Immunity to viruses requires an array of critical cellular proteins that include IFN regulatory factor 3 (IRF3). Consequently, most viruses that infect vertebrates encode proteins that interfere with IRF3 activation. This review describes the cellular pathways linked to IRF3 activation and where those pathways are targeted by human viral pathogens. Moreover, key regulatory pathways that control IRF3 are discussed. Besides viral infections, IRF3 is also involved in resistance to some bacterial infections, in anticancer immunity, and in anticancer therapies involving DNA damage agents. A recent finding shows that IRF3 is needed for T cell effector functions that are involved in anticancer immunity and also in T cell autoimmune diseases. In contrast, unregulated IRF3 activity is clearly not beneficial, considering it is implicated in certain interferonopathies, in which heightened IRF3 activity leads to IFN-β–induced disease. Therefore, IRF3 is involved largely in maintaining health but sometimes contributing to disease.

Candida albicans, a dimorphic fungus composed of yeast and mycelial forms, is the most common human fungal pathogen. Th1 cytokines such as interleukin-2 (IL-2), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), which are induced by macrophage IL-12, are critical to resistance against systemic candidiasis, while Th2 cytokines such as IL-4 and IL-5 are less critical. Farnesol is a quorum-sensing molecule produced byC. albicansthat controls the formation of mycelia but is also a virulence factor. To determine whether farnesol enhances the virulence ofC. albicansby modulating the production of Th1 and Th2 cytokines, mice were pretreated with farnesol prior to intravenous infection with a sublethal dose of farnesol-producingC. albicans. Production of IL-2, IL-4, IL-5, TNF-α, IFN-γ, and IL-12 was evaluated by bead-array flow cytometry and enzyme-linked immunosorbent assay. Mice exhibited an elevation in serum TNF-α levels at 48 h and an elevation in IFN-γ and IL-12 levels at 6 to 12 h after infection withC. albicans. Pretreatment with farnesol significantly reduced the elevation of both IFN-γ and IL-12 but not TNF-α. In contrast, mice pretreated with farnesol exhibited an unexpected elevation in IL-5 levels. To determine whether farnesol has a direct effect on macrophage production of IL-12, peritoneal macrophages were pretreated with farnesol prior to stimulation with IFN-γ plus lipopolysaccharide (LPS). Farnesol inhibited production of both IL-12 p40 and p70 from IFN-γ/LPS-stimulated macrophages. Therefore, the role of farnesol in systemic candidiasis is likely due to its ability to inhibit the critical Th1 cytokines IFN-γ and IL-12 and perhaps to enhance a Th2 cytokine, IL-5.

Candida albicans causes candidiasis, secretes farnesol, and switches from yeast to hyphae to escape from macrophages after phagocytosis. However, bef

The severe consequences of the Zika virus (ZIKV) infections resulting in congenital Zika syndrome in infants and the autoimmune Guillain–Barre syndrome in adults warrant the development of safe and efficacious vaccines and therapeutics. Currently, there are no approved treatment options for ZIKV infection. Herein, we describe the development of a bacterial ferritin-based nanoparticle vaccine candidate for ZIKV. The viral envelope (E) protein domain III (DIII) was fused in-frame at the amino-terminus of ferritin. The resulting nanoparticle displaying the DIII was examined for its ability to induce immune responses and protect vaccinated animals upon lethal virus challenge. Our results show that immunization of mice with a single dose of the nanoparticle vaccine candidate (zDIII-F) resulted in the robust induction of neutralizing antibody responses that protected the animals from the lethal ZIKV challenge. The antibodies neutralized infectivity of other ZIKV lineages indicating that the zDIII-F can confer heterologous protection. The vaccine candidate also induced a significantly higher frequency of interferon (IFN)-γ positive CD4 T cells and CD8 T cells suggesting that both humoral and cell-mediated immune responses were induced by the vaccine candidate. Although our studies showed that a soluble DIII vaccine candidate could also induce humoral and cell-mediated immunity and protect from lethal ZIKV challenge, the immune responses and protection conferred by the nanoparticle vaccine candidate were superior. Further, passive transfer of neutralizing antibodies from the vaccinated animals to naïve animals protected against lethal ZIKV challenge. Since previous studies have shown that antibodies directed at the DIII region of the E protein do not to induce antibody-dependent enhancement (ADE) of ZIKV or other related flavivirus infections, our studies support the use of the zDIII-F nanoparticle vaccine candidate for safe and enhanced immunological responses against ZIKV.