An Experimental Model of Meningoencephalomyelitis by Rocio Flavivirus in Balb/C Mice: Inflammatory Response, Cytokine Production, and Histopathology

Abstract

Rocio virus (ROCV) is a flavivirus, probably transmitted by Culex mosquitoes and maintained in nature as a zoonosis of wild birds. Rocio virus caused a human epidemic of severe encephalitis that lasted from 1973 to 1980 in the Ribeira valley, in the southeastern coast of Brazil. After this outbreak, serologic evidence of ROCV circulation has been reported and public health authorities are concerned about a return of ROCV outbreaks in Brazil. We show here a study on the pathogenesis and the physiopathology of ROCV disease in the central nervous system of a Balb/C young adult mice experimental model. The animals were intraperitoneally infected by ROCV and followed from 0 to 9 days after infection, when all of them died. Nervous tissue samples were collected from infected animals for immunohistochemistry and molecular biology analysis. We observed the virus in the central nervous system, the inflammatory changes induced by Th1 and Th2 cytokines, and the final irreversible damage of nervous tissues by neuronal degeneration and apoptosis. These findings can help to better understand the pathogenesis and physiopathology of the human meningoencephalomyelitis by ROCV and other flaviviruses.

CCR2 Plays a Protective Role in Rocio Virus–Induced Encephalitis by Promoting Macrophage Infiltration Into the Brain

“…Despite its potential for further geographical spread, little is known about ROCV pathogenesis. In a mouse model of ROCV infection, a high virus titer was detected in the brain, and an elevated number of inflammatory macrophages was found in the central nervous system (CNS) [13,14], implying a role for macrophages during infection. However, further details on the role of these cells in the pathogenesis of ROCV have not been reported.…”

“…The CNS contains resident innate immune sentinels such as microglia that are among the first responders to infection, but peripheral leukocytes, including monocytes, and T cells, are nevertheless recruited to aid in local inflammatory responses. These cells are reported to play a role in neurotropic viral infections, including those due to WNV, coronavirus (mouse hepatitis virus), and herpes simplex virus type 1 [13][14][15][16][17]. In addition, migration of monocytes to the brain is heavily dependent on the interaction between CCL2 and its receptor, CCR2 [18][19][20].…”

Influence of the CCR-5/MIP-1 α Axis in the Pathogenesis of Rocio Virus Encephalitis in a Mouse Model

“…24 A chronic persistence infection was also observed after intraperitoneal infection of ROCV into golden hamsters in which virus replicated and was excreted continuously. 25 Recently, our group showed that severe encephalitis developed in BALB/C mice infected with ROCV and these mice had inflammatory cell infiltrates in the CNS, 21 which suggested that infection of the CNS recruits leukocytes, and that this recruitment generates tissue damage in an attempt to control infection.…”

“…27 Our group also reported the ability of ROCV to induce apoptosis in neurons, which caused neuronal death. 21 However, it was not possible to state if neuronal death was caused directly by viral replication or was a consequence of the inflammatory process.…”

“…Neuronal damage most likely occurred as a consequence of ROCV infection and apoptosis induced by cytokines produced by glial and macrophage activated cells. 21 One study reported that flavivirus (e.g., WNV) encephalitis is characterized by entry of macrophages, CD4…”