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: 4.92). 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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Available from: Robert Finberg, Jul 23, 2014
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    • "Additionally, while lymphoid organ development and immunity in mice at 7 days is comparable to term human neonates, there is little information regarding the ontogeny of the mouse immune system early enough to compare to human preterms [3], [36]. Because age and route of infection can play fundamental roles in both risk of infection and immune responses to SE [37], [38], we sought to develop a model in newborn mice <24 h old via the IV route. "
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    ABSTRACT: Staphylococcus epidermidis (SE) causes late onset sepsis and significant morbidity in catheterized preterm newborns. Animal models of SE infection are useful in characterizing disease mechanisms and are an important approach to developing improved diagnostics and therapeutics. Current murine models of neonatal bacterial infection employ intraperitoneal or subcutaneous routes at several days of age, and may, therefore, not accurately reflect distinct features of innate immune responses to bacteremia. In this study we developed, validated, and characterized a murine model of intravenous (IV) infection in neonatal mice <24 hours (h) old to describe the early innate immune response to SE. C57BL/6 mice <24 h old were injected IV with 10(6), 10(7), 10(8) colony-forming units (CFU) of SE 1457, a clinical isolate from a central catheter infection. A prospective injection scoring system was developed and validated, with only high quality injections analyzed. Newborn mice were euthanized between 2 and 48 h post-injection and spleen, liver, and blood collected to assess bacterial viability, gene expression, and cytokine production. High quality IV injections demonstrated inoculum-dependent infection of spleen, liver and blood. Within 2 h of injection, SE induced selective transcription of TLR2 and MyD88 in the liver, and increased systemic production of plasma IL-6 and TNF-α. Despite clearance of bacteremia and solid organ infection within 48 h, inoculum-dependent impairment in weight gain was noted. We conclude that a model of IV SE infection in neonatal mice <24 h old is feasible, demonstrating inoculum-dependent infection of solid organs and a pattern of bacteremia, rapid and selective innate immune activation, and impairment of weight gain typical of infected human neonates. This novel model can now be used to characterize immune ontogeny, evaluate infection biomarkers, and assess preventative and therapeutic modalities.
    PLoS ONE 09/2012; 7(9):e43897. DOI:10.1371/journal.pone.0043897 · 3.23 Impact Factor
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    • "ssRNA viruses, like VSV, have been shown to elicit pDC activation through TLR7 and TLR8 (Diebold et al, 2004; Heil et al, 2004; Lund et al, 2004; Malmgaard, 2005), which signal through the MyD88 pathway (reviewed in Crozat and Beutler, 2004). A role for TLR 4 in VSV activation of pDCs has been suggested (Georgel et al, 2007; Jiang et al, 2005), as has the requirement for MyD88 signaling in VSV infection of the neuroepithelium (Zhou et al, 2007). In the case of VSV, activation of IFN production by pDCs has been demonstrated in vitro and in vivo following peripheral inoculation (Barchet et al, 2002; Lund et al, 2004). "
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    ABSTRACT: Type I interferon (IFN) is critical for resistance of mice to infection with vesicular stomatitis virus (VSV). Wild type (wt) VSV infection did not induce type I IFN production in vitro or in the central nervous system (CNS) of mice; however IFN-beta was detected in lungs, spleen, and serum within 24 h. The M protein mutant VSV, T1026R1 (also referred to as M51R), induced type I IFN production in vitro and in the CNS, with poor expression in spleens. In addition, VSV T1026R1 was not pathogenic to mice after intranasal infection, illustrating the importance of IFN in controlling VSV replication in the CNS. Experiments with chemical sympathectomy, sRAGE, and neutralizing antibody to VSV were performed to investigate the mechanism(s) utilized for induction of peripheral IFN; neither sRAGE infusion nor chemical sympathectomy had an effect on peripheral IFN production. In contrast, administration of neutralizing antibody (Ab) readily blocked the response. Infectious VSV was transiently present in lungs and spleens at 24 h post infection. The results are consistent with VSV traffic from the olfactory neuroepithelium to peripheral lymphoid organs hematogenously or via lymphatic circulation. These results suggest that VSV replicates to high titers in the brains of mice because of the lack of IFN production in the CNS after intranasal VSV infection. In contrast, replication of VSV in peripheral organs is controlled by the production of large amounts of IFN.
    Journal of NeuroVirology 11/2007; 13(5):433-45. DOI:10.1080/13550280701460565 · 2.60 Impact Factor
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    • " spread ( Lund et al . , 2006 ) . However , TLR9 or MyD88 are not required for protection from HSV - 1 infection in a footpad injection or corneal scarification model ( Krug et al . , 2004b ) . The susceptibility of Tlr7 À / À mice to infection has not been analyzed although MyD88 - deficient mice are susceptible to intranasal infection with VSV ( Zhou et al . , 2007 ) , a virus that is recognized in part via TLR7 . The lack of a consistent role for individual TLRs in pro - tection from viral infection should not come as a surprise given the more restricted distribution of these receptors compared to the RLR family , the possibility of redundancy among distinct TLRs , and the overlap between the end"
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    ABSTRACT: Virus infection elicits potent responses in all cells intended to contain virus spread before intervention by the adaptive immune system. Central to this process is the virus-elicited production of type I interferons (IFNs) and other cytokines. The sensors involved in coupling recognition of viruses to the induction of the type I IFN genes have only recently been uncovered and include endosomal and cytosolic receptors for RNA and DNA. Here, we review their properties and discuss how their ability to recognize the unusual presence of atypical nucleic acids in particular subcellular compartments is used by the body to detect virus presence.
    Immunity 10/2007; 27(3):370-83. DOI:10.1016/j.immuni.2007.08.012 · 21.56 Impact Factor
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