Pathogenesis of aerosolized Eastern Equine Encephalitis virus infection in guinea pigs

Abstract

Mice and guinea pigs were experimentally exposed to aerosols containing regionally-distinct strains (NJ1959 or ArgM) of eastern equine encephalitis virus (EEEV) at two exclusive particle size distributions. Mice were more susceptible to either strain of aerosolized EEEV than were guinea pigs; however, clinical signs indicating encephalitis were more readily observed in the guinea pigs. Lower lethality was observed in both species when EEEV was presented at the larger aerosol distribution (> 6 μm), although the differences in the median lethal dose (LD 50 ) were not significant. Virus isolation and immunohistochemistry indicated that virus invaded the brains of guinea pigs within one day postexposure, regardless of viral strain or particle size distribution. Immunohistochemistry further demonstrated that neuroinvasion occurred through the olfactory system, followed by transneuronal spread to all regions of the brain. Olfactory bipolar neurons and neurons throughout the brain were the key viral targets. The main microscopic lesions in infected guinea pigs were neuronal necrosis, inflammation of the meninges and neuropil of the brain, and vasculitis in the brain. These results indicate that guinea pigs experimentally infected by aerosolized EEEV recapitulate several key features of fatal human infection and thus should serve as a suitable animal model for aerosol exposure to EEEV.

Encephalitic Development in Alphaviral Infection

“…Vasculitis is evident in some late stage cases and characterized by fragmentation of the vessel walls, intramural infiltrates of inflammatory cells, and fibrinoid necrosis. No peripheral organs examined had detectable infectious virus, and osteoblasts were only rarely infected again in contrast to mice (King, 1938;Roy, et al, 2009;Sorrentino, et al, 1968).…”

“…Unsurprisingly given the higher mortality rates, children display far more severe neurological symptoms with muscular rigidity, involuntary movements, and paralysis (Calisher, 1994;Steele & Twenhafel, 2010). Cerebral spinal fluid (CSF) pressure may be mildly elevated with normal glucose, protein and elevated leukocyte counts (<500/mm 3 ) (Calisher, 1994;Rozdilsky, et al, 1968). While typical CSF white blood cell counts are in this range, they have been reported to be as high as 2000/mm 3 , (Romero & Newland, 2003;.…”

“…Aerosol infection of animals indicated that mice infected with EEE show neuronal tropism and brain lesions similar to peripherally infected mice. In these animals, infection is presented at 24 hours as with peripheral infection, but only presented in the olfactory bulbs and evidence of infection of the olfactory neuroepithelium suggesting neuroinvasion via direct infection of the neuroepithelium in contrast to peripherally infected animals (Roy, et al, 2009;Steele & Twenhafel, 2010). Thus, route of infection likely plays a significant role in mechanism of CNS entry.…”

“…Histopathological features include destruction, of neurons, inflammatory cell infiltration of the neuropil, gliosis, and microhemorrahages as well as vasculitis (Dremov, et al, 1978;Paessler, et al, 2004). Guinea pigs infected via aerosol by EEE develop clinical signs within 24 hours (Paessler, et al, 2004;Roy, et al, 2009). Symptomatic disease includes decreased activity, dorsal tremors, and progress to coma and death.…”

“…Additionally, smaller areas of focal necrosis with and without cellular infiltrate are found throughout the brain in the striatum, globus pallidus, susbtantia nigra, cerebral cortex, thalamus, and pons. A subset of lethally infected patients displayed predominant concentrations of brain lesions in the subcortical white matter (Anderson, 1984;Rozdilsky, et al, 1968).…”