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.

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    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.
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