Parasitic nematodes continue to cause significant morbidity and mortality in humans and animals on a global scale. Central to their virulence is the ability to infect specific tissues and to evade and/or subvert the host?s immune response. A better understanding of the molecules and pathways triggered by the nematode parasite that govern its survival and migration through the host could allow identification of new therapeutic targets for nematode infection. It is widely recognized that helminth immune modulation and the pathology they cause is largely effected through the release of proteins and small molecules that interact with host cells and tissues, and that these molecules are key factors in tissue tropism. Previous and current helminth secretome and excreted/secreted protein (ESP) studies have been done in vitro, due to the difficulty of obtaining large volumes of ESPs from small helminth parasites. However, there has been no rigorous validation that the in vitro induction of ESPs mimics in vivo conditions. Additionally, the effects of host immune pressure on expression of ESPs and other nematode genes are unknown. To fill these current gaps in knowledge, we propose to perform high resolution transcriptomic profiling at the single nematode level of Nippostrongylus brasiliensis throughout its life cycle in a genetically susceptible or resistant rodent host. We will profile the transcription of parasites as they transition from free-living to being actively parasitic, and as they infect the lung and the intestine. N. brasiliensis is in the order Strongylida, closely related to hookworm, and it shares many life cycle features with hookworm, such as skin penetration, infection of the lungs, and infection of the intestine. Data from this project will provide stage-specific gene signatures that are associated with the tissue tropism of hookworms and determine how they are influenced by host immune pressure. Our proposed study will test the assumption that i) intestinal nematodes initiate specific genetic programs and ESPs that determine tissue tropism; ii) the context of host immune pressure affects parasite transcriptional programs. Further, by comparing transcriptional profiles of nematodes under in vivo culture conditions and comparing them to nematodes under in vitro conditions, we can directly test the assumption that in vitro conditions mimic in vivo infection. Data generated will lay the foundation for future studies on helminth tissue tropism, ESPs, and immune-targeted helminth pathways.
Nematodes are extremely successful and devastating parasites of humans. Part of their success comes from their ability to infect specific host tissues and avoid or suppress the host immune system, which is facilitated in part by certain protein effectors that they secrete into their hosts. This research contributes to our understanding of the genes the nematodes use to infect specific tissues and to produce immune-modulating proteins.
