Virulence variation among isolates of western equine encephalitis virus in an outbred mouse model

Abstract

Little is known about viral determinants of virulence associated with western equine encephalitis virus (WEEV). Here, we have analysed six North American WEEV isolates in an outbred CD1 mouse model. Full genome sequence analyses showed ¡2.7 % divergence among the six WEEV isolates. However, the percentage mortality and mean time to death (MTD) varied significantly when mice received subcutaneous injections of 10 3 p.f.u. of each virus. Two WEEV strains, McMillan (McM) and Imperial 181 (IMP), were the most divergent of the six in genome sequence; McM caused 100 % mortality by 5 days post-infection, whereas IMP caused no mortality. McM had significantly higher titres in the brain than IMP. Similar differences in virulence were observed when McM and IMP were administered by aerosol, intranasal or intravenous routes. McM was 100 % lethal with an MTD of 1.9 days when 10 3 p.f.u. of each virus was administered by intracerebral inoculation; in contrast, IMP caused no mortality. The presence of IMP in the brains after infection by different routes and the lack of observed mortality confirmed that IMP is neuroinvasive but not neurovirulent. Based on morbidity, mortality, MTD, severity of brain lesions, virus distribution patterns, routes of infection and differences in infection of cultured cells, McM and IMP were identified as high-and low-virulence isolates, respectively.

Entry Sites of Venezuelan and Western Equine Encephalitis Viruses in the Mouse Central Nervous System following Peripheral Infection

“…We have previously shown that i.n. exposure of outbred CD-1 mice to WEEV.McM leads to virus entry into the CNS through the long axonal projections of olfactory sensory neurons (OSNs) (6,7) and supports other studies showing that VEEV and EEEV utilize OSNs as an important route of entry into the brain following i.n. or aerosol inoculation (8)(9)(10).…”

“…A full-length infectious clone of the WEEV.McM was derived from a virus isolate obtained from the Arbovirus Reference Collection at the Centers for Disease Control and Prevention in Fort Collins, CO, and has been previously described (6). Passage history for virus strains used has been previously published (13,14).…”

Liposome-Antigen-Nucleic Acid Complexes Protect Mice from Lethal Challenge with Western and Eastern Equine Encephalitis Viruses

“…Cell culture supernatants were collected at 48 h postinfection (hpi) and stored in aliquots at Ϫ80°C. Virus titers were determined by plaque assay on Vero cells as previously described (26).…”

Encephalitic Development in Alphaviral Infection

“…McM when administered IN also causes extensive damage to the neurons of the CNS. The alterations in pathogenicity between the two strains are possible attributed to either slower replication of the attenuated strain or changes in the response to the innate immune system (Logue, et al, 2009). Accumulated data from EEE and VEE indicate that alterations in response of the host and susceptibility of the virus to the immune response are a strong determinant of outcome.…”

“…Like in humans, age and strain of mouse infected, route of inoculations, and virulence of virus strain all influence the susceptibility of the host (Aguilar, 1970;Bianchi, et al, 1993;Logue, et al, 2009;Monath, et al, 1978;Nagata, et al, 2006). Peripheral routes of infection result in approximately 50% mortality with intracerebral (IC) or intranasal (IN) challenge resulting in more uniform, dose-dependent mortality depending on strain of virus and background of murine model (Hardy, et al, 1997;Julander, et al, 2007;Liu, et al, 1970).…”