Article

The roles of chemokines in rabies virus infection: overexpression may not always be beneficial.

Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
Journal of Virology (Impact Factor: 5.08). 10/2009; 83(22):11808-18. DOI: 10.1128/JVI.01346-09
Source: PubMed

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 1alpha (MIP-1alpha), 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 recombinant 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-1alpha 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 controlling virus infection, may not always be beneficial to the host.

0 Bookmarks
 · 
102 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Infection of rabies virus (RABV) causes central nervous system (CNS) dysfunction and results in high mortality in human and animals. However, it is still unclear whether and how CNS inflammation and immune response contribute to RABV infection.
    Journal of Neuroinflammation 08/2014; 11(1):146. · 4.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Noroviruses are an emerging threat to public health, causing large health and economic costs, including at least 200,000 deaths annually. The inability to replicate in cell culture or small animal models has limited the understanding of the interaction between human noroviruses and their hosts. However an alternative strategy to gain insights into norovirus pathogenesis is to study murine norovirus (MNV-1) that replicates in cultured macrophages. While the innate immune response is central to the resolution of norovirus disease, the adaptive immune response is required for viral clearance. The specific responses of infected macrophages and dendritic cells to infection drive the adaptive immune response, with chemokines playing an important role. In this study we have conducted microarray analysis of RAW264.7 macrophages infected with MNV-1 and examined the changes in chemokine transcriptional expression during infection. While the majority of chemokines showed no change, there was specific up-regulation in chemokines reflective of a bias towards a Th1 response, specifically CCL2, CCL3, CCL4, CCL5, CXCL2, CXCL10 and CXCL11. These changes in gene expression were reflected in protein levels as determined by ELISA assay. This virus-induced chemokine response will affect the resolution of infection and may limit the humoral response to norovirus infection.
    Virus Research 12/2013; · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Infection with laboratory-attenuated rabies virus (RABV) enhances Blood-brain Barrier (BBB) permeability, which has been demonstrated to be an important factor for host survival since it allows immune effectors to enter into the CNS to clear RABV. To probe the mechanism by which RABV infection enhances BBB permeability, the expression of tight junction (TJ) proteins in the CNS was investigated following intracranial inoculation with laboratory-attenuated or wt RABV. BBB permeability was significantly enhanced in mice infected with laboratory-attenuated, but not wt, RABV. The expression levels of TJ proteins (claudin-5, occludin, and Zonula Occludens-1) were decreased in mice infected with laboratory-attenuated, but not wt, RABV, suggesting that enhancement of BBB permeability is associated with reduction of TJ protein expression in RABV infection. RABV neither infects the brain microvascular endothelial cells (BMECs) nor modulates the expression of TJ proteins in BMECs. However, brain extracts prepared from mice infected with laboratory-attenuated, but not wt, RABV reduced TJ protein expressions in BMECs. It was found that brain extracts from mice infected with laboratory-attenuated RABV contained significantly higher levels of inflammatory chemokines/cytokines than those from mice infected with wt RABV. Pathway analysis indicates that IFN-γ is located in the center of the cytokine network in RABV-infected mouse brain and neutralization of IFN-γ ameliorated both disruption of BBB permeability in vivo and down-regulation of TJ protein expression in vitro. These findings indicate that enhancement of BBB permeability and reduction of TJ protein expressions are not due to RABV infection per se, but due to virus-induced inflammatory chemokines/cytokines. Previous studies have shown that infection with only laboratory-attenuated, not wild-type, rabies virus (RABV) enhances Blood-brain Barrier (BBB) permeability, which allows immune effectors to enter into the central nervous system (CNS) and clear RABV from the CNS. This study investigated the mechanism by which RABV infection enhances BBB permeability. It was found that RABV infection enhances BBB permeability by down-regulation of tight junction (TJ) protein expression in the brain microvasculature. It was further found that it is not RABV infection per se, but the chemokines/cytokines induced by RABV infection that down-regulate the expression of TJ proteins and enhance the BBB permeability. Blocking some of the cytokines such as IFN-γ ameliorated both disruption of BBB permeability and down-regulation of TJ protein expression. These studies may provide a foundation for developing therapeutics for clinical rabies such as medication that could be used to enhance the BBB permeability.
    Journal of Virology 02/2014; · 5.08 Impact Factor

Full-text (2 Sources)

Download
34 Downloads
Available from
May 29, 2014