Migratory phase of Litomosoides sigmodontis filarial infective larvae is associated with pathology and transient increase of S100A9 expressing neutrophils in the lung

Abstract

Filarial infections are tropical diseases caused by nematodes of the Onchocercidae family such as Mansonella perstans. The infective larvae (L3) are transmitted into the skin of vertebrate hosts by blood-feeding vectors. Many filarial species settle in the serous cavities including M. perstans in humans and L. sigmodontis, a well-established model of filariasis in mice. L. sigmodontis L3 migrate to the pleural cavity where they moult into L4 around day 9 and into male and female adult worms around day 30. Little is known of the early phase of the parasite life cycle, after the L3 is inoculated in the dermis by the vector and enters the afferent lymphatic vessels and before the moulting processes in the pleural cavity. Here we reveal a pulmonary phase associated with lung damage characterized by haemorrhages and granulomas suggesting L3 reach the lung via pulmonary capillaries and damage the endothelium and parenchyma by crossing them to enter the pleural cavity. This study also provides evidence for a transient inflammation in the lung characterized by a very early recruitment of neutrophils associated with high expression levels of S100A8 and S100A9 proteins.

Author summary

Mansonella perstans is a widespread human filarial parasite in Africa responsible for pleural and peritoneal cavity filariasis. Compared to other filarial parasites such as Wuchereria bancrofti, Brugia malayi, and Loa loa, the biology of M. perstans is poorly known. The blood-feeding vectors inject infective larvae (L3) into the host skin during a blood meal. Depending on the species, the L3 will then migrate to its specific site. In the murine model of filariasis Litomosoides sigmodontis L3 also reach the pleural cavity where they moult twice then mate and produce microfilariae. Migration patterns from the skin to the pleural cavity are partially known and involve a lymphatic phase. Here we present a sequential analysis of L3 infection from their inoculation to day 8 when they are settled in the pleural cavity, revealing the presence of L3 in the lung. Pulmonary damage including haemorrhages and granulomas is also observed suggesting that L3 could migrate to the pulmonary circulation and capillaries from where they could exit the lung to reach the pleural cavity. This induces a local inflammatory response characterized by neutrophil activation and upregulation.