IL-4/5 signalling plays an important role during Litomosoides sigmodontis infection, influencing both immune system regulation and tissue pathology in the thoracic cavity

Abstract

Approximately 100 million people suffer from filarial diseases including lymphatic filariasis (elephantiasis), onchocerciasis (river blindness) and loiasis. These diseases are amongst the most devastating of the neglected tropical diseases in terms of social and economic impact. Moreover, many infection-induced immune mechanisms in the host, their relationship to disease-related symptoms and the development of pathology within the site of infection remain unclear. To improve on current drug therapies or vaccines, further studies are necessary to decipher the mechanisms behind filaria-driven immune responses and pathology development, and thus the rodent model of Litomosoides sigmodontis can be used to unravel host-filaria interactions. Interestingly, BALB/c mice develop a patent state (release of microfilariae, the transmission life-stage, into the periphery) when exposed to L. sigmodontis. Thus, using this model, we determined levels of host inflammation and pathology development during a L. sigmodontis infection in vivo for the first known time. Our study reveals that after 30days p.i., inflammation and pathology began to develop in infected wild type BALB/c mice between the lung and diaphragm, close to the site of infection - the thoracic cavity. Interestingly, infected IL-4Rα/IL-5^-/- BALB/c mice had accentuated inflammation of the pleural lung and pleural diaphragm, and higher parasite burdens. Corresponding to the pleural inflammation, levels of IP-10, MIP-1α, MIP-1β, MIP-2 and RANTES were significantly elevated in the thoracic cavity fluid of infected IL-4Rα/IL-5^-/- mice compared with wild type controls. Moreover, upon L. sigmodontis antigen stimulation, IFN-γ and IL-17A secretions by cells isolated from draining lymph nodes of IL-4Rα/IL-5^-/- mice were significantly elevated, whereas secretion of IL-5, IL-13 and IL-10 was reduced. Elevated filaria-specific IFN-γ secretion was also observed in spleen-derived CD4⁺ T cell co-cultures from IL-4Rα/IL-5^-/- mice. In summary, this study unravels the essential role of IL-4/IL-5 signalling in controlling immunity against filarial infections and demonstrates the requirement of this pathway for the host to control ensuing pathology and inflammation.

Keywords: Diaphragm; IL-4Rα/IL-5(−/−); Immune regulation; Litomosoides sigmodontis; Lung; Pathology; Thoracic cavity.