Malaria transmission blocking through mosquito contact with treated surfaces

PROJECT ABSTRACT
Malaria parasites are transmitted by the bite of female Anopheles mosquitoes. Current malaria
control strategies rely extensively on the use of antimalarial drugs as human therapeutics, and on
long-lasting insecticide-treated bed nets (LLINs) and insecticide indoor residual sprays of house
walls (IRS) to target the Anopheles mosquito. LLINs and IRS play a key role in malaria prevention,
accounting for more than 70% of all cases prevented in the last two decades. However, these
interventions suffer from the alarming spread of insecticide resistance emerging in most Anopheles
populations in sub-Saharan Africa, which threatens their effectiveness. Combined with the emergence of
drug resistance in Plasmodium parasites, these issues stress the need for new tools to prevent malaria
transmission. In a recent study we have built the foundation for a novel malaria control strategy based on
combining antimalarials with mosquito-targeting interventions. Our idea proposes to incorporate antimalarials
on mosquito nets or other surfaces such as walls, so that female Anopheles landing on these surfaces will
uptake the antimalarial compounds via their legs the way they generally uptake insecticides on LLINs or IRS.
As a proof of principle, we coated a glass substrate with the potent antimalarial atovaquone (ATQ), a
cytochrome b inhibitor, and allowed Anopheles gambiae females to rest on this surface for a few minutes
immediately prior to P. falciparum infection. Strikingly, P. falciparum development was completely
abrogated in females exposed to low concentrations of ATQ (EC50 = 1.77 µmol/m2). Parasite
development was also completely aborted when mosquitoes were exposed to ATQ 24 hours prior to or
12 hours post infection, and when ATQ was deposited on a net substrate, demonstrating the broad
potential of this approach. Other cytochrome b inhibitors showed similar effects. In this project, we will
validate the use of antimalarials to kill P. falciparum in the Anopheles female. Specifically, we will: Aim 1)
screen a library of antimalarials to identify additional compounds that kill P. falciparum upon uptake by
the mosquito, in collaboration with Medicine for Malaria Venture (MMV), the Malaria Drug Accelerator
(MalDA) and others; Aim 2) determine the ability of ATQ and hit compounds from our screens to kill drug-
resistant P. falciparum parasites, in collaboration with MalDA and Dyann Wirth at the Harvard Chan
School; and Aim 3) assess whether insecticide resistance mechanisms operating in the mosquito affect
uptake and efficacy of ATQ, in collaboration with the Institut de Recherche pour le Développement (IRD,
Burkina Faso) and the Liverpool School of Tropical Medicine. By combining compound screens with
laboratory and field analyses, our project will validate the use of compounds with antimalarial activity in the
mosquito vector, aiding in the generation of an innovative malaria control tool.

Grant Number: 5R01AI148646-05
NIH Institute/Center: NIH
Principal Investigator: Flaminia Catteruccia