A novel blood-feeding detoxification pathway in Nippostrongylus brasiliensis L3 reveals a potential checkpoint for arresting hookworm development

As part of on-going efforts to control hookworm infection, the “human hookworm vaccine initiative” has recognised blood feeding as a feasible therapeutic target for inducing immunity against hookworm infection. To this end, molecular approaches have been used to identify candidate targets, such as Necator americanus (Na) haemoglobinase aspartic protease-1 (APR-1), with immunogenicity profiled in canine and hamster models. We sought to accelerate the immune analysis of these identified therapeutic targets by developing an appropriate mouse model. Here we demonstrate that Nippostrongylus brasiliensis (Nb), a phylogenetically distant strongylid nematode of rodents, begins blood feeding early in its development and that immunisation with Na-APR-1 can block its growth and completion of its life cycle. Furthermore, we identify a new haem detoxification pathway in Nb required for blood feeding that can be blocked by drugs of the quinolone family, reducing both infection burden and the associated anaemia in rodents. Collectively, our findings show that haem metabolism has potential as a checkpoint for interrupting hookworm development in early stages of the hookworm life cycle and that the Nippostrongylus brasiliensis rodent model is relevant for identifying novel therapeutic targets against human hookworm.
Author summary Hookworm infections (Necator americanus or Ancylostoma duodenale) represent a major neglected tropical disease affecting approximately 450 million people worldwide and causing morbidity due to their need to feed on host blood resulting in severe anemia. New chemotherapy and vaccines are needed to combat hookworm infections. Using a rodent parasite model, we describe a new haem detoxification pathway that is a metabolic checkpoint for parasite development, survival and reproduction. This provides a starting point for the development of novel therapies against such metazoan blood-feeders.