Differential Dengue Tropism & Neutralization: Potential Mechanisms of Pathogenesis.

摘要

The mechanisms underlying the pathogenesis of dengue hemorrhagic fever (DHF) remain poorly understood. Intriguing evidence suggest a role for viral strain differences. Consistent genetic differences exist in the envelope glycoproteins of dengue 2 strains associated with DHF epidemics (Asian genotype) and dengue 2 strains only associated with DF (American genotype). It has also been established that dengue virus infection can be mediated by C-type lectins DC-SIGN and L-SIGN. We developed an assay that uses cells expressing these relevant lectin receptors and low-passage viral isolates. Using this assay, we examined whether Asian and American genotype dengue 2 viruses exhibit differences in utilization of these two receptors. Our results showed that American strains infect DC-SIGN bearing cells to a greater extent than L-SIGN bearing cells while Asian strains preferentially infect L-SIGN bearing cells. A single mutation in the envelope glycoprotein of an American strain at E390 from aspartic acid (American) to asparagine converted the C-type lectin binding phenotype from an American strain to an Asian strain by the observation that the E390 amino acid (aa) in the Asian strain is also asparagine. Asian and American strains differed in their sensitivity to antibody neutralization. The neutralizing capacity of mAbs 3H5 and 4G2 for Asian virus was significantly decreased when infection was measured in L-SIGN bearing cells compared to DC- SIGN bearing cells. Serum from Venezuelan DF patients had much greater neutralizing capacity for Asian virus in L-SIGN cells than serum from patients who progressed to DHF. Magnitude of neutralization of L-SIGN-mediated Asian virus infection was inversely associated with disease severity. Our studies suggest that differences in receptor utilization and neutralization sensitivity may contribute to our understanding of the role that viral strain differences play in dengue pathogenesis.