Parasitic nematodes are able to avoid and suppress the immune system of their hosts so successfully that more than 25% of the global population is infected by nematode parasites. Current strategies to control nematode infections are inadequate and increased drug resistance is a global concern. One strategy to reduce the prevalence of nematode infections is to prevent these parasites from suppressing host immunity, thus allowing the host's immune response to counter or eliminate infections. However, little is known about how nematode parasites avoid detection or how they suppress immunity. A growing body of research suggests that nematode fatty acid- and retinol-binding (FAR) proteins are involved in parasitism and help the parasites suppress immunity. The most successful and widely used drug to treat nematode infections, Ivermectin, has been show to bind directly to or interfere with the binding of nematode FAR proteins. Here I propose to: 1) identify the arsenal of FAR proteins that parasitic nematodes secrete into hosts, 2) determine the binding affinity and specificity of these FAR proteins to fatty acid immune signaling molecules, and 3) determine the effect of FAR proteins in an in vivo infection model. I will investigate the role of FAR proteins i nematode infections using the insect-parasitic nematode Steinernema carpocapsae and the model insect host Drosophila melanogaster. These models overcome technical obstacles associated with studying human parasites and have been successfully used to increase our understanding of vertebrate parasites and innate immunity. This K22 award will provide the experimental resources, time, and training to identify the FAR proteins used in parasitism and to determine their functional role in infection. Specifically, this award will allow me to develop 1) skills in the purification and identification of secreted proteins, 2) tools and expertise in the cloning and expression of transgenic proteins and, 3) generate novel and important data that will establish the foundation of a new research program. These studies address an understudied area in immunology: how parasitic nematodes suppress host immunity. Moreover, by exploiting the powerful fruit fly and insect-parasitic nematode model systems I will establish a unique set of tools to define the molecular underpinnings of immune suppression that can then be taken and tested in an appropriate vertebrate system and used to develop and test treatments that target these parasitic immune effectors.
Nematodes are extremely successful and devastating parasites of humans, infecting nearly two billion people worldwide. Part of their success is due to their ability to avoid and/or suppress the immune system of their hosts, which is facilitated in some measure by certain protein effectors that they secrete into their hosts. Understanding the identity, binding properties, and functional role of these proteins during infection is critical tothe development of better treatments and alleviating the suffering of those dealing with nematode infections.
