Toll-like Receptors and Viral Immunity

A major advance in the field of immunology was the discovery of Toll-like receptors (TLR), which mediate recognition of certain pathogen-specific components and trigger appropriate immune responses. In fact, the identification of TLRs as pattern recognition receptors led in part to a Nobel Prize for “discoveries concerning the activation of innate immunity” (http://www.nobelprize.org/nobel_prizes/lists/all/). In recent years, considerable progress has been made in elucidating the roles of TLRs in antiviral immunity. In this regard, the current issue of Viral Immunology features several papers that address key facets of TLR involvement in innate immune responses. Yu et al. investigated the innate antiviral response to Hantaan virus (HTNV) infection, which is responsible for endothelial cell dysfunction and pathogenicity mediated by this virus. Recent studies have indicated a role for TLR4 ligation, through its triggering of the secretion of several cytokines during infection. Here the authors confirm that TLR4 mediates these effects through a MyD88-independent signaling pathway that involves the NF-κB and IRF-3 transcription factors. The capacity of TLR to trigger innate immune responses is also an important consideration for vaccine design. Parvizi et al. investigated the capacity of a TLR-3 ligand, synthetic double-stranded RNA polyriboinosinic polyribocytidylic [poly(I:C)], to enhance the efficacy of a Marek's disease virus (MDV) vaccine in chickens. The data indicate that poly(I:C) treatment administered prior to and after vaccination considerably improved protection against MDV-induced tumors. TLR and other pattern recognition receptors elicit the production of interferons, which act against viral infection. Kanda et al. investigated the effects of interferon-λ on the inhibition of hepatitis A and C internal ribosomal entry site-mediated translation in cell lines. These studies demonstrate a novel antiviral effect of interferon-λ against hepatitis A and C infection through the suppression of translation.

In addition to directly mediating antiviral effects, TLRs also play a key role in triggering adaptive immune responses against invading viruses. Several articles in this issue address adaptive immunity to a number of different viruses. The cross-reactivity and neutralizing activities of immunoglobulin A (IgA) responses to influenza virus were studied by Tanimoto et al. The authors show that the polymerization of IgA enhances its efficacy, but does not increase the number of influenza virus strains neutralized by the antibody. In another study, Friberg et al. analyzed human monoclonal antibodies generated by dengue virus (DENV)-specific memory B cells. DENV can cause exacerbated disease in the presence of serotype cross-reactive antibodies that had been elicited by a prior infection. Here the authors characterize human DENV-specific antibodies in detail, and shed light on the breadth of specificities generated by a single immune donor. The capacity of prime-boost vaccine regimens to elicit strong cellular and humoral immune responses is addressed by Hallengärd et al. The authors analyzed a regimen involving recombinant modified vaccinia Ankara or recombinant protein, and a multigene DNA vaccine delivered by electroporation. The data emphasize the importance of including multiple vaccine modalities that can stimulate both T and B cells to elicit strong and balanced immune responses.

Two articles in this issue of Viral Immunology address the capacity of viruses to modify the host response. Gabriel et al. analyzed the capacity of virally-encoded chemokine binding protein (vCCI) to influence vaccinia virus infection. The authors show that vCCI decreased specific cellular immunity elicited by DNA vaccines. In another study, Heiske et al. investigated the activation of human cytomegalovirus (HCMV) and elevated levels of vascular endothelial growth factor (VEGF) associated with transplant rejection. The data indicate that active HCMV infection is required to induce both VEGF and a key VEGF receptor. Furthermore, the upregulation of these molecules is a direct viral effect, and not a secondary effect mediated by inflammatory cytokines. These findings support the concept that virally-induced immune mediators play a key role in transplant rejection.

Finally, two articles address other aspects of antiviral immunity. Shen et al. show that the effects of immunosuppressants on hepatitis B virus genes in vitro were different from those seen in clinical recipients, suggesting that the formation of quasispecies contributes to HBV re-infection after liver transplantation. And Kim et al. show that the 2009 pandemic H1N1 influenza virus is more pathogenic in pregnant mice than seasonal H1N1 influenza virus.

Taken together, the articles in this issue of Viral Immunology illustrate the depth and breadth of our journal's coverage of the sub-field, with articles on topics that range from TLRs and innate immunity to adaptive immunity and viral modification of host responses.