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...

Dengue virus (DENV) infection is associated to exacerbated inflammatory response and structural and functional alterations in the vascular endothelium. However, the mechanisms underlying DENV-induced endothelial cell activation and their role in the inflammatory response were not investigated so far. We demonstrated that human brain microvascular endothelial cells (HBMECs) are susceptible to DENV infection, which induces the expression of the cytoplasmic pattern recognition receptor (PRR) RIG-I. Infection of HBMECs promoted an increase in the production of type I IFN and proinflammatory cytokines, which were abolished after RIG-I silencing. DENV-infected HBMECs also presented a higher ICAM-1 expression dependent on RIG-I activation as well. On the other hand, ablation of RIG-I did not interfere with virus replication. Our data suggest that RIG-I activation by DENV may participate in the disease pathogenesis through the modulation of cytokine release and expression of adhesion molecules, probably contributing to leukocyte recruitment and amplification of the inflammatory response.

Sindbis virus (SINV) induces inflammatory and vasoactive responses that are associated with rash and arthritis in human infections. The mechanisms underlying infection-associated microvasculopathy are still unknown. We investigated whether endothelial cells infected by SINV are differentially responsive to bradykinin (BK), a potent inducer of inflammatory edema in a broad range of infectious diseases. Human endothelial cells (HBMECs) infected with SINV presented an upregulation of bradykinin B2 receptors (BK2R) expression. Also, BK reduced SINV-induced apoptosis and enhanced virus replication in HBMECs in a way dependent on BK2R, PI3 kinase and ERK signaling. Strikingly, intracerebral infection of mice in the presence of a BK2R antagonist reduced the local viral load. Our data suggest that SINV infection renders human endothelial cells hypersensitive to BK, which increases host cell survival and viral replication. Ongoing studies may clarify if the deregulation of the kinin pathway contributes to infection-associated vasculopathies in life-threatening arbovirus infections.

Since exacerbated inflammation and microvascular leakage are hallmarks of dengue virus (DENV) infection, here we interrogated whether systemic activation of the contact/kallikrein-kinin system (KKS) might hamper endothelial function. In vitro assays showed that dextran sulfate, a potent contact activator, failed to generate appreciable levels of activated plasma kallikrein (PKa) in the large majority of samples from a dengue cohort (n = 70), irrespective of severity of clinical symptoms. Impaired formation of PKa in dengue-plasmas correlated with the presence of cleaved Factor XII and high molecular weight kininogen (HK), suggesting that the prothrombogenic contact system is frequently triggered during the course of infection. Using two pathogenic arboviruses, DENV or Zika virus (ZIKV), we then asked whether exogenous BK could influence the outcome of infection of human brain microvascular endothelial cells (HBMECs). Unlike the unresponsive phenotype of Zika-infected HBMECs, we found that BK, acting via B2R, vigorously stimulated DENV-2 replication by reverting nitric oxide-driven apoptosis of endothelial cells. Using the mouse model of cerebral dengue infection, we next demonstrated that B2R targeting by icatibant decreased viral load in brain tissues. In summary, our study suggests that contact/KKS activation followed by BK-induced enhancement of DENV replication in the endothelium may underlie microvascular pathology in dengue.

ABSTRACT(Seasonal variation of phenolic content in galls and non-galled tissues of Calliandra brevipes Benth (Fabaceae: Mimosoidae)). Two species, Tanaostigmodes ringueleti and T. mecanga, induce distinct galls on Calliandra brevipes Benth (Fabaceae: Mimosoidae), a globose and a fusiform gall morphotype. Seasonal changes of phenolic content in the tissues of the two distinct galls were compared to those of non-galled leaves and stems of the host plants over one year. Th e variation in the phenolic content profi les was similar in both non-galled and galled tissues, and was primarily associated with changes in the levels of rainfall, indicating a direct response to hydric stress. In periods of drastic changes in water precipitation, the alterations were signifi cantly higher in non-galled than in galled tissues suggesting that the gall inducers might limit the variation in the phenolic concentration for their own benefi t.