Lymphangiogenesis induced by microfilariae (tube-like structures) in vitro. Image courtesy of S. Bennuru, US National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.

Lymphatic filariasis, a disease caused by the nematodes Brugia malayi and Wuchereria bancrofti, leads to elephantiasis, which is the result of severe fluid retention and tissue swelling in the lymphatic system, where the nematodes reside. The signals that induce elephantiasis are unknown, but, writing in a recent issue of PLoS Pathogens, Bennuru and Nutman now show that filarial antigens can induce the proliferation of lymphatic endothelial cells (LECs).

“nematode factors are in part responsible for inducing the changes that are seen in the lymphatic system”

B. malayi and W. bancrofti replicate through a complicated life cycle that begins in humans with a bite from an infected mosquito, followed by growth of the nematode and its localization in the lymphatic system. Male and female nematodes then mate to produce microfilariae, which enter the blood stream and can be taken up by mosquitoes during a blood meal.

Bennuru and Nutman observed that exposure to antigens in soluble extracts from mature B. malayi nematodes induced proliferation of LECs. Similarly, serum from patients infected with filarial nematodes could induce proliferation of LECs, suggesting that the filarial antigens or the induced angiogenic factors were present in the blood. Furthermore, antigens and live nematodes could induce the formation of lymphatic tube-like structures by LECs in an in vitro assay. Microfilariae induced these tube-like structures more efficiently than adult nematodes, even when they were physically separated from the LECs by a filter.

To understand the host factors involved in the remodelling of infected tissues, the authors investigated the gene expression pattern that was induced in LECs by microfilariae. Two groups of genes stood out in this analysis, the first of which contained factors known to be involved in lymphangiogenesis, pointing to a possible mechanism by which the changes in the tissue take place. Looking in more detail at a subset of factors, the authors found that tissue inhibitor of metalloproteinases 1 (TIMP1) and TIMP2, which inhibit metalloproteases involved in tissue remodelling, were downregulated, whereas two of the proteases that they regulate, matrix metalloproteinase 1 (MMP1) and MMP2, were upregulated in response to nematode antigens. In addition, many genes involved in cell-to-cell contact at tight junctions and adherens junctions were upregulated. This possible increase in cell–cell adhesion was surprising, as the lymph system was previously thought to be more permeable after infection with a nematode. However, the authors found that nematode antigens decrease the permeability of LEC monolayers and can counteract the increase in permeability that is experimentally induced by interleukin-1α and tumour necrosis factor.

These data indicate that nematode factors are in part responsible for inducing the changes that are seen in the lymphatic system during filariasis. Uncovering the identity of these factors may allow for treatment of the currently irreversible, severe pathological consequences of lymphatic filariasis.