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

Julien Pompon, Menchie Manuel, Geok Kee Ng, Benjamin Wong, Chao Shan, Gayathri Manokaran, Ruben Soto-Acosta, Shelton Bradrick, Eng Eong Ooi, Dorothée Missé, Pei-Yong Shi, Mariano Garcia-Blanco

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1006535
JournalPLoS Pathogens
Volume13
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Dengue
Salivary Glands
Culicidae
Immunity
RNA
Viruses
Dengue Virus
Saliva
Aedes
Virulence
Infection
Reverse Genetics
3' Untranslated Regions
Cytomegalovirus
Innate Immunity
Epidemiology

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Dengue subgenomic flaviviral RNA disrupts immunity in mosquito salivary glands to increase virus transmission. / Pompon, Julien; Manuel, Menchie; Ng, Geok Kee; Wong, Benjamin; Shan, Chao; Manokaran, Gayathri; Soto-Acosta, Ruben; Bradrick, Shelton; Ooi, Eng Eong; Missé, Dorothée; Shi, Pei-Yong; Garcia-Blanco, Mariano.

In: PLoS Pathogens, Vol. 13, No. 7, e1006535, 01.07.2017.

Research output: Contribution to journalArticle

Pompon, J, Manuel, M, Ng, GK, Wong, B, Shan, C, Manokaran, G, Soto-Acosta, R, Bradrick, S, Ooi, EE, Missé, D, Shi, P-Y & Garcia-Blanco, M 2017, 'Dengue subgenomic flaviviral RNA disrupts immunity in mosquito salivary glands to increase virus transmission', PLoS Pathogens, vol. 13, no. 7, e1006535. https://doi.org/10.1371/journal.ppat.1006535
Pompon, Julien ; Manuel, Menchie ; Ng, Geok Kee ; Wong, Benjamin ; Shan, Chao ; Manokaran, Gayathri ; Soto-Acosta, Ruben ; Bradrick, Shelton ; Ooi, Eng Eong ; Missé, Dorothée ; Shi, Pei-Yong ; Garcia-Blanco, Mariano. / Dengue subgenomic flaviviral RNA disrupts immunity in mosquito salivary glands to increase virus transmission. In: PLoS Pathogens. 2017 ; Vol. 13, No. 7.
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