Abstract
Dengue constitutes a global health concern. The clinical manifestation of this disease varies from mild febrile illness to severe hemorrhage and/or fatal hypovolemic shock. Flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein that is displayed on the surface of infected cells but is absent in viral particles. NS1 accumulates at high levels in the plasma of dengue virus (DENV)-infected patients, and previous reports highlight its involvement in immune evasion, dengue severity, liver dysfunction and pathogenesis. In the present study, we performed a yeast two-hybrid screen to search for DENV2 NS1-interacting partners using a human liver cDNA library. We identified fifty genes, including human complement component 1 (C1q), which was confirmed by coimmunoprecipitation, ELISA and immunofluorescence assays, revealing for the first time the direct binding of this protein to NS1. Furthermore, the majority of the identified genes encode proteins that are secreted into the plasma of patients, and most of these proteins are classified as acute-phase proteins (APPs), such as plasminogen, haptoglobin, hemopexin, α-2-HS-glycoprotein, retinol binding protein 4, transferrin, and C4. The results presented here confirm the direct interaction of DENV NS1 with a key protein of the complement system and suggest a role for this complement protein in the pathogenesis of DENV infection.
Highlights
Dengue constitutes a major global health concern
Dengue virus (DENV) nonstructural protein 1 (NS1) directly interacts with C1q Because the interaction of flavivirus NS1 with complement system proteins and its regulators appears to play an important role in the immune evasion process [32,35,36], we focused our studies on the confirmation of the DENV NS1 and C1q interaction
We identified 50 putative interacting partners of DENV2 NS1 by screening a human liver cDNA library using a yeast two-hybrid system
Summary
It is estimated that nearly half of the worldwide population lives in risk areas and that fifty to one hundred million infections occur each year, including 500,000 hospitalizations of patients with severe dengue illness [1,2]. Infection with DENV may induce a spectrum of symptoms varying from none to severe plasma leakage, hemorrhage and organ impairment [3]. Several studies have been published attempting to elucidate the principal phenomenon that leads to severe disease. It has been established that the risk of developing severe dengue may be associated with secondary heterologous infection, leading to the phenomenon of antibody-dependent enhancement (ADE) [4], in addition to high viral loads [5,6,7] and multiple host factors including age, gender, genotype and prior immunity, among others [8,9]. Disease severity can be correlated to circulating levels of certain cytokines and chemokines such as tumor necrosis factor-alpha (TNF-a), interleukin 1b (IL-1b), interleukin 6 (IL-6), interleukin 10 (IL-10), interferon-gamma (IFN-c), interleukin 8
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