Pathogenesis of flavivirus encephalitis

Abstract

Within the flavivirus family, viruses that cause natural infections of the central nervous system (CNS) principally include members of the Japanese encephalitis virus (JEV) serogroup and the tick-borne encephalitis virus (TBEV) serocomplex. The pathogenesis of diseases involves complex interactions of viruses, which differ in neurovirulence potential, and a number of host factors, which govern susceptibility to infection and the capacity to mount effective antiviral immune responses both in the periphery and within the CNS. This chapter summarizes progress in the field of flavivirus neuropathogenesis. Mosquito-borne and tickborne viruses are considered together. Flavivirus neuropathogenesis involves both neuroinvasiveness (capacity to enter the CNS) and neurovirulence (replication within the CNS), both of which can be manipulated experimentally. Neuronal injury as a result of bystander effects may be a factor during flavivirus neuropathogenesis given that microglial activation and elaboration of inflammatory mediators, including IL-1β and TNF-α, occur in the CNS during these infections and may accompany the production of nitric oxide and peroxynitrite, which can cause neurotoxicity.

Figures

Fig 1

Soluble IgM-deficient mice are highly sensitive to peripheral infection with WNV. Mice were infected by subcutaneous inoculation of the footpad with 100 plaque-forming units of WNV NY 99 and monitored for mortality from CNS disease.

Fig 2

C3-deficient mice are highly sensitive to peripheral infection with WNV. Mice were infected as described in Fig. 1 and monitored for mortality from CNS disease.

Fig 5

Yellow fever encephalitis in the rhesus monkey showing microglial nodule with neuronophagia of a cortical neuron stained for viral antigen. Courtesy of USAMRIID. (See Color Insert.)

Fig 4

Yellow fever encephalitis in the rhesus monkey showing focus of perivascular infiltrate with mononuclear cells in the cerebral cortex. Courtesy of USAMRIID. (See Color Insert.)

Fig 3

Yellow fever virus meningoencephalitis in the rhesus monkey showing leptomeningeal accumulation of acute inflammatory cells. Courtesy of the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). (See Color Insert.)

Fig 6

Electron micrograph of a mouse CNS neuron infected with SLE virus showing characteristic cytoplasmic pathology but integrity of the nuclear (N) envelope. Arrow indicates virions within inner and outer nuclear membranes. From Murphy et al. (1968), with permission.

Fig 7

WNV infection in the Syrian golden hamster. (A) Viral antigen-positive neurons in the cerebral cortex. (B) TUNEL-positive apoptotic neurons in the cortex. Courtesy of Dr. Shu-Yan Xiao. From Xiao et al., 2001. (See Color Insert.)

Fig 8

Wild-type or B-cell-deficient (uMT) mice were inoculated with WNV in the footpad, and the virus content in serum, peripheral tissues, and brain was measured serially using plaque assay or quantitative polymerase chain reaction. From Diamond et al. (2003), with permission.

Fig 9

Neutralizing IgM and IgG antibody responses in acute WNV encephalitis in the mouse model. From Diamond et al. (2003), with permission.