Article
Role of chemokines in the enhancement of BBB permeability and inflammatory infiltration after rabies virus infection.
Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
Virus Research (impact factor:
2.94).
10/2009;
144(1-2):18-26.
DOI:10.1016/j.virusres.2009.03.014
pp.18-26
Source: PubMed
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Citations (0)
- Cited In (3)
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Article: Intracerebral administration of recombinant rabies virus expressing GM-CSF prevents the development of rabies after infection with street virus.
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ABSTRACT: Recently it was found that prior immunization with recombinant rabies virus (RABV) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) (LBNSE-GM-CSF) resulted in high innate/adaptive immune responses and protection against challenge with virulent RABV (Wen et al., JVI, 2011). In this study, the ability of LBNSE-GM-CSF to prevent animals from developing rabies was investigated in mice after infection with lethal doses of street RABV. It was found that intracerebral administration of LBNSE-GM-CSF protected more mice from developing rabies than sham-treated mice as late as day 5 after infection with street RABV. Intracerebral administration of LBNSE-GM-CSF resulted in significantly higher levels of chemokine/cytokine expression and more infiltration of inflammatory and immune cells into the central nervous system (CNS) than sham-administration or administration with UV-inactivated LBNSE-GM-CSF. Enhancement of blood-brain barrier (BBB) permeability and increases in virus neutralizing antibodies (VNA) were also observed in mice treated with LBNSE-GM-CSF. On the other hand, intracerebral administration with UV-inactivated LBNSE-GM-CSF did not increase protection despite the fact that VNA were induced in the periphery. However, intracerebral administration with chemoattractant protein-1 (MCP-1, also termed CCL2) increased significantly the protective efficacy of UV-inactivated LBNSE-GM-CSF. Together these studies confirm that direct administration of LBNSE-GM-CSF can enhance the innate and adaptive immunity as well as the BBB permeability, thus allowing infiltration of inflammatory cells and other immune effectors enter into the CNS to clear the virus and prevent the development of rabies.PLoS ONE 01/2011; 6(9):e25414. · 4.09 Impact Factor -
Article: The Roles of Chemokines in Rabies Virus Infection: Overexpression May Not Always Be Beneficial
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ABSTRACT: It was found previously that induction of innate immunity, particularly chemokines, is an important mechanism of rabies virus (RABV) attenuation. To evaluate the effect of overexpression of chemokines on RABV infection, chemokines macrophage inflammatory protein 1 (MIP-1), RANTES, and IP-10 were individually cloned into the genome of attenuated RABV strain HEP-Flury. These recombinant RABVs were characterized in vitro for growth properties and expression of chemokines. It was found that all the recom-binant viruses grew as well as the parent virus, and each of the viruses expressed the intended chemokine in a dose-dependent manner. When these viruses were evaluated for pathogenicity in the mouse model, it was found that overexpression of MIP-1 further decreased RABV pathogenicity by inducing a transient innate immune response. In contrast, overexpression of RANTES or IP-10 increased RABV pathogenicity by causing neurological diseases, which is due to persistent and high-level expression of chemokines, excessive infiltration and accumulation of inflammatory cells in the central nervous system, and severe enhancement of blood-brain barrier permeability. These studies indicate that overexpression of chemokines, although important in con-trolling virus infection, may not always be beneficial to the host. Rabies virus (RABV) is a negative-strand RNA virus belong-ing to the Rhabidoviridae family, genus Lyssavirus, which causes rabies (fatal encephalomyelitis) in many species of mammals (5). More than 55,000 humans die of rabies each year worldwide (26). Once clinical signs develop, rabies is always fatal (12, 53). Despite the lethality of rabies, only mild inflammation and little neuronal destruction were observed in the central nervous system (CNS) of rabies patients (31, 32). Adaptation of wild-type (wt) RABV in laboratory animals and/or cell culture leads to attenuation in phenotype, and lab-oratory-adapted RABVs have been used for vaccine develop-ment (1, 10). To delineate the mechanism(s) of RABV atten-uation, previous studies compared the host responses to infection with either laboratory-attenuated or wt RABV (52). It was found that laboratory-attenuated RABV induced exten-sive inflammation, apoptosis, and neuronal degeneration, as well as induction of expression of innate immune genes in the CNS; however, wt RABV caused little or no neuronal damage and avoided the activation of expression of innate molecule genes. Other investigators also reported the induction of in-nate immunity in mice or neuronal cells infected with labora-tory-attenuated viruses (20, 33, 37). The mostly upregulated genes in the innate immune responses after infection with attenuated RABV include genes encoding for inflammatory chemokines and type I interferon (IFN) as well as IFN-related proteins (20, 33, 378). Further studies have shown that the expression of chemokines (mRNA and proteins), particularly macrophage inflammatory protein 1 (MIP-1; CCL3), RAN-TES (CCL5), and IP-10 (CXCL10), correlates with the infil-tration of inflammatory cells and enhancement of blood-brain barrier (BBB) permeability (23). Chemokines are a group of small (8-to 14-kDa), basic, structurally related molecules that can attract inflammatory cells along concentration gradients and enhance leukocyte-endothelial cell interactions (55). The tertiary structure of che-mokines is highly conserved; they contain at least four cysteine residues that form two disulfide bonds (50). Chemokines have been divided into major subfamilies on the basis of the ar-rangement of the