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Principal Investigator: Richard John Martin
Organization: IOWA STATE UNIVERSITY
Fiscal Year: 2023
Award: $469,119
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Filariases are a group of neglected tropical diseases produced by infection with microfilaria of Clade III
parasitic nematodes that are transmitted by biting insects. One example is the lymphatic filariasis
produced by Brugia malayi. Lymphatic filariasis is a debilitating and disfiguring disease which occurs in
120 million people worldwide. Other filarial diseases are River Blindness produced by Onchocerca
volvulus and loiasis produced by Loa loa. Prevention and treatment of these nematode parasite diseases
relies on the use of anthelmintic drugs because no effective vaccines are available. Prophylaxis using
Mass Drug Administration [MDA] programs are limited by the efficacy of existing anthelmintics.
Diethylcarbamazine is a mainstay for the treatment of lymphatic filariasis and loiasis in most parts of the
world, except in areas where onchocerciasis is present because it is contra-indicated by risks of blindness.
Diethylcarbamazine produces rapid clearance of microfilaria and causes ~40% mortality of adult parasites
(macrofilaricide). A number of studies have suggested that diethylcarbamazine has an indirect host-
mediated mode of action and that diethylcarbamazine acts by changing host arachidonic acid pathways.
We have observed that diethylcarbamazine has direct effects on filarial nematodes. We present
preliminary observations that show that diethylcarbamazine increases the opening of TRP-2 channels in
Brugia malayi, and opening of calcium-activated SLO-1 K channels. The effect is a rapid, transient
inhibition of motility followed by recovery: the response accommodates.
Emodepside is an emerging and important cyclooctadepsipeptide class of anthelmintic that also has
effects on microfilaria and adult filaria. Emodepside treatments could allow a major advance over existing
mass drug administration (MDA) programs which require regular treatments to kill adult parasites. One
of the sites of action of emodepside is on nematode SLO-1 K channels where opening of the channels
inhibits motility, but it is not effective against all filaria. Here we propose to compare effects on filarial SLO-
1 K channels from Brugia, Onchocerca and Loa and to examine actions and interactions of these two
drugs to explore their mode of action.
We have 3 aims:
Aim #1: Characterize, in vitro, the concentration motility-inhibition-response relationships of
diethylcarbamazine and emodepside and their combination on: A) Brugia microfilaria; B) Brugia
adult females; C) Brugia adult males.
We will test the hypothesis that effects of diethylcarbamazine
and emodepside are additive, synergistic or antagonistic and dependent of life-cycle stage and sex.
Aim #2 Characterize the SLO-1 K channel current responses to diethylcarbamazine and
emodepside in isolated Brugia malayi muscle flaps under patch-clamp
We will test the hypotheses:
a) that the effects of emodepside and diethylcarbamazine interact; b) that the interactions of
diethylcarbamazine and emodepside are dependent on the presence of TRP-2 by knockdown of TRP-2
channels; and c) that TRP-2 and SLO-1 channel message & channel opening accommodates during
prolonged exposure to diethylcarbamazine or emodepside.
Aim #3: Characterize the comparative molecular pharmacology of: a) different SLO-1 K channels
of Brugia malayi, Onchocerca volvulus and Loa loa and; b) TRP-2 channels of Brugia malayi and
Loa loa expressed in oocytes.
We will test the hypothesis that the pharmacology and potencies of
emodepside and diethylcarbamazine on SLO-1 K channels and TRP-2 channels of, Brugia, Onchocerca
and Loa are different and also different to a human channel homologue. We will examine channel
desensitization.
The proposal is innovative, using a combination of techniques to test the effects of diethylcarbamazine
and emodepside on their putative target sites, SLO-1 K channels of filarial. The overall impact of using
our mixture of techniques, will be discovery and comparison of effects of diethylcarbamazine and
emodepside on different species of filarial TRP-2 channels and SLO-1 K channels. Knowledge of the
molecular actions of these drugs is required for: a) molecular detection of sensitivity of different filarial
species and resistance; b) designing new drugs and combination therapies; c) predicting and
understanding sensitivities of different nematode parasite species; and d) predicting possible host toxicity.
Terms: <21+ years old><Adult><Adult Human><Adverse effects><African><Anthelmintics><Antihelminthic Agent><Antihelminthic Drugs><Arachidonic Acids><Area><Bancroftian Elephantiasis><Basic Research><Basic Science><Blindness><Brugia><Brugia malayi><Calcium><Carbamazine><Cell Locomotion><Cell Migration><Cell Movement><Cellular Migration><Cellular Motility><Combined Modality Therapy><Development><Diethylcarbamazine><Disease><Disorder><Disputes><Dopachrome isomerase><Drug Interactions><Drug Therapy><Drugs><Evolution><Exposure to><Eye><Eyeball><Female><Filarial Elephantiases><Filariasis><Filarioidea Infections><GeneHomolog><Homolog><Homologous Gene><Homologue><Human><In Situ><In Vitro><Infection><Insect Bites><Intestinal Volvulus><Intestine Volvulus><Ion Channel><Ionic Channels><K channel><Knowledge><Larva><Life Cycle><Life Cycle Stages><Loa><Loa loa><Loiasis><Lymphatic Filariasis><Mediating><Medication><Membrane Channels><Messenger RNA><Microfilaria><Modern Man><Molecular><Motility><Multimodal Therapy><Multimodal Treatment><Muscle><Muscle Tissue><Nematoda><Nematode infections><Nematodes><Ocular Onchocerciasis><Onchocerca><Onchocerca volvulus><Onchocerciasis><Oocytes><Ovocytes><Parasites><Parasitic nematode><Pathway interactions><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacology><Pharmacotherapy><Potassium Channel><Potassium Ion Channels><Prevention><Prophylactic treatment><Prophylaxis><RNA Splicing><Recovery><Research><Resistance><Risk><River Blindness><Services><Site><Splicing><TRP-2><Techniques><Testing><Toxic effect><Toxicities><Transmission><Tyrosinase-Related Protein-2><Variant><Variation><Vermifuges><Volvulus><access to vaccination><access to vaccines><adulthood><antihelminthic><cell motility><combination therapy><combined modality treatment><combined treatment><comparative><desensitization><design><designing><detection sensitivity><developmental><differential expression><differentially expressed><dopachrome conversion factor><dopachrome oxidoreductase><dopachrome tautomerase><drug action><drug treatment><drug/agent><filaria><filariae><filarial disease><filarial infection><gastrointestinal><human model><innovate><innovation><innovative><knock-down><knockdown><life course><mRNA><male><model of human><mortality><multi-modal therapy><multi-modal treatment><muscular><neglected tropical diseases><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><onchocercosis><parasitic roundworm><patch clamp><pathway><phase 2 trial><phase II trial><programs><resistant><response><roundworm><roundworm infection><sex><success><transcriptional differences><transmission process><vaccination access><vaccination availability><vaccine access><vaccine availability><vision loss><visual loss><volvulosis>