Hoerauf A et al. (2002) Curr Opin Investig Drugs "Antibiotics for the treatment of onchocerciasis and other filarial infections."

Hoerauf A, Buttner DW, Adjei O

[Curr Opin Investig Drugs, 2002]

More effective drugs are needed for the treatment of human filarial diseases and the elimination of these infections as a public health problem. The drugs must either kill or sterilize adult worms. The relevant filariae, Onchocerca volvulus, Wuchereria bancofti and Brugia species, harbor rickettsial endoboacteria of the genus Wolbachia as symbionts. Animal experiments have shown that the elimination of these endobacteria causes inhibition of embryogenesis, and with Onchocerca ochengi a macrofilaricidal effect. Trials with human onchocerciasis patients using doxycydine demonstrated a long-term sterilizing activity, opening up a new strategy for the control of filarial infections. Indications of antiwolbachial therapy against onchocerciasis are discussed.

Hoerauf A et al. (2011) Clin Microbiol Infect "Filariasis in Africa--treatment challenges and prospects."

Mand S, Specht S, Hoerauf A, Debrah AY, Pfarr K

[Clin Microbiol Infect, 2011]

Lymphatic filariasis (LF) and onchocerciasis are parasitic nematode infections that are responsible for a major disease burden in the African continent. Disease symptoms are induced by the immune reactions of the host, with lymphoedema and hydrocoele in LF, and dermatitis and ocular inflammation in onchocerciasis. Wuchereria bancrofti and Onchocerca volvulus, the species causing LF and onchocerciasis in Africa, live in mutual symbiosis with Wolbachia endobacteria, which cause a major part of the inflammation leading to symptoms and are antibiotic targets for treatment. The standard microfilaricidal drugs ivermectin and albendazole are used in mass drug administration programmes, with the aim of interrupting transmission, with a consequent reduction in the burden of infection and, in some situations, leading to regional elimination of LF and onchocerciasis. Co-endemicity of Loa loa with W. bancrofti or O. volvulus is an impediment to mass drug administration with ivermectin and albendazole, owing to the risk of encephalopathy being encountered upon administration of ivermectin. Research into new treatment options is exploring several improved delivery strategies for the classic drugs or new antibiotic treatment regimens for anti-wolbachial chemotherapy.

Pfarr KM et al. (2009) Parasite Immunol "Filariasis and lymphoedema."

Pfarr KM, Specht S, Debrah AY, Hoerauf A

[Parasite Immunol, 2009]

Among the causes of lymphoedema (LE), secondary LE due to filariasis is the most prevalent. It affects only a minority of the 120 million people infected with the causative organisms of lymphatic filariasis (LF), Wuchereria bancrofti and Brugia malayi/timori, but is clustered in families, indicating a genetic basis for development of this pathology. The majority of infected individuals develop filarial-specific immunosuppression that starts even before birth in cases where mothers are infected and is characterized by regulatory T-cell responses and high levels of IgG4, thus tolerating high parasite loads and microfilaraemia. In contrast, individuals with this pathology show stronger immune reactions biased towards Th1, Th2 and probably also Th17. Importantly, as for the aberrant lymph vessel development, innate immune responses that are triggered by the filarial antigen ultimately result in the activation of vascular endothelial growth factors (VEGF), thus promoting lymph vessel hyperplasia as a first step to lymphoedema development. Wolbachia endosymbionts are major inducers of these responses in vitro, and their depletion by doxycycline in LF patients reduces plasma VEGF and soluble VEGF-receptor-3 levels to those seen in endemic normals preceding pathology improvement. The search for the immunogenetic basis for LE could lead to the identification of risk factors and thus, to prevention; and has so far led to the identification of single-nucleotide polymorphisms (SNP) with potential functional relevance to VEGF, cytokine and toll-like receptor (TLR) genes. Hydrocele, a pathology with some similarity to LE in which both lymph vessel dilation and lymph extravasation are shared sequelae, has been found to be strongly associated with a VEGF-A SNP known for upregulation of this (lymph-)angiogenesis factor.

Tamarozzi F et al. (2011) Clin Microbiol Rev "Onchocerciasis: the role of Wolbachia bacterial endosymbionts in parasite biology, disease pathogenesis, and treatment."

