T Cells Facilitate Recovery from Venezuelan Equine Encephalitis Virus-Induced Encephalomyelitis in the Absence of Antibody

Abstract

Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne RNA virus of the genusAlphavirus that is responsible for a significant disease burden in Central and South America through sporadic outbreaks into human and equid populations. For humans, 2 to 4% of cases are associated with encephalitis, and there is an overall case mortality rate of approximately 1%. In mice, replication of the virus within neurons of the central nervous system (CNS) leads to paralyzing, invariably lethal encephalomyelitis. However, mice infected with certain attenuated mutants of the virus are able to control the infection within the CNS and recover. To better define what role T cell responses might be playing in this process, we infected B cell-deficient MT mice with a VEEV mutant that induces mild, sublethal illness in immune competent mice. Infected MT mice rapidly developed the clinical signs of severe paralyzing encephalomyelitis but were eventually able to control the infection and recover fully from clinical illness. Recovery in this system was T cell dependent and associated with a dramatic reduction in viral titers within the CNS, followed by viral persistence in the brain. Further comparison of the relative roles of T cell subpopulations within this system revealed that CD4 ؉ T cells were better producers of gamma interferon (IFN-␥) than CD8 ؉ T cells and were more effective at controlling VEEV within the CNS. Overall, these results suggest that T cells, especially CD4 ؉ T cells, can successfully control VEEV infection within the CNS and facilitate recovery from a severe viral encephalomyelitis.

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

“…Nonetheless, antibody response appeared to be dispensable for clearance of VEEV from CNS [231]. In addition, antibody response was not required for recovery of μMT mice from encephalomyelitis induced by attenuated strains of VEEV [232], such that these mice were able to reduce dramatically virus titers in the CNS and clear virus from CSF, in the absence of antiviral antibody.…”

“…CD4 T cells are also required for protection against infection with other arboviruses, including JEV [237], yellow fever virus [244], TBEV [242], RVFV [229], and VEEV [231]. CD4 Tcell response resulted in a dramatic reduction of virus titers in the CNS and mediated full recovery of μMT mice from VEEV-induced encephalomyelitis [232].…”

Encephalitic Development in Alphaviral Infection

“…Mechanistic studies demonstrated that artificial attenuation of EEE results in a marked increase in sensitivity to type I IFN associated with decreased virulence of the virus (Aguilar, et al, 2005;Brown & Officer, 1975;Brown, et al, 1975;Gardner, et al, 2009;Murphy, 1975;Wagner, 1963). Combined with studies in WEE, this led researchers to hypothesize that differences in disease presentation and incidence in humans between South American and North American isolates could be attributed to IFN sensitivity (Brown & Officer, 1975;Brown, et al, 1975). Indeed, comparison of replication of North American and South American strains in IFN pre-treated Vero cells showed a depressive effect on replication of the South American isolates.…”

“…Chimeric vaccines of EEE and WEE have also been proposed as have trivalent vaccines utilizing immunogens from all three encephalitic alphaviruses or recombinant genetic systems (Atasheva, et al, 2009;Barber, et al, 1978;Pedersen, 1976;Schoepp, et al, 2002). In murine models with pre-existing immunity generated via vaccination, neutralizing antibody is typically detected ten days following infection (Brown & Officer, 1975;Brown, et al, 1975). Neutralizing antibody also develops in the spinal fluid of rabbits vaccinated with either a live or formalin-inactivated vaccine, and such animals are able to resist vigorous challenge routes by IC injection of active virus.…”

“…Research efforts in the 1970's indicated that Fc-dependent clearance of the virus does not rely on complement . Vaccinated mice with non-functional B-cells (μMT deficient) are highly susceptible to intranasal infection, and when infected with attenuated strains develop persistent viral infection (Brooke, et al, 2010;Paessler, et al, 2007;Yun, et al, 2009). …”