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Cytomegalovirus CMV another member of herpesviradae family c
Cytomegalovirus (CMV), another member of herpesviradae family, causes latent infection in humans (Gianella et al., 2015). The signaling role of the IL-33/ST2 axis in the NK cell response during CMV infection in mice was reported by Nabekura et al. They showed in a murine model of MCMV infection that ST2-deficient Ly49H+ NK hif pathway were impaired in their ability to drive MCMV-specific expansion of naïve cells into memory cells. Furthermore, when re-challenged with MCMV, IL-18R signaling was required for the secondary expansion of memory Ly49H+ NK cells. These findings suggest that IL-33 is released by damaged cells in the early phase of MCMV infection and that ST2 signaling transiently enhances MyD88 signaling to augment the proliferation of naive and memory Ly49H+ NK cells (Nabekura et al., 2015).
The Combined Effect of HIV and Co-infections on the IL-33/ST2 Axis
The Therapeutic Potential of the IL-33/ST2 Axis
There have been increasing efforts to develop a vaccine and a cure for HIV infection (Routy et al., 2016). Knowing the critical role played by the T-cell response in host defense, these strategies mainly focus on inducing effective Th1 and cytotoxic CD8 T-cell responses, although strategies that induce beneficial antibody responses are also being investigated. The use of molecules acting as DAMPs, including IL-33, as vaccine adjuvants that enhance Th1 potency has gained considerable attention in recent years (Villarreal and Weiner, 2015, Villarreal et al., 2014, Villarreal et al., 2015a). Unlike other peptide-adjuvant conjugates that directly activate antigen presenting cells (APCs) through pattern recognition pathways, an IL-33-boosted vaccine was shown to activate NKT-cells via several mechanisms, resulting in an indirect enhancement of APC function in a murine model of allergic airway inflammation (Anderson et al., 2014).
A few animal studies have been conducted in which IL-33 was tested as an adjuvant in vaccines against various pathogens. An intranasal vaccine containing recombinant influenza virus hemagglutinin and IL-33 induced elevated, influenza-specific plasma IgG levels, mucosal influenza-specific IgA, and increased expression of both Th1 and Th2–related cytokines, all of which led to the protection of the challenged mice that received this vaccine; in contrast, control mice whose vaccines did not contain IL-33 adjuvant were not protected (Kayamuro et al., 2010). In a murine LCMV model, Villarreal et al. reported an increase in the magnitude and in the function of antigen-specific CD8 T-cells upon immunization with a DNA vaccine coadministered with IL-33 (Villarreal et al., 2015b). Antigenic re-stimulation led to the expansion of these polyfunctional cytotoxic cells in vivo, which conferred efficient protection against a lethal dose of LCMV. The IL-33 adjuvant also enhanced potent HIV-specific responses in a vaccine setting. Moreover, IL-33 co-administration led to increased numbers of effector CD8 T-cells compared to the administration of vaccine alone.
A few animal studies have also shown the benefits of IL-33 in different models of infection. For example, Bonilla et al. showed in a murine model of LCMV infection that the IL-33 released by necrotic cells enhanced the activation and the clonal expansion of ST2+ CD8+ T lymphocytes, resulting in a LCMV-specific cytotoxic response (Bonilla et al., 2012). Other investigators used recombinant IL-33 in a murine influenza model to reduce lung impairment (Monticelli et al., 2011), while in a murine coxsackie B virus model of experimental pancreatitis, IL-33 induced the production of IFN-γ and TNF-α by CD8+ T and by NK cells, resulting in viral clearance (Sesti-Costa et al., 2013).
We have shown that in early HIV infection, sST2 levels are elevated (Mehraj et al., 2016). These sST2 levels correlated with the CD8 T-cell count, with immune activation and with microbial translocation, suggesting that sST2 is a marker of gut damage and of disease progression. Interestingly, no such associations were observed in patients with chronic HIV infection. As the roles of IL-33 and ST2 in viral infections are phase-dependent, therapeutic strategies need to be rationally designed according to each phase. Therefore, blockade of sST2 should be of therapeutic value during the acute phase, while blockade of IL-33 should be considered for the chronic phase (Okragly et al., 2016) when fibrosis develops in lymphoid tissues or in the liver. Further studies of the regulation of the intracellular and cytoplasmic expression of IL-33 during tissue damage in the gut will be required in order to develop therapeutic interventions, with a focus on epithelial cells, ILC2 and other cells that express the ST2 receptor.