Location: Animal Parasitic Diseases Laboratory
2020 Annual Report
Objectives
Objective 1. Determine the change in the intestinal metabolome and microbiome during parasitic nematode infection and after anti-parasitic clearance.
Sub-objective #1. Characterize parasite-induced molecular mechanisms that modulate intestinal inflammation.
Sub-objective #2. Evaluate the potential impact of Cry5B on the native and parasitized gut microbiome.
Objective 2. Identify pan-nematode secretome products with immune modulating activity that along with nutritional supplements eliminate parasites and enhance enteric health.
Sub-objective #1. Use antibodies from parasite infected pigs and goats to select for immunogenic cloned parasite products that have been computationally identified as vaccine targets.
Sub-objective #2: Test for cloned parasite products that induce innate immune responses at the mucosal surface of explanted intestinal tissues from pigs and goats.
Approach
Objective 1. Determine the change in the intestinal metabolome and microbiome during parasitic nematode infection and after anti-parasitic clearance.
Sub-objective #1. Characterize parasite-induced molecular mechanisms that modulate intestinal inflammation.
Hypothesis #1: Parasitic infections alter the relative abundance of butyrate-producing bacteria in the gut and change the composition and concentration of total short-chain fatty acids (SCFA) as well as anti-inflammatory butyrate, which in turn modulates intestinal inflammation and host immunity.
Sub-objective #2. Evaluate the potential impact of Cry5B on the native and parasitized gut microbiome.
Hypothesis #2: The administration of the Cry5B anthelmintic will have minimal effects on the native microbial community in the gut due to its transient nature and invertebrate gut targets.
Hypothesis #3: Parasite-induced changes in the microbiome will be restored to the native structure and function after treatment with Cry5B that reduces worm burden.
Experimental design: Quantifying changes in the intestinal metabolome and gut microbiome induced by parasitic infection, and characterizing the abilities of anti-parasitic treatments to restore altered gut microbiota, are important in dissecting mechanisms of host pathophysiology and immunity. We will conduct an in-depth comparison of the gut metabolome and microbiome between animals randomly assigned to two conditions (naive and infected) and exposed to Cry5B in an optimally determined delivery system.
Objective 2. Identify pan-nematode secretome products with immune modulating activity that along with nutritional supplements eliminate parasites and enhance enteric health.
Sub-objective #1. Use antibodies from parasite infected pigs and goats to select for immunogenic cloned parasite products that have been computationally identified as vaccine targets.
Hypothesis #1: Immunization of target host species with computationally selected immunogenic cloned parasite products will disrupt parasitism and prevent infections.
Sub-objective #2: Test for cloned parasite products that induce innate immune responses at the mucosal surface of explanted intestinal tissues from pigs and goats.
Hypothesis #2: Selected cloned immunogens that also have innate immune features defined by responses in intestinal explants will enhance vaccine efficacy and disrupt parasitism.
Experimental design:
Powerful new technologies to characterize the transcriptomes from multiple life stages of parasitic nematodes (Heizer et al., 2013) can be used to predict secreted peptides common to the pan-secretome. Combining this bioinformatics approach with antibody detection systems of immune peptides and innate responses of intestinal explanted tissues from pigs and goats will be used to identify vaccine candidates for immunization in the target host species of interest.
Progress Report
Related parasites in the genus Ascaris infect people and pigs. ARS scientists in Beltsville, Maryland, previously showed that these worms profoundly change the pig’s intestinal microbiome. The parasite decreases microbial diversity and disrupts microbial interactions. Host health may improve if parasitic cure restores microbiome composition and function. This question is easier to answer in pigs, in part because its parasite remains susceptible to the drug Fenbendazole. We therefore used pigs to examine how drug clearance influences microbial composition and function. A single therapeutic dose eliminated the roundworm and altered the microbiome. We are now evaluating how quickly and extensively microbial diversity and composition responds after clearing animals of worms using drugs. To do so, we are using metagenomic and untargeted metabolomic approaches, aided by advanced bioinformatic algorithms. This information may improve the health and well-being of pigs, and people, cured of their parasitic infections.
Accomplishments
1. Microbial signatures predictive anthelmintic efficacy in goats. Parasitic infections are the primary constraint for profitable animal production in small ruminants like goats. Resistance to drugs is growing at an alarming rate in the barber's pole worm. This harms the economies of many countries. ARS scientists in Beltsville, Maryland, developed a way to predict parasitic egg counts shed by Boer goats by determining the frequency of two families of gut bacteria. The discovery shows intimate interactions between parasites and bacteria in the goat gut. The insight should improve de-wormer strategies and promote goat health.
