Parasitic helminths exhibit the remarkable ability to establish chronic, often lifelong, infections by triggering multiple mechanisms to regulate the host immune response. In turn, the host induces a balanced immune response that mediates helminth killing while limiting tissue damage. In this multi-PI exploratory proposal, we identify the endocannabinoid (eCB) system as a previously unrecognized contributor to this dynamic host-helminth interaction. The lipid signaling molecules eCBs are the body?s natural cannabis-like molecules that regulate neural behaviors such as addiction and feeding. Receptors for eCBs are expressed throughout the body, including by immune cells, where eCB-mediated signaling can dampen inflammation. Following Nippostrongylus brasiliensis (Nb) infection as a mouse model of geohelminth infection, we observed significant eCB production and eCB receptor expression in the infected tissue that functionally impacted the host immune response and helminth egg burden. Moreover, we show that Nb produces eCBs at every life cycle stage, and identify putative genes for eCB synthetic and degradative enzymes in genome of Nb and parasitic nematodes that infect humans. Our central hypothesis is that eCBs mediate bi-directional communication between the host and helminth that dictates host physiology, immune response and helminth parasitism.
In Aim 1 we will investigate how helminth infection-induced endocannabinoids affect the host by (i) quantifying eCB levels and eCB signaling following Nb infection; (ii) abrogating eCB receptor signaling by pharmacologic reagents or eCBR deficient mice; (iii) integrating the datasets to identify functional interactions with statistical models.
In Aim 2 we will use molecular tools and high throughput microscopy to delineate the endocannabinoid pathway in the parasitic helminth. We will (i) evaluate Nb-derived eCBs and eCB signaling utilizing pharmacologic tools to promote or abrogate eCB signaling in Nb; and (ii) examine the role of eCBs in Nb-host immune cell interaction utilizing a novel co-culture system.
As a result of millions of years of co-evolution, helminths and their mammalian hosts have developed complex mechanisms of interaction for their own mutual benefit. Here, we identify the lipid signaling molecules, endocannabinoids, as previously unrecognized regulators of host immunity to intestinal helminth Nippostrongylus brasiliensis. In this exploratory proposal, we will elucidate the function of the endocannabinoid system utilizing pharmacologic inhibitors and endocannabinoid receptor deficient mice, which could reveal new therapeutic targets to treat helminth infection.
| Pine, Gabrielle M; Batugedara, Hashini M; Nair, Meera G (2018) Here, there and everywhere: Resistin-like molecules in infection, inflammation, and metabolic disorders. Cytokine 110:442-451 |
| Lainez, Nancy M; Jonak, Carrie R; Nair, Meera G et al. (2018) Diet-Induced Obesity Elicits Macrophage Infiltration and Reduction in Spine Density in the Hypothalami of Male but Not Female Mice. Front Immunol 9:1992 |
| Batugedara, Hashini M; Argueta, Donovan; Jang, Jessica C et al. (2018) Host- and Helminth-Derived Endocannabinoids That Have Effects on Host Immunity Are Generated during Infection. Infect Immun 86: |
