Targeting the blood feeding pathway of the hookworm parasites
The academic research program within this laboratory is focused on gaining an improved understanding of how helminth parasites and commensal bacteria interact with the immune system both to provide the host with adequate protection against excessive colonisation with these organisms and to understand how their presence impacts on organ function, immune homeostasis and heterologous immune responses. We are routinely using two rodent models of hookworms, Nippostrongylus brasiliensis and Heligmosomoides polygyrus.
Hookworm infections, which cause severe anaemia, are considered to be one of the major neglected tropical diseases, affecting 700 million people worldwide. Despite important effort in the eradication of those helminths, current drugs are inefficient at sterilising the parasite. As a consequence, reinfections are common, thus allowing the infection to persist. The main pathology associated with hookworm infection is anaemia and is due to the chronic blood-feeding of the adult parasites throughout many years.
The overall goal of the project is to identify and validate new compounds that can be use as drugs for targeting the blood-feeding pathway of helminth parasites. We propose to use the rodent model Nippostrongylus brasiliensis, as this parasite recapitulates many of the characteristics of the major human blood-feeding helminth, the hookworms. It has recently been shown that N. brasiliensis is blood feeding and that targeting blood feeding by vaccination against this stage confers protection.
We have recently optimised a drug-screening assay using the parasite in a culture system with purified red blood cells to screen for new drugs affecting the worm viability during blood-feeding. Several interesting “natural compounds” candidates have been identified, some specific of the blood-feeding pathway, others capable of targeting the parasite viability through unknown mechanisms.
The project will consist in investigating those candidates in more details in other in vitro assays, notably with the adult stage of the parasite, as well as other related nematodes. Candidates than then pass this second screening phase will be further tested in vivo using rodent model of hookworm infections.
In parallel, using our already established assay, we will : i) validate candidate drugs from collaborators targeting Haemonchus contortus, a related sheep parasite. Those compounds have been identified using a traditional mobility assay and will now be subjected to our high-throughput viability assay ii) screen a more extensive drug library of small chemicals (14 000 compounds) to identify chemically optimisable drugs that target hookworm viability.
Keywords: helminth, drug targeting, blood-feeding, detoxification
Faculty of Medicine Nursing and Health Sciences - Immunology department
Monash in the Alfred’s campus