2. Ingesting krill oil dampens intestinal inflammation and promotes mucosal healing. Intestinal inflammation impairs livestock and human health worldwide. Available treatments are costly and may cause adverse effects. ARS scientists in Beltsville, Maryland, examined krill oil as a dietary supplement to reduce intestinal inflammation. They found that this natural product reduces colitis and improves the effect of omega three and astaxanthan in treating anti-inflammatory colitis induced by parasitic whipworms. Veterinarians and physicians can use the therapy to improve treatment of intestinal inflammation markedly.
3. New tools identify new anti-parasitic drugs. Industry requires better and less costly tools to identify anti-parasitic drugs. ARS scientists in Beltsville, Maryland, and academic collaborators therefore developed a better strategy. They integrated data from the intestinal tract of three unrelated parasitic nematodes and a fourth, non-parasitic nematode. They screened for compounds capable of inhibiting an important physiological process in a large roundworm (Ascaris suum), a filarial worm (Brugia pahangi), a whipworm (Trichuris muris), and a non-parasitic nematode (Caenorhabditis elegans). Several drugs acted against all three parasites. A pathologic profile was established for each inhibitor. New, broad-spectrum drugs may result, benefiting livestock and human health.
Review Publications
Liu, F., Xie, Y., Zajaz, A.M., Hu, Y., Aroian, R.V., Urban Jr, J.F., Li, R.W. 2020. Gut microbial signatures with predictive power for moxidectin treatment outcomes in. Journal of Parasitology. 242(2020):108607. https://doi.org/10.1016/j.vetmic.2020.108607.
Jarjour, N.N., Bradstreet, T.R., Schwarzkopf, E.A., Cook, M.E., Lai, C., Huang, S., Taneja, R., Stappenbeck, T.S., Urban Jr, J.F., Edelson, B.T. 2020. BBhlhe40 promotes TH2 cell-mediated anti-helminth immunity and reveals cooperative Csf2rb family cytokines. Journal of Immunology. 204(4):923-932. https://doi.org/10.4049/jimmunol.1900978.
Nagashima, H., Mahlakoiv, T., Shih, H., Davis, F.P., Meylan, F., Huang, Y., Harrison, O., Yao, C., Mikami, Y., Urban Jr, J.F., Caron, K., Belkaid, Y., Kanno, Y., Artis, D.C., O'Shea, J.J. 2019. Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation. Immunity. 51(4):682-695e6. https://doi.org/10.1016/j.immuni.2019.06.009.
Liu, F., Smith, A.D., Solano Aguilar, G., Wang, T.T., Pham, Q., Tang, Q., Urban Jr, J.F., Xue, C., Li, R.W. 2020. Mechanistic insights into the attenuation of intestinal inflammation and modulation of the gut microbiome by krill oil using in vitro and in vivo models. Microbiome. 8:83. https://doi.org/10.1186/s40168-020-00843-8.
Angelino, D., Carregora, D., Domenech-Coca, C., Savi, M., Figueira, I., Brindani, N., Jang, S., Lakshman, S., Molokin, A., Urban Jr, J.F., Davies, C.D., Britto, M.A., Kim, K.S., Brighenti, F., Curti, C., Blade, C., Del Bas, J.M., Stilli, D., Solano Aguilar, G., Nunes Del Santos, C., Del Rio, D., Mena, P. 2019. 5-(Hydroxyphenyl)-y-valerolactone-sulfate, a key microbial metabolite of flavan-3-ols, is able to reach the brain: evidence from different in silico, in vitro and in vivo experimental models. Nutrients. 11(11). pii: E2678. https://doi.org/10.3390/nu11112678.
Walker, M., Matthan, N., Goldbaum, A., Meng, H., Lamon-Fava, S., Lakshman, S., Jang, S., Molokin, A., Solano Aguilar, G., Urban Jr, J.F., Lichtenstein, A.H. 2019. Dietary patterns influence epicardial adipose tissue fatty acid composition and inflammatory gene expression in the Ossabaw pig. Journal of Nutritional Biochemistry. 70:138-146. https://doi.org/10.1016/j.jnutbio.2019.04.013.
Gao, Y., Yang, L., Chin, Y., Liu, F., Li, R.W., Cao, W., Yuan, S., Xue, C., Xu, J., Tang, Q. 2020. Astaxanthin n-octanoic acid diester ameliorated insulin resistance in high-fat and high-sucrose diet-fed mice by modulating the gut microbiome. Scientific Reports. 21:2149. https://doi.org/10.3390/ijms21062149.
Dawson, H.D., Chen, C.T., Li, R.W., Bell, N., Shea-Donohue, T., Kringel, H., Beshah, E., Hill, D.E., Urban Jr, J.F. 2020. Molecular and metabolomic changes in the proximal colon of pigs infected with Trichuris suis. Scientific Reports. 10, 12853. https://doi.org/10.1038/s41598-020-69462-5.
