Schistosomiasis is a devastating, potentially fatal tropical disease that affects hundreds of millions worldwide. In the absence of treatment, schistosome infections are chronic and persistent, often lasting for years or decades, resulting in significant and permanent damage to various organs, severe morbidity, and, in some cases, death. The disease is caused by parasitic flatworms of the genus Schistosoma. Though schistosomes do not replicate within the host, they produce hundreds or thousands of eggs each day. Those eggs that are not excreted remain within the host and evoke an immunopathological response that can lead to chronic disease. How the host immune system responds to schistosome infection determines in large part the balance between protective immunity (health) and immunopathology (morbidity). Several studies have shown that molecules excreted, secreted, or derived from both eggs and worms have potent immunomodulatory properties, but the underlying mechanisms by which these factors are presented to the host have remained elusive. Some of these molecules are potential substrates of ATP binding cassette (ABC) proteins. Members of the ABC superfamily of proteins are efflux transporters associated with the phenomenon of multidrug resistance. In addition to their roles in efflux of drugs and toxins, ABC transporters play critical roles in a wide variety of physiological processes including regulation of immune function. For example, they transport known immunomodulators with high affinity, are involved in antigen presentation, and have been implicated in modulation of immune functions such as T cell migration, T helper cell polarization, and dendritic cell maturation and migration. We hypothesize that schistosomes use a subset of their ABC transporters to mediate excretion, secretion, or presentation of parasite signaling molecules that shape host immune responses and influence pathology.
The specific aims of this project will focus on parasite egg-evoked host responses, testing this hypothesis both in vitro (Aim 1) and in vivo (Aim 2). These experiments will provide a unique opportunity to define basic molecular mechanisms underlying polarization of host T-cell responses. Preliminary results we have obtained support our hypothesis, and speak to the feasibility of the proposed experiments. This exploratory project provides a unique opportunity to define basic molecular mechanisms underlying parasite-host interactions, and also holds the promise of offering new therapeutic targets that can be exploited to reduce or eliminate disease pathology.
Schistosomes are parasitic flatworms that cause schistosomiasis, a devastating and neglected tropical disease that affects hundreds of millions of people worldwide. Schistosomes and other parasitic worms use various strategies to control how the host's immune system responds to the infection. We hypothesize that a certain set of parasite proteins that transport substances across cell membranes are involved in this modulation of host immunity. The experiments in this exploratory proposal will test this hypothesis, and could provide new therapeutic targets that could be exploited to reduce or eliminate disease pathology.
|Kasinathan, Ravi S; Sharma, Lalit Kumar; Cunningham, Charles et al. (2014) Inhibition or knockdown of ABC transporters enhances susceptibility of adult and juvenile schistosomes to Praziquantel. PLoS Negl Trop Dis 8:e3265|