Dengue subgenomic flaviviral RNA disrupts immunity in mosquito salivary glands to increase virus transmission

PLoS Pathogens

Shelton S. Bradrick¹  Mariano A. Garcia-Blanco¹  Gayathri Manokaran¹  Eng Eong Ooi¹  Ruben Soto-Acosta²  Geok Kee Ng²  Julien Pompon²  Dorothée Missé²  Benjamin Wong²  Chao Shan²  Menchie Manuel³  Pei-Yong Shi³ 

[1] Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, United States of America;Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore;UMR IRD-CNRS MIVEGEC, IRD, Montpellier, France

关键词: Mosquitoes;    Salivary gl;    s;    3' UTR;    Blood;    Saliva;    Gene expression;    Dengue virus;    Immune response;   

DOI  :  10.1371/journal.ppat.1006535

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Globally re-emerging dengue viruses are transmitted from human-to-human by Aedes mosquitoes. While viral determinants of human pathogenicity have been defined, there is a lack of knowledge of how dengue viruses influence mosquito transmission. Identification of viral determinants of transmission can help identify isolates with high epidemiological potential. Additionally, mechanistic understanding of transmission will lead to better understanding of how dengue viruses harness evolution to cycle between the two hosts. Here, we identified viral determinants of transmission and characterized mechanisms that enhance production of infectious saliva by inhibiting immunity specifically in salivary glands. Combining oral infection of Aedes aegypti mosquitoes and reverse genetics, we identified two 3’ UTR substitutions in epidemic isolates that increased subgenomic flaviviral RNA (sfRNA) quantity, infectious particles in salivary glands and infection rate of saliva, which represents a measure of transmission. We also demonstrated that various 3’UTR modifications similarly affect sfRNA quantity in both whole mosquitoes and human cells, suggesting a shared determinism of sfRNA quantity. Furthermore, higher relative quantity of sfRNA in salivary glands compared to midgut and carcass pointed to sfRNA function in salivary glands. We showed that the Toll innate immune response was preferentially inhibited in salivary glands by viruses with the 3’UTR substitutions associated to high epidemiological fitness and high sfRNA quantity, pointing to a mechanism for higher saliva infection rate. By determining that sfRNA is an immune suppressor in a tissue relevant to mosquito transmission, we propose that 3’UTR/sfRNA sequence evolution shapes dengue epidemiology not only by influencing human pathogenicity but also by increasing mosquito transmission, thereby revealing a viral determinant of epidemiological fitness that is shared between the two hosts.

【 授权许可】

CC BY