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    Dengue is a mosquito-borne infectious disease highly endemic to tropical and subtropical countries. Symptomatic patients can rapidly progress to severe conditions of hemorrhage, plasma extravasation and hypovolemic shock that leads to death. Severe dengue patients' blood tests typically report low levels of high-density lipoprotein (HDL), that is responsible for reverse cholesterol transport (RCT) and regulation of lipid composition on peripheral tissues. It is well known that Dengue virus (DENV) depends on membrane cholesterol rafts to infect and replicate in mammalian cells. Here we describe the interaction of the DENV nonstructural protein 1 (NS1) with Apolipoprotein A1 (ApoA1), which is the major protein component of HDL. NS1 is secreted by infected cells and can be found circulating in the serum of patients since the onset of the symptoms. NS1 concentration in plasma is related to dengue severity, attributed to immune evasion and acute inflammatory response. Our data show that the DENV NS1 protein induces the increase of lipid rafts in non-infected cell membrane and enhances further DENV infection. We also show that ApoA1-mediated lipid raft depletion inhibits DENV attachment to cell surface. In addition, ApoA1 was able to neutralize NS1-induced cell activation and to prevent NS1-mediated enhancement of DENV infection. Furthermore, we demonstrate that the ApoA1 mimetic peptide 4F is also capable of mediating lipid raft depletion to control DENV infection. Taken together, our results suggest the potential of RCT-based therapies for dengue treatment. These results should motivate studies to assess the importance of RCT in dengue infection in vivoIMPORTANCEDengue virus (DENV) is one of the most relevant mosquito-transmitted viruses worldwide, infecting more the 390 million people every year and leading to more than 20 thousand deaths. Despite a DENV vaccine has already been approved, its potential side-effects have hampered its use in large scale immunization. Therefore, new treatment options are urgent either to prevent disease worsening or improve current clinical management of severe cases. In the present study, we describe a new interaction of the NS1 protein, one of the major viral components, with a key component of high-density lipoprotein, the Apolipoprotein A1 (ApoA1). This interaction seems to alter membrane susceptibility to virus infection and modulates the mechanisms triggered by DENV to evade immune response. We also propose the use of a mimetic peptide named 4F, originally developed for atherosclerosis, as a potential therapy for relieving DENV symptoms. Copyright © 2021 American Society for Microbiology.


    Diego R Coelho, Pedro H Carneiro, Lucas Mendes-Monteiro, Jonas N Conde, Iamara Andrade, Thu Cao, Diego Allonso, Michael White-Dibiasio, Richard J Kuhn, Ronaldo Mohana-Borges. ApoA1 neutralizes pro-inflammatory effects of Dengue virus NS1 protein and modulates the viral immune evasion. Journal of virology. 2021 Apr 07

    PMID: 33827950

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