Intestinal Helminth Infection Modulates the Immune Response to Airway Allergens

Abstract

Chronic diseases such as asthma have increased dramatically over the last century, coinciding with a decline in parasitic helminth infections. Allergic asthma is characterised by the expansion of type 2 immune cells, including the activation of group 2 innate lymphoid cells (ILC2). While helminth infections have been linked to lower incidence of allergic airway inflammation, the mechanisms underlying this protection remain incompletely understood. This thesis investigated whether chronic infection with the intestinal helminth <em>Trichuris muris</em> protects against allergic airway inflammation by inducing a metabolic restraint in lung ILC2s. Chronic <em>T. muris</em> infection significantly reduced ILC2 numbers, proliferation, and cytokine production in a model of murine asthma. ILC2s from <em>T. muris</em>-infected mice displayed impaired lipid metabolism, increased cellular ROS, reduced mitochondrial membrane potential, and a decreased NAD⁺/NADH ratio, corresponding with disrupted mitochondrial function and redox imbalance. Despite these metabolic impairments, the protein translation was preserved, suggesting metabolic dysfunction rather than complete metabolic shutdown. Protection from airway inflammation was associated with a type 1 skewed immune environment and elevated IFNγ levels. In vitro, IFN_γ promoted an enhanced oxidative intracellular environment in ILC2s, leading to impaired lipid metabolism and reduced mTOR signaling, effects that could be partially rescued by buffering reactive oxygen species using antioxidants NAC and GSH in vitro. Importantly, blocking local IFN_γ in vivo during <em>T. muris</em> and papain rescued the function and metabolic impairments in ILC2. Together, these findings demonstrate that chronic <em>T. muris</em> infection enforces a redox-linked metabolic restraint on pathogenic ILC2 through an IFN_γ dependent pathway.