Host- and helminth-derived endocannabinoids that have effects on host immunity are generated during infection

Hashini M. Batugedara, Donovan Argueta, Jessica C. Jang, Dihong Lu, Marissa Macchietto, Jaspreet Kaur, Shaokui Ge, Adler R. Dillman, Nicholas V. DiPatrizio, Meera G. Nair

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Helminths have coevolved with their hosts, resulting in the development of specialized host immune mechanisms and parasite-specific regulatory products. Identification of new pathways that regulate helminth infection could provide a better understanding of host-helminth interaction and may identify new therapeutic targets for helminth infection. Here we identify the endocannabinoid system as a new mechanism that influences host immunity to helminths. Endocannabinoids are lipid-derived signaling molecules that control important physiologic processes, such as feeding behavior and metabolism. Following murine infection with Nippostrongylus brasiliensis, an intestinal nematode with a life cycle similar to that of hookworms, we observed increased levels of endocannabinoids (2-arachidonoylglycerol [2-AG] or anandamide [AEA]) and the endocannabinoid-like molecule oleoylethanolamine (OEA) in infected lung and intestine. To investigate endocannabinoid function in helminth infection, we employed pharmacological inhibitors of cannabinoid subtype receptors 1 and 2 (CB1R and CB2R). Compared to findings for vehicle-treated mice, inhibition of CB1R but not CB2R resulted in increased N. brasiliensis worm burden and egg output, associated with significantly decreased expression of the T helper type 2 cytokine interleukin 5 (IL-5) in intestinal tissue and splenocyte cultures. Strikingly, bioinformatic analysis of genomic and transcriptome sequencing (RNA-seq) data sets identified putative genes encoding endocannabinoid biosynthetic and degradative enzymes in many parasitic nematodes. To test the novel hypothesis that helminth parasites produce their own endocannabinoids, we measured endocannabinoid levels in N. brasiliensis by mass spectrometry and quantitative PCR and found that N. brasiliensis parasites produced endocannabinoids, especially at the infectious larval stage. To our knowledge, this is the first report of helminth- and host-derived endocannabinoids that promote host immune responses and reduce parasite burden.

Original languageEnglish (US)
Article numbere00441-18
JournalInfection and immunity
Volume86
Issue number11
DOIs
StatePublished - Nov 1 2018

Bibliographical note

Funding Information:
These studies were supported by the NIH (grants 1R01AI091759-01A1 and R21AI137830 to M.G.N., R00DA034009 to N.V.D., K22AI119155 to A.R.D., and R21AI135500 to M.G.N., N.V.D., and A.R.D.) and initial complement from the UCR School of Medicine (to M.G.N. and N.V.D.).

Keywords

  • Endocannabinoid
  • Gastrointestinal helminth
  • Nematode

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