Immunoregulatory Mechanisms in a Mouse Model of Hookworm Infection
- Author(s): Batugedara, Hashini Maneesha
- Advisor(s): Nair, Meera G
- et al.
Parasitic worms infect billions of people worldwide. In humans, these infections and inflammation are chronic and debilitating. Therefore, it is imperative to explore host factors that regulate immunity and promote parasite clearance and host protection. In this thesis we discuss two such host factors; resistin like molecules and endocannabinoids.
We describe here that during infection with the rodent hookworm Nippostrongylus brasiliensis (Nb), a host molecule named RELM alpha dampens Th2 inflammatory responses. We use bone marrow (BM) chimera technology to show that RELM alpha from BM-derived cells and not non BM cells dampens Th2 immunity and prevents worm clearance. We show that of the BM cells, CD11c+ lung macrophages are the dominant source of RELM alpha. Next, we employ a macrophage-worm co-culture system and found that RELM alpha impairs the ability of macrophages to attach to and kill worms. By conducting gene expression analysis, we show that RELM alpha decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage-mediated helminth killing.
Second, we explored how endocannabinoid signaling influences host immunity to helminths. Endocannabinoids are lipid-derived signaling molecules that function in feeding behavior and metabolism. Following Nb infection, we detected elevated levels of endocannabinoids 2-AG and AEA in the worm infected mouse lung and intestine. To test how endocannabinoids influence helminth infection, we utilized pharmacological inhibitors of cannabinoid receptors. We found inhibition of CB1R resulted in higher worm and eggs burdens which was correlated with decreased amounts of the Th2 cytokine IL-5 in the host. Interestingly, bioinformatic analysis revealed putative genes encoding endocannabinoid biosynthetic and degradative enzymes in many parasitic nematodes. Additionally, we found that all lifecycle stages of Nb produce endocannabinoids. Therefore, we report for the first time that helminth and host-derived endocannabinoids promote host immune responses and reduce parasite burden.
Collectively, these studies demonstrate two mechanisms of immunomodulation during helminth infection. In the first mechanism, BM-derived RELM alpha dampens immune responses and inhibits macrophage killing of worms. In the second mechanism, we describe how host and parasite-derived endocannabinoids promote host immunity by upregulating Th2 immunity which drives parasite clearance. In summary, we have identified key regulators of immune responses in helminth infection.