title: Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins.
abstract: Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV-infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system.
  
  
  
  Dengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV). The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly, NS1 itself also inhibited MAC activity, suggesting a direct role of this protein in the inhibition process. Our findings imply a role for NS1 as a terminal pathway inhibitor of the complement system.
authors: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Jonas Nascimento
authors: JN
authors: Conde
authors: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Emiliana Mandarano
authors: EM
authors: da Silva
authors: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Diego
authors: D
authors: Allonso
authors: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Diego Rodrigues
authors: DR
authors: Coelho
authors: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil Faculdade de Educação Tecnológica do Estado do Rio de Janeiro-FAETERJ (FAETEC), Paracambi, RJ, Brazil.
authors: Iamara da Silva
authors: IDS
authors: Andrade
authors: Laboratório de Biologia Molecular e Bioquímica de Proteínas, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Luciano Neves
authors: LN
authors: de Medeiros
authors: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Joice Lima
authors: JL
authors: Menezes
authors: Laboratório de Bacteriologia, Instituto Butantan, São Paulo, SP, Brazil.
authors: Angela Silva
authors: AS
authors: Barbosa
authors: Laboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil mohana@biof.ufrj.br.
authors: Ronaldo
authors: R
authors: Mohana-Borges
mesh_terms: D045744:Cell Line, Tumor; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism*; D003715:Dengue / Q000378:metabolism* / Q000821:virology*; D003716:Dengue Virus / Q000378:metabolism*; D005416:Flavivirus / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D020798:Two-Hybrid System Techniques; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D019096:Vitronectin / Q000378:metabolism*; D014902:West Nile virus / Q000378:metabolism; D000071244:Zika Virus / Q000378:metabolism; D000071243:Zika Virus Infection / Q000378:metabolism / Q000821:virology
chemical_list: D015938:Complement Membrane Attack Complex; D017361:Viral Nonstructural Proteins; D019096:Vitronectin; D003165:Complement System Proteins