two N-terminal cysteine residues, CC and CXC. CC chemokines act primarily upon monocytes, whereas CXC family members are specific for neutrophils and lympho-cytes (14). Chemokines regulate cell trafficking of various types of leukocytes through interactions with G-protein-coupled re-ceptors with seven transmembrane regions (55). Most chemo-kine receptors are stimulated by more than one chemokine, and one ligand can bind to more than one receptor (50). This combination of redundancy and promiscuity might act as a safety factor to ensure adequate host defenses (15, 30). Che-mokines have direct antiviral activities and/or recruit inflam-matory cells to the site of infection to kill virus or virus-infected cells (30, 34). However, due to their ability to direct migration of inflammatory cells, overexpression of chemokines may have detrimental effects, especially in the process of autoimmune inflammation. In an experimental autoimmune encephalomy-elitis model, IP-10, monocyte chemoattractant protein 1 (MCP-1), and MIP-1 were strongly upregulated (14). Admin-istration of anti-IP-10 antibody decreased disease incidence and severity and the infiltration of mononuclear cells into the CNS (11).Journal of Virology 12/2009; 83:11808-11818. · 5.40 Impact Factor -
Article: Expression of MIP-1 (CCL3) by a Recombinant Rabies Virus Enhances Its Immunogenicity by Inducing Innate Immunity and Recruiting Dendritic Cells and B Cells Previously, we showed that overexpression of MIP-1 in mouse brain further decreased rabies virus (RABV) pathogenicity (L
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ABSTRACT: In the present study, the immunogenicity of recombinant RABV expressing MIP-1 (rHEP-MIP1) was determined. It was found that intramuscular immunization of BALB/c mice with rHEP-MIP1 resulted in a higher level of expression of MIP-1 at the site of inoculation, increased recruitment of dendritic cells (DCs) and mature B cells into the draining lymph nodes and the peripheral blood, and higher virus-neutralizing antibody titers than immunization with the parent rHEP and recombinant RABVs expressing RANTES (CCL5) or IP-10 (CXCL10). Our data thus demonstrate that expression of MIP-1 not only reduces viral pathogenicity but also enhances immunogenicity by recruiting DCs and B cells to the site of immunization, the lymph nodes, and the blood. Rabies continues to present public health problems world-wide and causes more than 55,000 human deaths each year, most of which occur in the developing nations of Asia and Africa, where dog rabies remains the main source of human exposure (8, 31). Current rabies vaccines are made with inac-tivated rabies virus (RABV) grown in cultured cells. Although these vaccines are safe and efficacious, multiple doses (at least 4) must be administered over an extended period of time (14 days) to stimulate optimal immune responses (24). Further-more, the high cost of cell culture-based vaccines makes it difficult to utilize them effectively in developing countries where they are needed most (28). A live attenuated RABV vaccine (SAG-2) and a recombinant vaccinia virus expressing RABV glycoprotein (VRG) have been licensed particularly for use in the oral immunization of wild animals (10, 29). These vaccines are effective; however, VRG may cause intense skin inflammation and systemic vaccinia infection (3, 25), and SAG-2 induces a low level of virus-neutralizing antibody (VNA) responses in wild animals (11). Recent studies demonstrated that the activation of innate immune responses is one of the mechanisms by which RABV is attenuated (16, 30). Induced innate-response genes include inflammatory chemokines and cytokines, interferons (IFNs) and IFN-related genes, and Toll-like receptors (14, 22–23). Furthermore, it was found that overexpression of the chemo-kine MIP-1 (CCL3) in mouse brain further decreased RABV pathogenicity, while overexpression of RANTES (CCL5) or IP-10 (CXCL10) increased RABV pathogenicity (35). In this study, the immunogenicity of the recombinant high egg pas-sage (rHEP) Flury strain of RABV that contains the MIP-1 gene (rHEP-MIP1) was investigated. To ensure that the decreased pathogenicity of rHEP-MIP1, as shown previously (35), is due to the overexpression of MIP-1, another rHEP virus was constructed with a MIP-1 gene cloned into the rHEP genome that does not express MIP-1 protein because two stop codons were introduced near the N terminus of the MIP-1 gene, one stop codon (TAG) replacing TCA (residues 68 to 70) and the other replacing the codon ATG (residues 78 to 80). The recombinant RABV was res-cued, using the procedures described by Inoue et al. (13), and was designated rHEP-MIP-1() (Fig. 1A). Characterization of rHEP-MIP1() in vitro revealed that its growth was sim-ilar to that of the parent rHEP virus and rHEP-MIP1 (Fig. 1B), and it failed to produce MIP-1 in infected cells (Fig. 1C). The pathogenicity of rHEP-MIP1() in mice was determined by intracranial (i.c.) inoculation. Neither obvious clinical signs nor weight loss was observed in sham-infected mice or mice infected with rHEP-MIP1 (Fig. 1D). Since rHEP-Flury is one of the most attenuated RABVs (13), only one mouse in each group infected with rHEP or rHEP-MIP-1() developed mild clinical signs, including rough fur and slow movement, at days 5 to 8 p.i., and they recovered very quickly. Compared with sham-or rHEP-MIP1-infected mice, rHEP-or rHEP-MIP-1()-infected mice lost about 7% of their body weight (P 0.05) between day 6 and 11 postinfection (p.i.). Together, these data indicate that the decreased pathogenicity ofJournal of Virology 01/2010; 84(83):9642-964811808. · 5.40 Impact Factor
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Keywords
Balb/c mice intramuscularly
BBB permeability
central nervous system
Chemokine expression
chemokines
day 3 post-infection
DRV-infected mice
induction
inflammatory cell infiltration
inflammatory cells
inflammatory chemokines
innate immunity
inversely correlated
laboratory-attenuated RABV
laboratory-attenuated RABV induces expression
mock-infected mice
rabies virus
RABV infection
upregulated chemokines
various time points
