Dr. Kenneth M. Pfarr

Research Focus 

The filarial nematodes Wuchereria bancrofti, Brugia malayi and Onchocerca volvulus are round worms that infect humans and cause the diseases lymphatic filariasis (lymphedema and hydrocele) and onchocerciasis (river blindness). An estimated 200 million people are infected with these worms and, in a proportion of the infected population, cause severe morbidity and even death. Current drugs used to interrupt the transmission of these worms to uninfected persons, while very effective at killing the first stage larvae, present with problems. The drugs require several years of annual administration (5-15 years). Additionally, there is evidence for resistance developing.
 
All three of these filarial nematodes contain essential, obligate endosymbiotic bacteria of the genus Wolbachia. Using tetracycline or derivatives of tetracycline (doxycycline), Wolbachia can be depleted from worms in infected animal models of filariasis and human patients. Worms that have been depleted of their endosymbionts are no longer to develop. In adult female worms, depletion of Wolbachia results in a permanent block in oogenesis and embryogenesis. Recently, we have shown that depletion of the endobacteria from W. bancrofti and O. volvulus results in death of the adult worms at the site of infection. Because of these spectacular effects, Wolbachia have gained great interest as targets for controlling filarial infections. However, little is known about the endosymbiotic relationship between Wolbachia and their nematode hosts.
 
My group has three research areas. The first is to understand the symbiosis between Wolbachia and filarial nematodes at the molecular level. One way to research this question is to characterize nematode genes that are differentially regulated during tetracycline treatment to deplete the endobacteria. Using this method, we have successfully identified a phosphate permease that is up-regulated in female and male worms as Wolbachia are depleted. Recently we have extended these results using the B. malayi micro-array chip to identify more genes that may be involved in symbiosis.
 
The second research area is to understand Wolbachia microbiology/biochemistry. The genome for Wolbachia has been sequenced and annotated. Analyzing the genome data has yielded some interesting questions. Of particular interest to my group is the Lipid II biosynthesis pathway, the core molecule for peptidoglycan synthesis. The Wolbachia genome encodes the genes necessary to make Lipid II. However, it lacks several essential proteins needed for downstream events in the synthesis of peptidoglycan (e.g. a cell wall), suggesting that any peptidogylcan-like molecule will be very different from that in other gram-negative bacteria. We are characterizing the functionality of the Lipid II biosynthesis proteins from Wolbachia by expressing recombinant proteins for in vitro Lipid II synthesis and isolating cell membranes from Wolbachia for ex vivo synthesis experiments.
 
The third research area in my lab is the genetics of lymphatic filariasis. Although ~150 million people are infected with the filarial worms W. bancrofti or B. malayi, only a small percentage develop lymphatic filarial pathology. Studies have shown that lymphedema clusters in families independent of environmental factors. Using a candidate gene approach, we have shown that single nucleotide polymorphisms (SNPs) in VEGF-A are associated with hydrocele. Further work is underway to genotype SNPs of cytokines, chemokines and vascular endothelial growth factors for association with lymphatic filariasis. We are also recruiting a large cohort of volunteers for a genome-wide scan project to identify genes involved in pathology.
 
Understanding these three areas will provide the information to drive the search for novel antibiotics to control filarial infections. This could result from a novel target identified in the microarray study, or use cell wall biosynthesis, which is empirically the best target for antibiotics. Additionally, knowing genetic factors that make people susceptible to infection or filarial pathology will allow for the development of screening tests to identify persons and families that could benefit from more personalized physician guidance to help prevent or ameliorate pathology.

 

Dr. Kenneth Pfarr

Group Leader

Phone: +49-228-287-11207

Fax:  +49-228-287-90-11207

Email: kenneth.pfarr @ ukbonn.de

Funding from DFG: PF673/3-2, PF673/4-1, PF673/6-1; DZIF, EU (NSETHIO), EFRE-NRW

Lab members

Dr. Andrea Schiefer

Post-Doc

Phone.:  +49-228-287-11476

Fax.: +49-228-287-11167

Email:  andrea.schiefer @ uni-bonn.de

Project:  Characterization of cell wall biosynthesis in Wolbachia, endosymbionts of filarial nematodes, pre-clinical development of Corallopyronin A as an anti-wolbachial antibiotice to treat filariasis

Technicians

Christine Lämmer

Helene Neufeld

Phone.:  +49-228-287-11510

Fax.: +49-228-287-11167

 

Students

Kirstin Meier

Ph.D. candidate

Project: Wolbachia cell wall biosynthesis, function of penicillin binding proteins in the absence of peptidoglycan

Julia Schulz

Ph.D. candidate

Project: Trascriptome and miRNome of filarial nematodes and their infected hosts – role of host background

Tanita Olbrich

MSc student, University of Bonn

Project: Analysis of murine microRNA expression during Litomosoides sigmodontis infection in different knock-out strains.

