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.

Neutrophil–macrophage cooperation and its impact on tissue repair

“…The transcriptomic profiling of the pulmonary neutrophils after helminth infection was shown to be distinct from the transcriptional profile to those activated by lipopolysaccharide, with the upregulation of genes involved in collagen production, ECM pathways and chitin metabolism. Studies in the field of cancer research also support the idea that neutrophils can polarize into N1 or N2 subset, akin to M1 or M2 macrophage . The idea that heterogeneity among neutrophils exists is apparent by their morphological differences (including nuclear appearance and cell density) and surface receptor expression.…”

“…Studies in the field of cancer research also support the idea that neutrophils can polarize into N1 or N2 subset, akin to M1 or M2 macrophage. 61,62 The idea that heterogeneity among neutrophils exists is apparent by their morphological differences (including nuclear appearance and cell density) and surface receptor expression. Whether this heterogeneity simply reflects different maturation states-or whether it correlates with the polarization of neutrophils into N1 and N2 subtypes is unclear.…”

S100A8/S100A9 deficiency increases neutrophil activation and protective immune responses against invading infective L3 larvae of the filarial nematode Litomosoides sigmodontis

“…Recently, it was demonstrated that L. sigmodontis L3 larvae trigger the expression of S100A9 in neutrophils during their migration through the lung into the thoracic cavity [38]. In the present study we investigated the impact of calprotectin during L. sigmodontis infection in C57BL/6 mice lacking S100A9 and compared the worm burden and immune responses to C57BL/6 WT controls.…”

“…Mice were exposed simultaneously to the same batch of O. bacoti mites to ensure a comparable infection of both groups [47]. For subcutaneous or intravenous infections of mice, L3 larvae were isolated from mites [38] or 5 day-infected gerbils (Meriones unguiculatus) [55] and 40 L3 larvae were subcutaneously injected into the neck region or inguinal regions or intravenously into the caudal vein. Necropsy was performed on day 12 after L. sigmodontis infection using an overdose of Isoflurane (Forene) and worms were isolated from the thoracic cavity by lavage and quantified using a binocular microscope.…”

“…Through the bite of the tropical rat mite vector (Ornithonyssus bacoti), infective L. sigmodontis L3 larvae are transmitted into the murine host's skin and migrate via the lymphatic system, reaching the pulmonary blood circulation, transiting the lung and entering the thoracic cavity, where the filariae finally reside (2-6 days after infection (dpi) in BALB/c mice) [38]. Within the thoracic cavity, L3 larvae molt into L4 larvae stages (8-12dpi) and subsequently into adult worms (~30dpi).…”