Mosquito Saliva Increases Endothelial Permeability in the Skin, Immune Cell Migration, and Dengue Pathogenesis during Antibody-Dependent Enhancement

Schmid MA, Glasner DR, Shah S, Michlmayr D, Kramer LD, Harris E.

PLoS Pathog. 2016 Jun 16; 12(6): e1005676.

Speaker: Martyr Yang （楊俊常）                                             Time: 14:00~15:00, May 15, 2017

Commentator: Dr. Oscar Guey-Chuen Perng (彭貴春教授)       Venue: Room 601

Abstract:

Dengue virus (DENV) is a positive-sense, single-stranded RNA virus with four serotypes (DENV1-4), which infects about 390 million people per year. Usually the primary (1°) DENV infection causes dengue fever or subclinical disease, and individuals generate memory immune responses that protect against infection with the same DENV serotype. During secondary infection, antibodies that were generated during the 1° infection cross-react with the next infecting DENV serotype do not neutralize but instead enhance infection of Fcγ receptor-bearing cells, such as macrophages; this phenomenon is known as antibody-dependent enhancement (ADE) ^[1]. While probing for blood vessels, Aedes mosquito inject virus-containing saliva into the skin ^[2], but the role of mosquito saliva in dengue pathogenesis is not well understood. In this study, the authors examined the impact of Ae. aegypti salivary gland extract (SGE) on dengue pathogenesis, the host response, and DENV infection in the skin using mice lacking the interferon-α/β receptor (Ifnar^–/–). Inoculating Ifnar^–/– mice intradermally with DENV revealed that SGE exacerbates dengue pathogenesis specifically in the presence of enhancing serotype-cross-reactive antibodies. Furthermore, SGE increases viral titers in the skin, boosts antibody-enhanced DENV infection of dendritic cells (DCs) and macrophages in the dermis, and amplifies DCs migration to skin-draining lymph nodes. In addition, SGE increases endothelial permeability in vitro and induces vascular leak in the skin. Finally, removing the site of DENV infection in the ear after 4 hours rescued mice from severe disease in the absence of SGE, but this rescue was lost when SGE was present. Overall, these results indicate that SGE accelerates the dynamics of dengue pathogenesis after virus transmission in the skin and induces severe antibody-enhanced disease systemically.

References:

1)    Guzman MG, Alvarez M, Halstead SB (2013). Secondary infection as a risk factor for dengue hemorrhagic fever/dengue shock syndrome: an historical perspective and role of antibody-dependent enhancement of infection. Arch Virol 158: 1445–1459.

2)    Ribeiro JM, Francischetti IM (2003). Role of arthropod saliva in blood feeding: sialome and post-sialome perspectives. Annu Rev Entomol 48: 73–88.