Role of Complement in Dengue Virus Infection: Protection or Pathogenesis?

Dengue viruses (DENV) cause a spectrum of disease in humans, ranging from dengue fever (DF) to a severe, life-threatening syndrome called dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Despite the global morbidity and mortality associated with DENV infection, mechanisms of immune control and viral pathogenesis are poorly understood. In a recent article, Avirutnan et al. [mBio 2(6):e00276-11, 201122167226] demonstrated that DENV can be directly neutralized via the mannose binding lectin (MBL) pathway of the complement system and that deficiency in MBL level or activity due to host polymorphisms in the MBL2 gene correlates with reduced levels of DENV neutralization. These findings implicate a role for the MBL pathway in controlling DENV infections and modulating DHF/DSS manifestations

Enhanced Infection of Liver Sinusoidal Endothelial Cells in a Mouse Model of Antibody-Induced Severe Dengue Disease

SummaryDengue virus (DENV) causes disease ranging from dengue fever (DF), a self-limited febrile illness, to the potentially lethal dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). DHF/DSS usually occurs in patients who have acquired DENV-reactive antibodies prior to infection, either from a previous infection with a heterologous DENV serotype or from an immune mother. Hence, it has been hypothesized that subneutralizing levels of antibodies exacerbate disease, a phenomenon termed antibody-dependent enhancement (ADE). However, given the lack of suitable animal models for DENV infection, the mechanism of ADE and its contribution to pathology remain elusive. Here we demonstrate in mice that DENV-specific antibodies can sufficiently increase severity of disease so that a mostly nonlethal illness becomes a fatal disease resembling human DHF/DSS. Antibodies promote massive infection of liver sinusoidal endothelial cells (LSECs), resulting in increased systemic levels of virus. Thus, a subprotective humoral response may, under some circumstances, have pathological consequences