Maheshie Senevriatne

MSc Studnet, Hochschule Bonn-Rhein-Sieg, University of Applied Sciences

Project: Differentiation of Wuchereria bancrofti microfilarial status in archived blood sediment using reverse transcribed real-time PCR

 

 

Lab Contact Information

Phone: +49-228-287-11510

Fax.:+49-228-287-11167

 

Collaborations

Dr. A. Debrah

Kumasi Centre for Collaborative Research (KCCR) and Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Project: Monitoring depletion of Wolbachia from W. bancrofti and O. volvulus in patients enlisted in clinical trials of antiwolbachial drugs, and genotyping of single nucleotide polymorphisms of patients with lymphatic filariasis

Dr. S. Wanji

Head of Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Cameroon

Project: Developing rapid diagnostics for lymphatic filariasis, onchocercaias, loiasis and mansonellosis

Dr. H.G. Sahl

Institute for Medical Microbiology, Immunology and Parasitology

University Medical Center Bonn, Bonn, Germany

Project: Lipid II biosynthesis in the alpha-proteobacteria Wolbachia of filarial nematodes

Dr. G. König

Institute for Pharmaceutical Biology

University of Bonn, Germany

Project: Corallopyronin A development as an antifilarial chemotherpeutic agent

 

Publications

Globisch, D., Eubanks, L.M., Shirey, R.J., Pfarr, K.M., Wanji, S., Debrah, A.Y., Hoerauf, A., and Janda, K.D. (2017). Validation of onchocerciasis biomarker N-acetyltyramine-O-glucuronide (NATOG). Bioorg Med Chem Lett 27, 3436-3440.

Wewer, V., Makepeace, B.L., Tanya, V.N., Peisker, H., Pfarr, K., Hoerauf, A., and Dormann, P. (2017). Lipid profiling of the filarial nematodes Onchocerca volvulus, Onchocerca ochengi and Litomosoides sigmodontis reveals the accumulation of nematode-specific ether phospholipids in the host. Int J Parasitol.

Wilmes, M., Meier, K., Schiefer, A., Josten, M., Otten, C.F., Klöckner, A., Henrichfreise, B., Vollmer, W., Hoerauf, A., and Pfarr, K. (2017). AmiD is a novel peptidoglycan amidase in Wolbachia endosymbionts of Drosophila melanogaster. Front Cell Infect Microbiol 7.

Ajendra, J., Specht, S., Ziewer, S., Schiefer, A., Pfarr, K., Parcina, M., Kufer, T.A., Hoerauf, A., and Hubner, M.P. (2016). NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae. Sci Rep6, 39648.

Colebunders, R., Mandro, M., Mokili, J.L., Mucinya, G., Mambandu, G., Pfarr, K., Reiter-Owona, I., Hoerauf, A., Tepage, F., Levick, B., et al. (2016). Risk factors for epilepsy in Bas-Uele Province, Democratic Republic of the Congo: a case-control study. Int J Infect Dis49, 1-8.

Elfaki, T.E., Arndts, K., Wiszniewsky, A., Ritter, M., Goreish, I.A., Atti El Mekki Mel, Y., Arriens, S., Pfarr, K., Fimmers, R., Doenhoff, M., et al. (2016). Multivariable Regression Analysis in Schistosoma mansoni-Infected Individuals in the Sudan Reveals Unique Immunoepidemiological Profiles in Uninfected, egg+ and Non-egg+ Infected Individuals. PLoS Negl Trop Dis10, e0004629.

Reiter-Owona, I., Rehkaemper-Schaefer, C., Arriens, S., Rosenstock, P., Pfarr, K., and Hoerauf, A. (2016). Specific K39 antibody response and its persistence after treatment in patients with imported leishmaniasis. Parasitol Res115, 761-769.

Weitzel, T., Rosas, R., Fica, A., Dabanch, J., Polanco, M., Egana, A., Triantafilo, V., Pfarr, K., Hoerauf, A., and Reiter-Owona, I. (2016). Is there a risk of filarial infection during long-term missions in Haiti? Travel Med Infect Dis14, 137-142.

Globisch, D., Specht, S., Pfarr, K.M., Eubanks, L.M., Hoerauf, A., and Janda, K.D. (2015). Litomosoides sigmodontis: A jird urine metabolome study. Bioorg Med Chem Lett25, 5804-5807.

Lentz, C.S., Sattler, J.M., Fendler, M., Gottwalt, S., Halls, V.S., Strassel, S., Arriens, S., Hannam, J.S., Specht, S., Famulok, M., et al. (2015). In vitro activity of wALADin benzimidazoles against different life cycle stages of Plasmodium parasites. Antimicrob Agents Chemother59, 654-658.

