and worldwide. The Alphavirus genus in the family Togaviridae contains three viruses capable of causing human encephalitis: Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV). WEEV and EEEV are endemic to the United States and South America while VEEV circulates in Central and South America; however, spread of epidemic outbreaks has resulted in disease in North America. No specific therapy or vaccine is currently available against these viruses. In this review, we summarize the development and progression of alphavirus encephalitis in both human populations and murine models of alphavirus infection. We concentrate on the host response that characterizes the development of central nervous system (CNS) disease following alphaviral infection. In addition, we focus on immune factors that influence successful resolution of infection. Alphaviruses represent a significant public health threat as both emerging infectious diseases and possible agents of bioterrorism. Natural, endemic infections of alphavirus disease are currently absent in certain areas of the globe where the mosquito vector capable of transmitting alphaviruses exists making potential virus introduction into such unaffected areas a significant public health concern (Calisher, 1994; Hawley & Eitzen, 2001; Weaver & Barrett, 2004; Zacks & Paessler, 2010). Additionally, many of the encephalitic alphaviruses are highly stable as an aerosol, cause significant mortality or incapacitating disease, and grow rapidly in easily utilized, readily available cell culture systems. This combination of factors makes this group of viruses of significant interest for biodefense in the United States (Hawley & Eitzen, 2001; Weaver, 2005). One of three of the original serological groups of arboviruses, the group A complex became the Alphavirus genus within the Togaviridae family representing enveloped, plus-strand RNA viruses (Porterfield, 1975; Porterfield, 1986). Pathogenic alphaviruses can be roughly grouped further by a combination of phylogenetics, geographical circulation, and disease manifestation into two groups. Viruses circulating in the Old World (Europe, Asia, and Africa) typically cause arthralgia, malaise or a rash. (Griffin, 2007; Zacks & Paessler, 2010). New World alphaviruses’ infections result in a flu-like syndrome that may progress to neurological involvement. New World encephalitic alphaviruses include EEE, WEE, and