The Discovery of Novel Lipid and Protein Biomarkers of Lymphatic Filariasis

Lymphatic filariasis (LF), also known as elephantiasis, is a parasitic disease caused by three phylogenetically highly related nematode worms: Wuchereria bancrofti, Brugia malayi and Brugia timori. LF is considered a major threat to public health as its classified as one of the most debilitating neglected tropical diseases worldwide; an estimated 800 million people across 50 countries are at risk of contracting LF, an estimated 51 million people are infected whilst 40 million remain disfigured or disabled as a result.

To tackle LF as a public health concern, WHO launched the Global programme to Eliminate LF (GPELF). To date, they have achieved elimination in 18 countries and have reduced the number of global infections by 74%. In 2020, the GPELF set out to eliminate LF in at least 80% of countries using preventative chemotherapy (in the form of mass drug administration; MDA) as part of the new 2021-2030 NTD road map. To interrupt transmission, LF eradication programmes administer multiple rounds of MDA for an average of 5 years to the entire at-risk population. However, there are several limitations associated with current diagnostics that are hindering the NTD road map. These limitations include:
- The persistence of parasite-specific antibodies and antigens - current antibody and antigen biomarkers used in diagnostic tests, such as Alere filariasis test strip or the Bm14 rapid test, can persist for years after the initial infection. Since they cannot readily distinguish between active infections from resolved infections, it unnecessarily delays the decision to stop MDA.
- Insensitivity against early-stage infections- current tests are insensitive of not directed at larval-stage biomarkers which can delay the detection of recrudescence of infection, which is particularly important during the country's surveillance phase.
- Cross reactivity with Loa loa antigens - several L. loa antigens have been implicated in binding to LF-diagnostic monoclonal antibodies via shared carbohydrate epitopes. This cross reactivity is an impediment to the successful elimination of LF, particularly in loiasis-endemic regions.
Due to these limitations, there is an urgent need to discover new diagnostic biomarkers that can detect early-stage infections, differentiate between active and past infections, and avoid cross-reactivity with other filarial diseases such as loiasis.

Pathogen-specific lipids are an under-studied source for the identification of disease-related biomarkers. Although lipid biomarker discovery is new, it has been applied in the diagnosis of diseases of poverty such as malaria and tuberculosis. In terms of novel protein-based biomarkers, research has started to define the secretome of B. malayi, and recent studies have determined the nature of glycan moieties responsible for cross-reactivity issues in current diagnostics.
Therefore, the aim of this project is to address the issues faced in current diagnostics by discovering new lipid and protein biomarkers of LF.
The research questions to be answered throughout the 3-year project are:
1) Are unique lipid metabolites produced by lymphatic filarial parasites and can they be measured in the circulation of the host for the purposes of detecting active infections?
2) Will removal of glycosylated cross-reactive antigens reveal novel and specific LF secreted protein antigens for antibody detection development?