Abstract
Rapid and accurate prevalence mapping of lymphatic filariasis (LF) is necessary to eliminate this disfiguring and disabling neglected tropical disease. Unfortunately, rapid tests such as the filariasis test strip (FTS) for Wuchereria bancrofti, the causative agent of LF in Africa, can cross-react with antigens circulating in some persons infected by the African eye worm, Loa loa, rendering the test unreliable in eleven co-endemic nations. The intended target of the FTS is a heavily glycosylated W. bancrofti circulating filarial antigen (Wb-CFA). Previously, we determined that the FTS monoclonal antibody, AD12.1, which detects a carbohydrate epitope on Wb-CFA, also detects multiple L. loa proteins in cross-reactive sera from persons with loiasis. Since the carbohydrate epitope recognized by AD12.1 is present on glycoproteins of other parasitic nematodes, including Brugia species, it is unclear why reactive glycoproteins are not detected in infections with other filarial parasites. To gain a better understanding of the proteins recognized by the FTS diagnostic antibody, we used proteomics and lectin array technology to characterize filarial glycoproteins that are bound by the AD12.1 antibody using Brugia malayi as a model. Distinct but overlapping sets of AD12 glycoproteins were identified from somatic and excretory/secretory worm products. One of the identified proteins, Bm18019 was confirmed as a secreted AD12-reactive glycoprotein by in-gel proteomics and immunoassays. Based on lectin binding patterns, Brugia AD12-reactive glycoproteins express glycans including core fucose, galactose, N-acetylglucosamine and galactose (β1-3)N-acetylgalactosamine in addition to the epitope recognized by AD12.1. None of the lectins that bound B. malayi AD12 glycoproteins had affinity for the Wb-CFA, highlighting a key difference between it and other AD12 glycoproteins. B. malayi somatic and excretory/secretory proteins are similar to L. loa antigens found in FTS-positive human sera, bolstering the hypothesis that circulating L. loa AD12 antigens result from worm tissue damage or death. The difference in glycan and protein composition between the Wb-CFA and other AD12 glycoproteins can be used to differentiate LF from cross-reactive loiasis.
Highlights
Filarial parasites are insect-borne, tissue-dwelling, parasitic nematodes that cause debilitating diseases such as lymphatic filariasis (LF, caused by Wuchereria bancrofti, Brugia malayi and Brugia timori), onchocerciasis, and loiasis
It is well established that sera from persons with Bancroftian filariasis have a single circulating filarial antigen, the W. bancrofti circulating filarial antigen (Wb-CFA), which is ~250 kDa in size and is abundantly decorated with the AD12 epitope” (AD12e) glycan epitope (Figure 1A)
AD12e was detected on multiple antigens of varying molecular weights in extracts from several filarial and non-filarial nematodes, but not in the trematode Paragonimus westermani (Figure 1B)
Summary
Filarial parasites are insect-borne, tissue-dwelling, parasitic nematodes that cause debilitating diseases such as lymphatic filariasis (LF, caused by Wuchereria bancrofti, Brugia malayi and Brugia timori), onchocerciasis (by Onchocerca volvulus), and loiasis (by Loa loa). Rapid diagnostic tests for Bancroftian filariasis (LF-RDT) recognize a carbohydrate epitope expressed on a high molecular weight circulating filarial antigen from W. bancrofti (Wb-CFA). We refer to this carbohydrate as the “AD12 epitope” (AD12e) based on its recognition by two monoclonal antibodies AD12.1 and DH6.5 [6]. Rapid and accurate prevalence mapping of lymphatic filariasis (LF) is necessary to eliminate this disfiguring and disabling neglected tropical disease Rapid tests such as the filariasis test strip (FTS) for Wuchereria bancrofti, the causative agent of LF in Africa, can cross-react with antigens circulating in some persons infected by the African eye worm, Loa loa, rendering the test unreliable in eleven co-endemic nations. Since the carbohydrate epitope recognized by AD12.1 is present on glycoproteins of other parasitic nematodes, including Brugia species, it is unclear why reactive glycoproteins are not detected in infections with other filarial parasites
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