Figure 8. Working hypothesis model.

Left: In a primary exposure to Ascaris parasites, after penetrating the intestine at the level of the cecum or proximal colon, the infective L3-stage larvae migrate through the portal vessels to the liver and subsequently to the lungs in their quest to reach the airways. Once in the lungs they migrate through the parenchyma, leading to a marked influx of neutrophils and correlated levels of IL-6, and penetrate into the alveolar spaces, causing bleeding and mechanical damage in the organ. These migrating Ascaris larvae, while growing in size toward the molting to L4 stages of biological development, induce a local inflammatory response in the lungs with a signature type 2 response, initially by early IL-5 levels, and later by IL-4 and IL-13 levels, culminating in the differentiation of M2 macrophages and eosinophilia in the tissue. However, this robust type 2 response is only fully mounted when most of the larvae have reached the airways, allowing the establishment of a chronic and long-standing infection. Right: HDM allergic sensitization prior to infection with Ascaris induces a robust Th2-dominated inflammatory response in the lung characterized by an increase in both IL-5/IL-13–producing type 2 innate lymphoid cells (ILC2s) and eosinophils. This allergen-driven inflammation in the lungs leads to an IL-4– and IL-13–rich environment that drives the differentiation of lung macrophages toward the M2 phenotype expressing arginase-1. When the Ascaris larvae migrate from the circulation to the lung tissue and airways in this HDM-sensitized environment, they encounter an eosinophil-dominated type 2 response, which leads to a 70% reduction in the number of lung-stage Ascaris larvae and a profound larval developmental arrest, allowing the reduction of intensity and burden of disease, inducing lower bleeding and mechanical damage in the tissue during their migration.