The PAGODAS protocol: pediatric assessment group of dengue and Aedes saliva protocol to investigate vector-borne determinants of Aedes-transmitted arboviral infections in Cambodia

Jessica E Manning ,Fabiano Oliveira ,Dara Kong ,Parker Ruhl ,Sokunthea Sreng ,Michael P Fay ,Soun Kimsan ,Shaden Kamhawi ,Daniel M Parker ,Somnang Man ,Thomas E Wellems ,Kimsour Nang ,Jesús G Valenzuela ,Hans Ackerman ,Sokha Ly ,Sreyngim Lay ,Seila Suon ,Rekol Huy ,Chanaki Amaratunga ,Rithea Leang

doi:10.1186/s13071-018-3224-7

Abstract

BackgroundMosquito-borne arboviruses, like dengue virus, continue to cause significant global morbidity and mortality, particularly in Southeast Asia. When the infectious mosquitoes probe into human skin for a blood meal, they deposit saliva containing a myriad of pharmacologically active compounds, some of which alter the immune response and influence host receptivity to infection, and consequently, the establishment of the virus. Previous reports have highlighted the complexity of mosquito vector-derived factors and immunity in the success of infection. Cumulative evidence from animal models and limited data from humans have identified various vector-derived components, including salivary components, that are co-delivered with the pathogen and play an important role in the dissemination of infection. Much about the roles and effects of these vector-derived factors remain to be discovered.Methods/DesignWe describe a longitudinal, pagoda (community)-based pediatric cohort study to evaluate the burden of dengue virus infection and document the immune responses to salivary proteins of Aedes aegypti, the mosquito vector of dengue, Zika, and chikungunya viruses. The study includes community-based seroprevalence assessments in the peri-urban town of Chbar Mon in Kampong Speu Province, Cambodia. The study aims to recruit 771 children between the ages of 2 and 9 years for a three year period of longitudinal follow-up, including twice per year (rainy and dry season) serosurveillance for dengue seroconversion and Ae. aegypti salivary gland homogenate antibody intensity determinations by ELISA assays. Diagnostic tests for acute dengue, Zika and chikungunya viral infections will be performed by RT-PCR.DiscussionThis study will serve as a foundation for further understanding of mosquito saliva immunity and its impact on Aedes-transmitted arboviral diseases endemic to Cambodia.Trial registrationNCT03534245 registered on 23 May 2018.

Highlights

Mosquito-borne arboviruses, like dengue virus, continue to cause significant global morbidity and mortality, in Southeast Asia
This study will serve as a foundation for further understanding of mosquito saliva immunity and its impact on Aedes-transmitted arboviral diseases endemic to Cambodia
Cambodia is rapidly changing and its urban population is projected to double in the decade [21]

Summary

Introduction

Mosquito-borne arboviruses, like dengue virus, continue to cause significant global morbidity and mortality, in Southeast Asia. Cumulative evidence from animal models and limited data from humans have identified various vector-derived components, including salivary components, that are co-delivered with the pathogen and play an important role in the dissemination of infection. Important Aedes mosquito-borne viruses such as chikungunya (CHIKV), yellow fever, dengue (DENV), and Zika (ZIKV) have re-emerged and caused public health alarm on a global scale [1,2,3]. Accumulating evidence in animal models suggest that mosquito saliva proteins (MSPs) increase the infectivity of these arboviruses [4,5,6,7,8,9,10]. Despite the evidence that mosquito saliva overall facilitates infection, relatively few proteins have been identified as immunomodulatory. Viral infection and dissemination differs between needle-inoculated versus arthropod-delivered infection models in mice, hamsters, beagles and primates [6, 7, 15, 16]

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