Attenuated Rabies Virus Activates, while Pathogenic Rabies Virus Evades, the Host Innate Immune Responses in the Central Nervous System

Abstract

Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-␣/␤) signaling pathways and inflammatory chemokines. For the IFN-␣/␤ signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2-5-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses.Rabies virus (RV) is a nonsegmented negative-stranded RNA virus of the Rhabdoviridae family and induces a fatal neurological disease in humans and animals (15). Although significant advances have been made in rabies prevention and control, the disease remains a major threat to public health and continues to cause numerous human deaths around the world. The dog remains the most important reservoir in Asia, Africa, and Latin America, where most human rabies cases occur (19). In the United States, dog rabies has been largely brought under control through pet vaccination programs, and there have been only a few incidents where large carnivores have transmitted rabies directly to humans (11,26). Most of the human cases in the past decade have been associated with RV found in bats, particularly silver-haired bats (11,18,39,47). Furthermore, most of the cases occurred without a history of exposure (11), suggesting that the silver-haired bat RV (SHBRV) is highly pathogenic and neuroinvasive (18,47).RV invades the nervous system by binding to neural receptors, such as acetylcholine receptor (31), neural cell adhesion molecule (52), or nerve growth factor receptor (NTR75) (53). Then, RV is transported to the central nervous system (CNS) by retrograde transportation, possibly by binding to cytoplasmic dynein (29,46). Despite extensive investigation in the past 100 years, the pathogenic mechanisms by which street (wildtype [wt]) RV infection results in neurological diseases and death in humans are not well understood. This is because there is very little neuronal pathology or d...

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

“…In immune cells, we have shown the ability of CRMP2 to bind vimentin and tubulin (Vincent et al, 2005) parenchyma (Kleine and Benes, 2006;Lane et al, 2000;Lee et al, 2004;Liu et al, 2000;Ransohoff et al, 2003). Chemokines are expressed at high levels in the virus infected CNS, as it is the case after RABV infection (Baloul and Lafon, 2003;Roy et al, 2007;Wang et al, 2005).…”

Ambivalent Role of the Innate Immune Response in Rabies Virus Pathogenesis

“…Like most viruses, RABV has developed a strategy to counteract the antiviral effect of the type I IFN response (23,34,40,41,55,56). Despite these mechanisms, IFN, chemoattractive, and inflammatory responses in the RABV-infected NS are far from abrogated, and RABV successfully infects the NS (28,58).In this study, we investigate to what extent the innate immune response in the NS is important for the efficiency of RABV, immunoevasive strategy, and pathogenesis. To disturb the innate immune response and thus reveal its role in RABV infection, we infected a new mouse transgenic model that overexpresses LGP2 (LGP2 TG) with a neurovirulent RABV strain.…”

Sensitivity of Rabies Virus to Type I Interferon Is Determined by the Phosphoprotein Gene

“…Therefore, it is presumed that these amino acid differences can change the distribution of P protein in the This study showed that the virulent CE(NiP) strain with the P gene from Ni strain in the Ni-CE genome is less sensitive to type I IFN than is the avirulent Ni-CE strain, suggesting that the IFN sensitivity of the virus determined by the P gene is inversely related to pathogenicity of the virus. Interestingly, it has been reported that type I IFN is produced in the mouse brain in response to rabies virus infection (9,15). Therefore, it is thought that the different IFN sensitivities of Ni-CE and CE(NiP) strains influence their propagation efficiencies in vivo and result in their different pathogenicities.…”