Giardia intestinalisreshapes mucosal immunity toward a Type 2 response that attenuates inflammatory bowel-like diseases

Abstract

ABSTRACTDiarrheal diseases are the second leading cause of death in children worldwide. Epidemiological studies show that co-infection withGiardia intestinalisdecreases the severity of diarrhea. Here, we show thatGiardiais highly prevalent in the stools of asymptomatic school-aged children. It orchestrates a Th2 mucosal immune response, characterized by increased antigen-specific Th2 cells, IL-25, Type 2-associated cytokines, and goblet cell hyperplasia.Giardiainfection expanded IL-10-producing Th2 and GATA3+Treg cells that promoted chronic carriage, parasite transmission, and conferred protection againstToxoplasma gondii-induced lethal ileitis and DSS-driven colitis by downregulating proinflammatory cytokines, decreasing Th1/Th17 cell frequency, and preventing collateral tissue damage. Protection was dependent on STAT6 signaling, asGiardia-infected STAT6-/-mice no longer regulated intestinal bystander inflammation. Our findings demonstrate thatGiardiainfection reshapes mucosal immunity toward a Type 2 response, which confers a mutualistic protection against inflammatory disease processes and identifies a critical role for protists in regulating mucosal defenses.