Lutz, P., Pfarr, K., Nischalke, H., Krämer, B., Goeser, F., Glässner, A., Wolter, F., Kokordelis, P., Nattermann, J., Sauerbruch, T., et al. (2015). The ratio of calprotectin to total protein as diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites. Clin Chem Lab Med53, 2031-2039.

Quintana, J.F., Makepeace, B.L., Babayan, S.A., Ivens, A., Pfarr, K.M., Blaxter, M., Debrah, A., Wanji, S., Ngangyung, H.F., Bah, G.S., et al. (2015). Extracellular Onchocerca -derived small RNAs in host nodules and blood. Parasit Vectors8, 58.

Schäberle, T.F., Schmitz, A., Zocher, G., Schiefer, A., Kehraus, S., Neu, E., Roth, M., Vassylyev, D.G., Stehle, T., Bierbaum, G., et al. (2015). Insights into Structure−Activity Relationships of bacterial RNA polymerase inhibiting Corallopyronin derivatives. J Nat Prod78, 2505-2509.

Albers, A., Sartono, E., Wahyuni, S., Yazdanbakhsh, M., Maizels, R.M., Klarmann-Schulz, U., Pfarr, K., and Hoerauf, A. (2014). Real-time PCR detection of the HhaI tandem DNA repeat in pre- and post-patent Brugia malayi infections: a study in Indonesian transmigrants. Parasit Vectors7, 146.

Arumugam, S., Hoerauf, A., and Pfarr, K.M. (2014). Localization of a filarial phosphate permease that is up-regulated in response to depletion of essential Wolbachia endobacteria. Exp Parasitol138, 30-39.

Johnston, K.L., Ford, L., Umareddy, I., Townson, S., Specht, S., Pfarr, K., Hoerauf, A., Altmeyer, R., and Taylor, M.J. (2014). Repurposing of approved drugs from the human pharmacopoeia to target Wolbachia endosymbionts of onchocerciasis and lymphatic filariasis. Int J Parasitol Drugs Drug Resist4, 278-286.

Lentz, C.S., Halls, V.S., Hannam, J.S., Strassel, S., Lawrence, S.H., Jaffe, E.K., Famulok, M., Hoerauf, A., and Pfarr, K.M. (2014). wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs. J Med Chem57, 2498-2510.

Lutz, P., Pfarr, K., Nischalke, H.D., Krämer, B., Goeser, F., Nattermann, J., Sauerbruch, T., Hoerauf, A., Strassburg, C.P., and Spengler, U. (2014). The ratio of ascites calprotectin to total protein is a diagnostic and prognostic marker for spontaneous bacterial peritonitis in liver cirrhosis. J Hepatol60, S231.

Schäberle, T.F., Schiefer, A., Schmitz, A., König, G.M., Hoerauf, A., and Pfarr, K. (2014). Corallopyronin A – A promising antibiotic for treatment of filariasis. Int J Med Microbiol304, 72-78.

Lentz, C.S., Halls, V., Hannam, J.S., Niebel, B., Strübing, U., Mayer, G., Hoerauf, A., Famulok, M., and Pfarr, K.M. (2013). A selective inhibitor of heme biosynthesis in endosymbiotic bacteria elicits antifilarial activity in vitro. Chem Biol20, 177-187.

Lentz, C.S., Stumpfe, D., Bajorath, J., Famulok, M., Hoerauf, A., and Pfarr, K.M. (2013). New chemotypes for wALADin1-like inhibitors of delta-aminolevulinic acid dehydratase from Wolbachia endobacteria. Bioorg Med Chem Lett23, 5558-5562.

Schiefer, A., Vollmer, J., Lämmer, C., Specht, S., Lentz, C., Ruebsamen-Schaeff, H., Brötz-Oesterhelt, H., Hoerauf, A., and Pfarr, K. (2013). The ClpP protease of Wolbachia endobacteria is a novel endobacterial target for anti-filarial therapy. J Antimicrob Chemother68, 1790-1800.

Specht, S., Debrah, A.Y., Klarmann, U., Mand, S., Hoerauf, A., and Pfarr, K. (2013). Chemotherapy of filariasis - established strategies and new developments. GMS Infect Dis1, 1-10.

Vollmer, J., Schiefer, A., Schneider, T., Jülicher, K., Johnston, K.L., Taylor, M.J., Sahl, H.-G., Hoerauf, A., and Pfarr, K. (2013). Requirement of lipid II biosynthesis for cell division in cell wall-less Wolbachia, endobacteria of arthropods and filarial nematodes. Int J Med Microbiol303, 140-149.

Albers, A., Esum, M.E., Tendongfor, N., Enyong, P., Klarmann, U., Wanji, S., Hoerauf, A., and Pfarr, K. (2012). Retarded Onchocerca volvulus L1 to L3 larval development in the Simulium damnosum vector after anti-wolbachial treatment of the human host. Parasit Vectors5, 12.

