Neutropenic Mice Provide Insight into the Role of Skin-Infiltrating Neutrophils in the Host Protective Immunity against Filarial Infective Larvae

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.

IL-33/ST2 pathway regulates neutrophil migration and predicts outcome in patients with severe alcoholic hepatitis

“…The migration capacity of PMN was assessed ex vivo. [25][26][27] Briefly, after isolation of PMNs 1×10 6 Phagocytosis. The Phagotest (ref.…”

Human Leukocytes Kill Brugia malayi Microfilariae Independently of DNA-Based Extracellular Trap Release

“…Although NET formation was initially characterized in response to bacteria and protozoa [20, 27], it has also been reported for larger multi-cellular pathogens including fungi and three species of parasitic nematodes [19, 24, 25]. Our initial experiments co-culturing B .…”

“…They have previously been implicated in the killing of nematode larvae, including Onchocerca volvulus Mf and L3 [16, 17], and have been reported to be a key component of the host innate immune response to nematode infections [18]. For example, increased numbers of PMNs in the skin and blood of infected mice reduced the success of invading L3 of the filarial nematode, Litomosoides sigmodontis [19]. A characteristic feature of PMN responses is the production of DNA-containing neutrophil extracellular traps (NETs) [20].…”

NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae

“…A recent study by Pionnier et al . using neutropenic mice also suggested a protective role of neutrophils during the early stage of L. sigmodontis infection53. Wolbachia endosymbionts are known to induce neutrophil activation and accumulation as shown in the in vivo model for ocular onchocerciasis5455, in human onchocerciasis30 and in vitro in which neutrophils are directly activated by human filarial Wolbachia lipoproteins29.…”