Location: Animal Parasitic Diseases Laboratory2013 Annual Report
1a. Objectives (from AD-416):
Objective 1: Determine the immune relationship between parasites and the mucosal immune response concentrating on epigenetic targets and the innate immune system. The goal of the proposed research project is to evaluate the influence of parasitic infection during gestation and in the pre-weaning period on mucosal macrophages and to explore dietary effects that regulate mucosal immune responses in pigs. Objective 2: Evaluate the ability of nutritional supplements and pathogen-associated molecules in modulating the immune response. Macrophages and related dendritic cells at mucosal surfaces provide the first line of defense as they respond to pathogen-associated molecular pattern (PAMP) molecules that bind toll-like receptors (TLRs) and trigger innate immune responses that link them to components of acquired immunity. They also respond to danger-associated molecular pattern (DAMP) molecules that trigger responses to cell injury and inflammation. The inherent potential of molecules from the parasite to modulate immune function to secure the parasitic relationship with the host may be met by nutritional conditions that influence host immunity. This objective will begin to evaluate these features of macrophage biology as they contribute to resistance to parasitic infection and the influence of nutrients on this process.
1b. Approach (from AD-416):
The approach for Objective 1 is to determine the immune relationship between parasites and the mucosal immune response concentrating on epigenetic targets and the innate immune system. Stimulation of primary pig alveolar macrophages (AM) by all-trans retinoic acid (ATRA), parasites, or parasite-derived products in vitro will provide information on transcriptomic markers and epigenetic sites to evaluate in later in vivo-treatment studies of pigs given ATRA and infected with Ascaris suum. Exposure of sows during gestation and neonates during the first 21 days of life to ATRA or infection with A. suum will polarize pig AM and imprint epigenetic traits that influence functional activity at mucosal surfaces. The approach used for Objective 2 is to evaluate the ability of nutritional supplements and pathogen-associated molecules in modulating the immune response. The aim is to identify parasite-derived nucleotide metabolizing enzymes, and in particular apyrases, that may control local inflammatory responses by modulating ATP levels in surrounding tissues. The AM will be used as a functional readout cell for parasite products and metabolites derived from parasite enzymatic activity. ATRA acting as a supplemental nutrient in the presence of adenosine will modulate adenosine receptor signaling of primary pig AM leading to synergistic effects on macrophage function, cytokine production, and gene expression. The study is designed to determine if ATRA co-stimulation with adenosine alters pig AM function in vitro.
3. Progress Report:
Ascaris suum is a widespread and prevalent parasite of pigs, and is closely related to Ascaris lumbricoides, which infects nearly 1/3 of the global human population. These parasites are highly capable of adapting to, and modifying, their host environments. Their ability to persist in pigs and people depends, in part, on being able to degrade excreted products that would otherwise provoke strong innate and acquired immune responses. Nucleotide metabolizing enzymes comprise one class of molecules that enables such parasites to blunt host immunity. These enzymes are generally secreted into the surrounding space and, by degrading interstitial nucleotides, prevent initiation of the innate immune response. ARS researchers at the Beltsville Agricultural Research Center and the Beltsville Human Nutrition Center cloned and expressed the gene encoding this enzyme and showed it to be biologically functional. The protein specifically degrades those nucleotides that would otherwise initiate stress responses. The team identified the active site within the enzyme by demonstrating that changes to it abrogated enzymatic function. Establishing the biological function and mechanistic basis for this enzyme’s action lays the groundwork for vaccines that might substantially limit the damage incurred by these prevalent and damaging parasites to veterinary and human health.
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