Virulence difference of five type I dengue viruses and the intrinsic molecular mechanism

Abstract

Dengue virus (DENV) is the most important vector-borne virus globally. The safe and effective vaccines are still under development and there are no antiviral drugs for DENV induced diseases. In this study, we obtained five DENV1 isolates (DENV1 A to E) from the outbreak of dengue fever in 2014 of Guangzhou, China, and analyzed their replication efficiency and virulence in vitro and in vivo. The results suggested that among the five DENV1 strains, DENV1 B has the highest replication efficiency in both human and mosquito cells in vitro, also causes the highest mortality to suckling mice. Further study suggested that nonstructural proteins from DENV1B have higher capacity to suppress host interferon signaling. In addition, the NS2B3 protease from DENV1B has higher enzymatic activity compared with that from DENV1 E. Finally, we identified that the 64th amino acid of NS2A and the 55th amino acid of NS2B were two virulence determining sites for DENV1. This study provided new evidences of the molecular mechanisms of DENV virulence.

A murine model of dengue virus infection in suckling C57BL/6 and BALB/c mice

“…Conversely, other mouse models in immunocompetent suckling mice using i.c. inoculation of DENV have shown lower survival rates and have been used to study virulence of DENV strains or antiviral agents 54‐56 . Furthermore, immunocompromised suckling mouse models of DENV that used the s.c. or iv routes of infection have exhibited lower survival rates than our immunocompetent mouse model, mainly due to the lack of IFN‐I and/or IFN‐II signaling pathways or to the enhanced effect of maternal antibodies 38,39,57 …”

Molecular evolution of dengue virus types 1 and 4 in Korean travelers

“…Specific amino acid changes in DV proteins are closely associated with altered virulence. For instance, mutation of amino acids 124 and 128 of the E protein, amino acid 64 of NS2A, or amino acid 55 of NS2B can increases DV virulence [ 11 , 12 ].…”

“…Dengue has a wide spectrum of clinical severity, from asymptomatic through a self-limiting febrile illness (dengue fever) to life-threatening severe infections such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The mechanisms underlying severe dengue infections are not completely understood, but an antibody-dependent enhancement phenomenon and infection with particularly virulent virus strains are known to correlate with severe dengue infection [9][10][11]. Specific amino acid changes in DV proteins are closely associated with altered virulence.…”

Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections

“…The ability of DENV NS5 to bind and degrade human but not mouse STAT2 may be the major reason behind DENV's efficient replication in human but not in wild-type mouse cells [185]. Recently, increased virulence of different type 1 DENV isolates has been associated with a higher capacity of NS proteins to suppress IFN signaling [186]. Likewise, sfRNA of DENV strains that are associated with greater epidemic potential prevents the ubiquitination-dependent activation of RIG-I by binding to the ubiquitin ligase tripartite motif protein 25 (TRIM25), subverting the RIG-I pathway, and consequently impairing IFN-I induction [162].…”