Abstract
Our knowledge and control of the pathogenesis induced by the filariae remain limited due to experimental obstacles presented by parasitic nematode biology and the lack of selective prophylactic or curative drugs. Here we thought to investigate the role of neutrophils in the host innate immune response to the infection caused by the Litomosoides sigmodontis murine model of human filariasis using mice harboring a gain-of-function mutation of the chemokine receptor CXCR4 and characterized by a profound blood neutropenia (Cxcr4+/1013). We provided manifold evidence emphasizing the major role of neutrophils in the control of the early stages of infection occurring in the skin. Firstly, we uncovered that the filarial parasitic success was dramatically decreased in Cxcr4+/1013 mice upon subcutaneous delivery of the infective stages of filariae (infective larvae, L3). This protection was linked to a larger number of neutrophils constitutively present in the skin of the mutant mice herein characterized as compared to wild type (wt) mice. Indeed, the parasitic success in Cxcr4+/1013 mice was normalized either upon depleting neutrophils, including the pool in the skin, or bypassing the skin via the intravenous infection of L3. Second, extending these observations to wt mice we found that subcutaneous delivery of L3 elicited an increase of neutrophils in the skin. Finally, living L3 larvae were able to promote in both wt and mutant mice, an oxidative burst response and the release of neutrophil extracellular traps (NET). This response of neutrophils, which is adapted to the large size of the L3 infective stages, likely directly contributes to the anti-parasitic strategies implemented by the host. Collectively, our results are demonstrating the contribution of neutrophils in early anti-filarial host responses through their capacity to undertake different anti-filarial strategies such as oxidative burst, degranulation and NETosis.
Highlights
Filarial nematodes constitute a large group of human pathogens (i.e. Onchocerca volvulus, Brugia malayi, Brugia timori, Wuchereria bancrofti, Loa loa, Mansonella spp.) infecting around 150 million people throughout the tropics with more than 1.5 billion at risk of infection
Filariases are chronic debilitating diseases caused by parasitic nematodes affecting more than 150 million people worldwide
In the present study we investigated the early interaction between the host and the L. sigmodontis murine filariasis with a focus on the neutrophils in the innate host responses
Summary
Filarial nematodes constitute a large group of human pathogens (i.e. Onchocerca volvulus, Brugia malayi, Brugia timori, Wuchereria bancrofti, Loa loa, Mansonella spp.) infecting around 150 million people throughout the tropics with more than 1.5 billion at risk of infection. Stages of infection are common to filarial nematodes with the infective stages of filariae (L3) being delivered in the skin of the host by blood feeding arthropods [2] Later in their life cycle, depending on the filarial species, adult stages settle in their preferred tissues for maturation/reproduction/release of microfilariae, strongly suggesting different migration paths for the larvae. Neutrophils were reported to contribute to macrophage-dependent resistance mechanisms against Strongyloides stercoralis and macrophages-dependent resolution of tissue damage induced by Nippostrongylus brasiliensis [21,22,23] Along with their essential role in responses to microbial pathogens, neutrophil activation and recruitment could be attributed to the endobacteria Wolbachia harbored by some filarial parasites [24,25,26]. The resistance mechanisms of the host in early defense against L3 target these symbionts [26, 27]
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