Filariasis research – from basic research to drug development and novel diagnostics, over a decade of research at the Institute for Medical Microbiology, Immunology and Parasitology, Bonn, Germany

Abstract

Filariae are vector borne parasitic nematodes, endemic in tropical and subtropical regions causing avoidable infections ranging from asymptomatic to stigmatizing and disfiguring disease. The filarial species that are the major focus of our institution’s research are Onchocerca volvulus causing onchocerciasis (river blindness), Wuchereria bancrofti and Brugia spp. causing lymphatic filariasis (elephantiasis), Loa loa causing loiasis (African eye worm), and Mansonella spp. causing mansonellosis. This paper aims to showcase the contribution of our institution and our collaborating partners to filarial research and covers more than two decades of research spanning basic research using the Litomosoides sigmodontis animal model to development of drugs and novel diagnostics. Research with the L. sigmodontis model has been extensively useful in elucidating protective immune responses against filariae as well as in identifying the mechanisms of filarial immunomodulation during metabolic, autoimmune and infectious diseases. The Institute for Medical Microbiology, Immunology and Parasitology (IMMIP), University Hospital Bonn (UKB), Bonn, Germany has also been actively involved in translational research in contributing to the identification of new drug targets and pre-clinical drug research with successful and ongoing partnership with sub-Saharan Africa, mainly Ghana (the Kumasi Centre for Collaborative Research (KCCR)), Cameroon (University of Buea (UB)) and Togo (Laboratoire de Microbiologie et de Contrôle de Qualité des Denrées Alimentaires (LAMICODA)), Asia and industry partners. Further, in the direction of developing novel diagnostics that are sensitive, time, and labour saving, we have developed sensitive qPCRs as well as LAMP assays and are currently working on artificial intelligence based histology analysis for onchocerciasis. The article also highlights our ongoing research and the need for novel animal models and new drug targets.

Comparative development of human filariae Loa loa, Onchocerca volvulus and Mansonella perstans in immunocompromised mouse strains

“…Research about human filarial infections is often hindered due to the complex life cycle and difficulties in obtaining the life stages of the parasites. Thus, the mouse model of human filariasis, Litomosoides sigmodontis , is a suitable tool to investigate the biology of filarial infections ( 40 , 41 ) and filarial-driven immune modulation of the host ( 42 ), and can be used as a preclinical model for drug testing ( 17 ). Nevertheless, findings obtained from the murine model of filariasis cannot be directly translated to the human situation.…”

The MraY Inhibitor Muraymycin D2 and Its Derivatives Induce Enlarged Cells in Obligate Intracellular Chlamydia and Wolbachia and Break the Persistence Phenotype in Chlamydia

“…These nematodes cause the neglected tropical diseases lymphatic filariasis (lymphedema or hydrocele) and onchocerciasis (severe skin disease or vision loss). Anti-wolbachial treatment with DOX or rifampicin is the only effective and safe treatment against adult worms as Wolbachia are obligate endosymbionts that support filarial development, growth, and survival [23,24,27]. Overall, contraindications for these antibiotics, including long treatment regimens for the anti-wolbachial treatment of filariasis, and treatment failure in Chlamydia require new strategies to fight these infections.…”

“…for development and adult worm survival, DOX or rifampicin, which both deplete the endobacteria from the worms, can also be used, with the benefit that the targeting of Wolbachia spp. leads to the killing of adult worms and, therefore, does not require annual or biannual treatment for the lifetime of the adult worms as it is required for diethylcarbamazine and ivermectin [23,24,27]. Anti-wolbachial treatment is the only safe and effective adult worm-killing therapy [28], and new drugs without the contraindications for DOX and rifampicin are needed.…”