Gentil K, Halliday A, Taylor MJ, Hoerauf A, Pearlman E, Tamarozzi F

[Clin Microbiol Rev, 2011]

The discovery of Wolbachia intracellular bacteria within filarial nematodes, including Onchocerca volvulus, the causative agent of onchocerciasis or "river blindness," has delivered a paradigm shift in our understanding of the parasite's biology, to where we now know that the bacterial endosymbionts are essential for normal development of larvae and embryos and may support the long-term survival of adult worms. The apparent mutualistic dependency has also offered a novel approach to the treatment of onchocerciasis through the use of antibiotics to eliminate Wolbachia, delivering for the first time a treatment which has significant macrofilaricidal efficacy. Studies with other filarial nematode species have also highlighted a role for Wolbachia in transmission and infection of the mammalian host through a fascinating manipulation of mast cell-mediated vasodilation to enhance infectivity of vector-borne larvae. Wolbachia has also been identified as the principal driver of innate and adaptive Th1 inflammatory immunity, which can either contribute to disease pathogenesis or, with the Wolbachia-mediated recruitment of mast cells, enhance infectivity. The Wolbachia activation of innate inflammation also drives inflammatory adverse events in response to chemotherapy with either diethylcarbamazine (DEC) or ivermectin. In this review we summarize the experimental and field trial data which have uncovered the importance of Wolbachia symbiosis in onchocerciasis.

Dietrich CF et al. (2019) Ultrasound Int Open "Review of Dancing Parasites in Lymphatic Filariasis."

Chaubal N, Steffgen L, Mand S, Hoerauf A, Kling K, Dietrich CF, Dong Y, Piontek MS

[Ultrasound Int Open, 2019]

Lymphatic filariasis is an infection transmitted by blood-sucking mosquitoes with filarial nematodes of the species <i>Wuchereria bancrofti, Brugia malayi und B. timori</i> . It is prevalent in tropical countries throughout the world, with more than 60 million people infected and more than 1 billion living in areas with the risk of transmission. Worm larvae with a length of less than 1mm are transmitted by mosquitoes, develop in human lymphatic tissue to adult worms with a length of 7-10cm, live in the human body for up to 10 years and produce millions of microfilariae, which can be transmitted further by mosquitoes. The adult worms can be easily observed by ultrasonography because of their size and fast movements (the so-called &quot;filarial dance sign&quot;), which can be differentiated from other movements (e.g., blood in venous vessels) by their characteristic movement profile in pulsed-wave Doppler mode. Therapeutic options include (combinations of) ivermectin, albendazole, diethylcarbamazine and doxycycline. The latter depletes endosymbiotic Wolbachia bacteria from the worms and thus sterilizes and later kills the adult worms (macrofilaricidal or adulticidal effect).

Allen JE et al. (2008) PLoS Negl Trop Dis "Of mice, cattle, and humans: the immunology and treatment of river blindness."

Taylor DW, Bain O, Adjei O, Trees AJ, Hoerauf A, Hoffmann WH, Wanji S, Makepeace BL, Allen JE, Schulz-Key H, Tanya VN

[PLoS Negl Trop Dis, 2008]

River blindness is a seriously debilitating disease caused by the filarial parasite Onchocerca volvulus, which infects millions in Africa as well as in South and Central America. Research has been hampered by a lack of good animal models, as the parasite can only develop fully in humans and some primates. This review highlights the development of two animal model systems that have allowed significant advances in recent years and hold promise for the future. Experimental findings with Litomosoides sigmodontis in mice and Onchocerca ochengi in cattle are placed in the context of how these models can advance our ability to control the human disease.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Wong C et al. (2003) Curr Biol "Dispatch. Centrosome biology: a SAS-sy centriole in the cell cycle."

Wong C, Stearns T

[Curr Biol, 2003]

A novel protein in Caenorhabditis elegans, SAS-4, is a component of centrioles and is required for centriole duplication. Depletion of SAS-4 results in stunted centrioles and a smaller centrosome, suggesting a link to organelle size control.

Hall PA et al. (1997) Curr Biol "Tumor suppressors: a developing role for p53?"

Hall PA, Lane DP

[Curr Biol, 1997]

An increasing body of evidence indicates that p53, the product of a tumour suppressor gene, has a role in development - could this developmental role have provided the primary driving force in the evolution of a protein best known as a stress-response integrator?

Smidt MP et al. (2009) Genome Biol "A passport to neurotransmitter identity."

Burbach JP, Smidt MP

[Genome Biol, 2009]

Comparison of a regulatory network that specifies dopaminergic neurons in Caenorhabditis elegans to the development of vertebrate dopamine systems in the mouse reveals a possible partial conservation of such a network.