Abstract

Lymphatic filariasis is a major tropical disease caused by the parasite Brugia malayi. Microfilariae (Mf) circulate in the peripheral blood for 2–3 hours in synchronisation with maximal feeding of the mosquito vector. When absent from the peripheral blood, Mf sequester in the capillaries of the lungs. Mf are therefore in close contact with vascular endothelial cells (EC) and may induce EC immune function and/or wound repair mechanisms such as angiogenesis. In this study, Mf were co-cultured with human umbilical vein EC (HUVEC) or human lung microvascular EC (HLMVEC) and the transendothelial migration of leukocyte subsets was analysed. In addition, the protein and/or mRNA expression of chemokine, cytokine and angiogenic mediators in endothelial cells in the presence of live microfilariae were measured by a combination of cDNA arrays, protein arrays, ELISA and fluorescence antibody tests.Surprisingly, our findings indicate that Mf presence partially blocked transendothelial migration of monocytes and neutrophils, but not lymphocytes. However, Mf exposure did not result in altered vascular EC expression of key mediators of the tethering stage of extravasation, such as ICAM-1, VCAM-1 and various chemokines. To further analyse the immunological function of vascular EC in the presence of Mf, we measured the mRNA and/or protein expression of a number of pro-inflammatory mediators. We found that expression levels of the mediators tested were predominantly unaltered upon B. malayi Mf exposure. In addition, a comparison of angiogenic mediators induced by intact Mf and Wolbachia-depleted Mf revealed that even intact Mf induce the expression of remarkably few angiogenic mediators in vascular EC. Our study suggests that live microfilariae are remarkably inert in their induction and/or activation of vascular cells in their immediate local environment. Overall, this work presents important insights into the immunological function of the vascular endothelium during an infection with B. malayi.

Highlights

  • The filarial parasite Brugia malayi is a causative agent of human lymphatic filariasis in South and South-East Asia

  • While sequestered in the lungs, B. malayi microfilarial stage (Mf) are likely to interact with vascular endothelial cells (EC) and we have observed them binding to the surface of vascular EC

  • Since vascular EC are potent immune cells functioning in the production of both immune mediators and regulating the migration of immune cells from the blood into the tissue, we have established an in vitro model in which to test the effect of live Mf upon vascular EC function

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Summary

Introduction

B. malayi is transmitted by mosquitoes, which take up the blood-borne microfilarial stage (Mf) of the parasite. For the majority of the day, Mf sequester predominantly in the lungs of the host and they only appear in the peripheral blood circulation for a few hours, which coincides with maximal mosquito feeding [1,2]. While sequestered in the lungs, B. malayi Mf are likely to interact with vascular endothelial cells (EC) and we have observed them binding to the surface of vascular EC (manuscript in preparation). Helminths are potent modulators of the immune response and filarial nematodes, in particular, have been shown to influence the secretion of inflammatory mediators from a number of different cell types [3,4,5]. Vascular EC themselves can modulate the immune response by producing pro-inflammatory cytokines and chemokines, in addition to several angiogenic mediators. Vascular EC play a critical role in extravasation of leukocytes to the site of inflammation [6,7]

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