O papel dos receptores inatos NOD1 e NOD2 na imunopatologia da ascaridose larval

Abstract

Human ascariasis, caused by the nematode Ascaris lumbricoides, is one of the most common parasitic diseases in the world, with an estimate of approximately 445 million people infected in more than 150 countries, resulting in about 2089 deaths and loss of 753 thousand disability-adjusted life years (DALYs), annually. In the acute phase of infection, characterized by the hepato-tracheal larval migration, named larval ascariasis, a polarized innate pro-inflammatory response, with the participation of IL-6 and TNF-α, as well as type-2 cytokines, including IL-4, IL-5 and IL33, is typically associated with a robust pulmonary tissue inflammatory infiltrate composed of neutrophils, followed by eosinophils and mononuclear cells. However, the underlying immunological pathways associated with a protective immunity to control the infection remains less studied. Thus, this study aimed to investigate the pathophysiological and immunological mechanisms involved in the innate immunity of larval ascariasis in an experimental murine model. For this, mice genetically deficient for the innate NOD1 (NOD1-/-) and NOD2 (NOD2-/-) receptors were infected with 2,500 fully embryonated eggs of Ascaris suum, and the parasitological, immunological, and pathophysiological evaluation was performed at days 0 (uninfected control - NI), 4 post-infection (4dpi), 8dpi, and 12dpi, which correspond with the peak of parasite burden in the liver, lung, and intestine, respectively. A. suum infection in NOD1-/- mice was characterized by a diminished parasite burden in the lungs, with deficient production of key cytokines and chemokines in the lung tissue, including IFN-γ, IL-1β, IL-5, IL-10 and IL-17, with a consequent marked improvement of lung physiology. Interestingly, NOD2-/- mice showed also a decrease in lung burden, associated with an increased activity of eosinophils, neutrophils, and macrophages in the lungs. On the other hand, we observed a significant increase in the Ascaris larval burden in the intestine of NOD2-/- mice at day 12, promoting greater tissue damage in the organ and alteration of the intestinal barrier integrity, allowing bacterial translocation to the lung and mesenteric lymph nodes. In conclusion, we observed that NOD1 and NOD2 receptors play an important role in mediating inflammatory processes related to the response caused by the helminth to host mucosal immunity, with relevant implications in the control of the infection.