Caspase Dependent Programmed Cell Death in Developing Embryos: A Potential Target for Therapeutic Intervention against Pathogenic Nematodes

Pathogenic nematodes currently infect billions of people around the world and pose serious challenges to the economic welfare and public health in most developing countries. At present, limitations of existing therapies warrant identification of new anti-parasitic drugs/drug targets to effectively treat and control neglected tropical diseases [NTD] caused by nematode pathogens. The current gold standard for measuring/screening drug effectiveness against most helminth parasites is in-vitro assessment of motility of parasites/larvae and larval development assays which fails to provide any conclusive idea about the precise mechanism of death of parasitic worms or their larval stages. Given the huge load of parasites or their larval stages in an infected host, a compound which shows promise in in-vitro/motility screening assays but induces necrotic death in parasites/larvae will be of limited use, as it may elicit severe inflammatory response in infected hosts. In this context, the present study, which demonstrates induction of apoptotic death in developing embryos of a pathogenic nematode as a potential drug target for the first time, and provides scope for high throughput screening of pharmacological agents for their apoptogenicity against nematode embryos, is a step forward to develop novel anti-parasitic measures to challenge NTD caused by nematode pathogens

Anti-filarial immunity blocks parasite development and plays a protective role.

Lymphatic filariasis is a complex parasitic disease having a spectrum of clinical parameters which are critical in deciding the severity of the pathogenesis. Individuals residing in the endemic areas are categorized into different clinical groups such as: EC (endemic controls-free of disease and infection), AS (asymptomatic carriers- free of disease but carries both antigens and microfilaria (Mf) in circulation), CR (cryptic-free of disease and Mf but having circulatory antigen) and CH (chronic-having manifestations of elephantiasis and hydrocele). The immune response to the parasitic infection is well studied, whereas the protective mechanism explaining the fate of antigenemia and filaremia between AS and CR group remains unexplained. Increased anti-Mf antibodies have been implicated for Mf clearance in experimental infection models whereas its role in clinical filariasis is not known. Here, we followed up two groups of 24 and 33 CR cases for 18 and 36 months respectively and analyzed both the clinical parameters and the anti-filarial antibody response. The humoral response to both whole filarial antigen and Mf antigens as well as recombinant active parasitic antigens was significantly higher in CR cases than AS individuals, whereas the clinical parameters remain unchanged. This study made insights into the protective immune mechanism responsible for the clearance of Mf from circulation in CR individuals

Anti-sheath antibody between AS and CR cases.

<p>Anti-sheath antibody between AS and CR cases.</p

Profile of IgG and IgG subclasses against different filarial antigens.

<p>Plasma levels of IgG and IgG subclasses were analyzed by ELISA. IgG against whole somatic antigen of adult Setaria worm (A) and Setaria MF (B) were analyzed. IgG isotypes against somatic antigen of adult setaria worm were analysed (C). Mean of 30 and 31 samples were shown.</p

Comparison of CFA between AS and CR cases.

<p>CFA levels of 30 asymptomatic Mf carriers and 31 cryptic individuals were taken in to consideration for comparison. They are age sex matched and other parameters has been taken care as narrated in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199090#pone.0199090.t002" target="_blank">Table 2</a>.</p

Mf status of cryptic individuals followed up for 18 and 36 months in village Kanapur and Jatni.

<p>Mf status of cryptic individuals followed up for 18 and 36 months in village Kanapur and Jatni.</p