Insulin receptor knockdown blocks filarial parasite development and alters egg production in the southern house mosquito, Culex quinquefasciatus.

Andrew Bradley Nuss,Mark R Brown,Monika Gulia-Nuss,Upadhyayula Suryanarayana Murty,Joshua B Benoit

doi:10.1371/journal.pntd.0006413

Abstract

Lymphatic filariasis, commonly known as elephantiasis, is a painful and profoundly disfiguring disease. Wuchreria bancrofti (Wb) is responsible for >90% of infections and the remainder are caused by Brugia spp. Mosquitoes of the genera Culex (in urban and semi-urban areas), Anopheles (in rural areas of Africa and elsewhere), and Aedes (in Pacific islands) are the major vectors of W. bancrofti. A preventive chemotherapy called mass drug administration (MDA), including albendazole with ivermectin or diethylcarbamazine citrate (DEC) is used in endemic areas. Vector control strategies such as residual insecticide spraying and long-lasting insecticidal nets are supplemental to the core strategy of MDA to enhance elimination efforts. However, increasing insecticide resistance in mosquitoes and drug resistance in parasite limit the effectiveness of existing interventions, and new measures are needed for mosquito population control and disruption of mosquito-parasite interactions to reduce transmission. Mosquito insulin signaling regulates nutrient metabolism and has been implicated in reduced prevalence and intensity of malaria parasite, Plasmodium falciparum, infection in mosquitoes. Currently no data are available to assess how insulin signaling in mosquitoes affects the development of multi-cellular parasites, such as filarial nematodes. Here, we show that insulin receptor knockdown in blood fed C. quinquefasciatus, the major vector of Wb in India, completely blocks the development of filarial nematode parasite to the infective L3 stage, and results in decreased ecdysteroid production and trypsin activity leading to fewer mosquito eggs. These data indicate that a functional mosquito insulin receptor (IR) is necessary for filarial parasite development and mosquito reproduction. Therefore, insulin signaling may represent a new target for the development of vector control or parasite blocking strategies.

Highlights

Lymphatic filariasis (LF) is one of the neglected tropical diseases and a major cause of permanent and long-term disability worldwide
Lymphatic filariasis (LF) is caused by infection with nematodes of the family Filarioidea. 90% of infections are caused by Wuchereria bancrofti and the remainder by Brugia spp
The present data strongly supports our previous findings in a different mosquito species and further explores the role of mosquito insulin receptor in the development of the filarial nematode to the infective stage

Summary

Introduction

Lymphatic filariasis (LF) is one of the neglected tropical diseases and a major cause of permanent and long-term disability worldwide. The disease is caused by three species of nematode worms (filariae)–Wuchereria bancrofti (Wb), Brugia malayi, and Brugia timori, which are transmitted by several mosquito species within the genera Culex, Anopheles, Aedes, and Mansonia. The southern house mosquito, Culex quinquefasciatus, is the major vector of Wb in India. India constitutes approximately 45% of the world’s LF burden where ~550 million people are at risk of infection, with 59 million infected and of which 19.6 million exhibit filariasis symptoms [1,2]. An estimated 120 million people across 55 countries are infected with Wb, leading to a loss of 5.9 million disability-adjusted life-years [3]

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