UC Riverside

The role of endocannabinoids in regulating host-parasitic interactions, particularly in the lungs, has previously not been well-characterized. The murine-infecting model for human hookworm, N. brasiliensis, has a spike in endocannabinoid production during the infectious larval stage, indicating the potential role for these lipid-derived molecules in staging an infection. The rates of endocannabinoid production decreases when the nematode transitions to the mandatory lung-infectious stage. At the same time, endocannabinoids have been shown to have an ameliorating effect on the immune system in the gut of mammals. In this project, we use mice lacking the genes for the mammalian endocannabinoid receptors, Cnr1 (CB1KO) and Cnr2 (CB2KO), in order to isolate the role of endocannabinoid signaling in the lung immune response.

The first chapter focuses on a survey of the small excreted/ secreted molecules that are involved in host and parasite interactions. The second chapter focuses on the immune response to the pathogenic nematode, in which macrophages and eosinophils are co-cultured with live nematode larvae. We found that macrophages isolated from the N. brasiliensis-infected lungs of CB1KO mice, but not CB2KO mice, had increased Relmα expression, indicating an increase in macrophage alternative activation. Both lung macrophages and eosinophils from CB1KO mice exhibited excessive binding to N. brasiliensis larvae in co-culture. This indicates that endocannabinoid signaling is important for regulating the immune response to the nematode in the lung. This chapter informs the exploration of host-nematode interactions in vivo, in which CB1KO mice produced more eosinophils in response to a Nippo infection. The third chapter of this project employs a bioinformatics approach to explore the effect of the host immune system on the gene expression of the nematode. The fourth chapter summarizes these findings. This project implicates a role for the endocannabinoid system in regulating immune cell-helminth interactions in the lungs and is the premise for the exploration of endocannabinoids as a target to regulate the immune response to pulmonary helminth infection.