Dissertation Defense: Vanessa Angelova
Candidate: Vanessa Angelova
Major: Biology
Advisor: Steven Singer, Ph.D.
Intestinal Epithelial and Immune Host Receptors in Giardiasis
Giardia duodenalis is a common protozoan parasite in low- and middle-income countries. Infection is not associated with life-threatening diarrhea and is often subclinical. Regardless of the presence of symptoms, however, giardiasis is linked to growth stunting in children under age two. Both the growth challenges seen in children and the absence of severe gastrointestinal distress are not well understood. There is a limited number of studies considering potential host-pathogen receptors in giardiasis and none of them are driven by the interest in exploring these clinical observations. During my dissertation work, I focused on the roles of the protease-activated receptor 2 (PAR2) and the macrophage galactose-binding lectin 1 (MGL1) in responding to Giardia infections. PAR2 modulates tight junctions between intestinal epithelial cells, while MGL1 is an innate immune receptor involved in maintaining tolerance to the resident microbiome via the anti-inflammatory cytokine IL-10. Antagonists of PAR2 prevent the loss of barrier integrity seen during in vitro Giardia stimulations. In animals, loss of PAR2 similarly reduces (but does not eliminate) the growth challenges observed in recently weaned infected mice fed a low-protein diet.
Up to 40% of children with Giardia have persistent infections; we also see that the animals in the malnutrition model have delayed parasite clearance and upregulated IL-10. MGL1 activation and the resulting production of the anti-inflammatory cytokine IL-10 might have a role in reducing intestinal inflammation and allowing Giardia to persist in the host. In vitro, Giardia acts via MGL1 to synergize with lipopolysaccharide (LPS) in the production of IL-10 but not of the pro-inflammatory cytokine TNF-ɑ. The parasite’s modulation of the LPS immune response is significant both for parasite interactions with resident bacteria and in the context of co-infections. We show that Giardia is likely not signaling through a protein since the IL-10 potentiation is maintained after the parasite extract is heated. Ultimately, both PAR2 and MGL1 are novel receptors in the immune response to Giardia and future work will further explore the relevant ligands.