Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. IL-22 and IL-17A are key cytokines in several infectious and inflammatory diseases. We have assessed the contribution of IL-22 and IL-17A in the pathogenesis of experimental dengue infection using a mouse-adapted DENV serotype 2 strain (P23085) that causes a disease that resembles severe dengue in humans. We show that IL-22 and IL-17A are produced upon DENV-2 infection in immune-competent mice. Eur. J. Immunol. 2013Immunol. . 43: 1529Immunol. -1544 Keywords: Dengue virus · IL-17A · IL-22 · Infection · Inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site
IntroductionDengue fever (DF) and its severe forms, dengue haemorrhagic fever (DHF) and dengue shock syndrome, are mosquito-borne diseases caused by one of four serotypes of Dengue virus (DENV 1-4). There are an estimated 50-100 million cases of DF annually mostly in tropical and subtropical regions of the world, and 20 000 deaths are estimated to occur each year [1,2]. DHF is defined by the WHO as fever with haemorrhagic manifestations, thrombocytopenia, haemoconcentration, or other signs of plasma leakage [1,3]. Treatment of DF and severe forms of dengue infection is largely supportive [2,3]. Human studies have demonstrated that secondary infection by a heterologous serotype is the single greatest risk factor for DHF/dengue shock syndrome [4,5]. However, manifestations of severe disease in primary infection are also frequently reported [6,7]. The immunopathogenesis of DENV infection involves the effects of cytokines on both infected and bystander immune cells [8][9][10]. High levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-8, CCL2/MCP-1 and IFN-γ, have been reported in patients with severe dengue disease [3,9,11]. However, it is not clearly understood how this massive cytokine production is induced and eventually controlled.IL-22 is a member of the IL-10 cytokine family and is believed to play important roles in inflammation and tissue homeostasis [12,13]. IL-22 receptor complex (IL-22R) is expressed in nonhaematopoietic cells in the skin, kidney, liver, lungs and gut, allowing for IL-22-mediated regulation of local responses after infection or inflammation [14,15]. IL-22 can be produced not only by Th17 cells but also by NK cells, NKT cells, γδT cells, or lymphoid tissueinducer-like cells [15][16][17]. The Th17-cell population coexpresses IL-17A, 15] . Both IL-17 and IL-22 induce an innate immune response in epithelial cells, but their functional spectra are generally distinct. Whereas IL-17 induces an inflammatory tissue response, IL-22 is believed to be mainly protective and/or regenerative [12,13,15].In viral infections, IL-22 seems to a play a marginal protective role in primary respiratory infection by Influenza A, not contributing to viral clearance, whereas IL-17 and its receptor IL-17RA contribute to acute lung injury caused by the flu [18,19]. IL-22 appears t...
