Article

Role of MyD88 in route-dependent susceptibility to vesicular stomatitis virus infection.

Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01605, USA.
The Journal of Immunology (Impact Factor: 5.36). 04/2007; 178(8):5173-81. DOI: 10.4049/jimmunol.178.8.5173
Source: PubMed

ABSTRACT TLRs are important components of the innate immune response. The role of the TLR signaling pathway in host defense against a natural viral infection has been largely unexplored. We found that mice lacking MyD88, an essential adaptor protein in TLR signaling pathway, were extremely sensitive to intranasal infection with vesicular stomatitis virus, and this susceptibility was dose dependent. We demonstrated that this increased susceptibility correlates with the impaired production of IFN-alpha and defective induction and maintenance of neutralizing Ab. These studies outline the important role of the TLR signaling pathway in nasal mucosae-respiratory tracts-neuroepithelium environment in the protection against microbial pathogen infections. We believe that these results explain how the route of infection, probably by virtue of activating different cell populations, can lead to entirely different outcomes of infection based on the underlying genetics of the host.

0 Followers
 · 
79 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Retinoic-acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are essential intracellular detectors of viral RNA. They contribute to the type I interferon (IFN) response that is crucial for host defense against viral infections. Given the potent anti-viral and pro-inflammatory activities elicited by the type I IFNs, its induction is tightly regulated. Members of the tripartite motif (TRIM) family of proteins have recently emerged as key regulators of anti-viral immunity. We show that TRIM13, an E3 ubiquitin ligase, is expressed in immune cells and is upregulated in bone marrow-derived macrophages upon stimulation with inducers of type I IFN. TRIM13 interacts with MDA5 and negatively regulates MDA5-mediated type I IFN production in vitro, acting upstream of IFN regulatory factor 3. We generated Trim13(-/-) mice and show that upon lethal challenge with encephalomyocarditis virus (EMCV), which is sensed by MDA5, Trim13(-/-) mice produce increased amounts of type I IFNs and survive longer than wild type mice. Trim13(-/-) murine embryonic fibroblasts (MEFs) challenged with EMCV or poly I:C also showed a significant increase in IFNβ levels, but in contrast, IFNβ responses to the RIG-I-detected Sendai virus were diminished, suggesting that TRIM13 may play a role in positively regulating RIG-I function. Conversely, we demonstrate that TRIM13 regulates the type I IFN response through inhibition of MDA5 activity, and that it functions non-redundantly to modulate MDA5 during EMCV infection.
    Journal of Virology 07/2014; 88(18). DOI:10.1128/JVI.02593-13 · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several studies indicated that TLR as well as retinoic acid-inducible gene I-like helicase (RLH) signaling contribute to vesicular stomatitis virus (VSV)-mediated triggering of type I IFN (IFN-I) responses. Nevertheless, TLR-deficient MyD88(-/-)Trif(-/-) mice and RLH-deficient caspase activation and recruitment domain adaptor inducing IFN-β (Cardif)(-/-) mice showed only marginally enhanced susceptibility to lethal VSV i.v. infection. Therefore, we addressed whether concomitant TLR and RLH signaling, or some other additional mechanism, played a role. To this end, we generated MyD88(-/-)Trif(-/-)Cardif(-/-) (MyTrCa(-/-)) mice that succumbed to low-dose i.v. VSV infection with similar kinetics as IFN-I receptor-deficient mice. Three independent approaches (i.e., analysis of IFN-α/β serum levels, experiments with IFN-β reporter mice, and investigation of local IFN-stimulated gene induction) revealed that MyTrCa(-/-) mice did not mount IFN-I responses following VSV infection. Of note, treatment with rIFN-α protected the animals, qualifying MyTrCa(-/-) mice as a model to study the contribution of different immune cell subsets to the production of antiviral IFN-I. Upon adoptive transfer of wild-type plasmacytoid dendritic cells and subsequent VSV infection, MyTrCa(-/-) mice displayed significantly reduced viral loads in peripheral organs and showed prolonged survival. On the contrary, adoptive transfer of wild-type myeloid dendritic cells did not have such effects. Analysis of bone marrow chimeric mice revealed that TLR and RLH signaling of radioresistant and radiosensitive cells was required for efficient protection. Thus, upon VSV infection, plasmacytoid dendritic cell-derived IFN-I primarily protects peripheral organs, whereas concomitant TLR and RLH signaling of radioresistant stroma cells as well as of radiosensitive immune cells is needed to effectively protect against lethal disease.
    The Journal of Immunology 08/2014; DOI:10.4049/jimmunol.1400959 · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of host-directed gene expression by the matrix (M) protein of vesicular stomatitis virus (VSV) effectively blocks host antiviral responses, promotes virus replication, and disables the host cell. However, dendritic cells (DC) have the capacity to resist these effects and remain functional during VSV infection. Here, the mechanisms of DC resistance to M protein and their subsequent maturation were addressed. Flt3L-derived murine bone marrow dendritic cells (FDC), which phenotypically resemble resident splenic DC, continued to synthesize cellular proteins and matured during single cycle (high multiplicity) and multi-cycle (low multiplicity) infection with VSV. GM-CSF-derived myeloid DC (GDC), which are susceptible to M protein effects, were nevertheless capable of maturing, but the response was delayed and occurred only during multi-cycle infection. FDC resistance was manifested early and was Type I IFN receptor (IFNAR) and MyD88-independent, but sustained resistance required IFNAR. MyD88-dependent signaling contributed to FDC maturation during single cycle infection, but was dispensable during multi-cycle infection. Similarly to FDC, splenic DC were capable of maturing in vivo during the first 24 hrs of infection with VSV, and neither TLR7 nor MyD88 was required. We conclude that FDC resistance to M protein is controlled by an intrinsic, MyD88-independent mechanism that operates early in infection, and is augmented later in infection by Type I IFN. In contrast, while GDC are not intrinsically resistant, they can acquire resistance during multi-cycle infection. In vivo, splenic DC resist the inhibitory effects of VSV, and as per multi-cycle FDC infection, MyD88-independent signaling events control their maturation.
    Journal of Virology 08/2013; DOI:10.1128/JVI.00680-13 · 4.65 Impact Factor

Full-text (2 Sources)

Download
11 Downloads
Available from
Jul 23, 2014