Schiefer, A., Schmitz, A., Schäberle, T.F., Specht, S., Lämmer, C., Johnston, K.L., Vassylyev, D.G., König, G.M., Hoerauf, A., and Pfarr, K. (2012). Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo. J Infect Dis206, 249-257.

Taylor, M.J., Ford, L., Hoerauf, A., Pfarr, K., Foster, J.M., Kumar, S., and Slatko, B.E. (2012). Drugs and Targets to Perturb the Symbiosis of Wolbachia and Filarial Nematodes. In Parasitic Helminths (Wiley-VCH Verlag GmbH & Co. KGaA), pp. 251-265.

Debrah, A.Y., Batsa, L., Albers, A., Mand, S., Toliat, M.R., Nürnberg, P., Adjei, O., Hoerauf, A., and Pfarr, K. (2011). Transforming Growth Factor-β 1 variant Leu10Pro is associated with both lack of microfilariae and differential microfilarial loads in the blood of people infected with lymphatic filariasis. Hum Immunol72, 1143-1148.

Debrah, A.Y., Mand, S., Marfo-Debrekyei, Y., Batsa, L., Albers, A., Specht, S., Klarmann, U., Pfarr, K., Adjei, O., and Hoerauf, A. (2011). Macrofilaricidal Activity in Wuchereria bancrofti after 2 Weeks Treatment with a Combination of Rifampicin plus Doxycycline. J Parasitol Res2011, 201617.

Hoerauf, A., Pfarr, K., Mand, S., Debrah, A.Y., and Specht, S. (2011). Filariasis in Africa-treatment challenges and prospects. Clin Microbiol Infect17, 977-985.

Niebel, B., Lentz, C., Pofahl, M., Mayer, G., Hoerauf, A., Pfarr, K.M., and Famulok, M. (2010). ADLOC: an aptamer-displacement assay based on luminescent oxygen channeling. Chemistry16, 11100-11107.

Strübing, U., Lucius, R., Hoerauf, A., and Pfarr, K.M. (2010). Mitochondrial genes for heme-dependent respiratory chain complexes are up-regulated after depletion of Wolbachia from filarial nematodes. Int J Parasitol40, 1193-1202.

Debrah, A.Y., Mand, S., Marfo-Debrekyei, Y., Batsa, L., Pfarr, K., Lawson, B., Taylor, M., Adjei, O., and Hoerauf, A. (2009). Reduction in levels of plasma vascular endothelial growth factor-A and improvement in hydrocele patients by targeting endosymbiotic Wolbachia sp. in Wuchereria bancrofti with doxycycline. Am J Trop Med Hyg80, 956-963.

Henrichfreise, B., Schiefer, A., Schneider, T., Nzukou, E., Poellinger, C., Hoffmann, T.J., Johnston, K.L., Moelleken, K., Wiedemann, I., Pfarr, K., et al. (2009). Functional conservation of the lipid II biosynthesis pathway in the cell wall-less bacteria Chlamydia and Wolbachia: why is lipid II needed? Mol Microbiol73, 913-923.

Mand, S., Pfarr, K., Sahoo, P.K., Satapathy, A.K., Specht, S., Klarmann, U., Debrah, A.Y., Ravindran, B., and Hoerauf, A. (2009). Macrofilaricidal activity and amelioration of lymphatic pathology in bancroftian filariasis after 3 weeks of doxycycline followed by single-dose diethylcarbamazine. Am J Trop Med Hyg81, 702-711.

Pfarr, K.M., Debrah, A.Y., Specht, S., and Hoerauf, A. (2009). Filariasis and lymphoedema. Parasite Immunol31, 664-672.

Arumugam, S., Pfarr, K.M., and Hoerauf, A. (2008). Infection of the intermediate mite host with Wolbachia-depleted Litomosoides sigmodontis microfilariae: impaired L1 to L3 development and subsequent sex-ratio distortion in adult worms. Int J Parasitol38, 981-987.

Hoerauf, A., Specht, S., Buttner, M., Pfarr, K., Mand, S., Fimmers, R., Marfo-Debrekyei, Y., Konadu, P., Debrah, A.Y., Bandi, C., et al. (2008). Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study. Med Microbiol Immunol197, 295-311.

Pfarr, K.M., Heider, U., Schmetz, C., Buttner, D.W., and Hoerauf, A. (2008). The mitochondrial heat shock protein 60 (HSP60) is up-regulated in Onchocerca volvulus after the depletion of Wolbachia. Parasitology135, 529-538.

Supali, T., Djuardi, Y., Pfarr, K.M., Wibowo, H., Taylor, M.J., Hoerauf, A., Houwing-Duistermaat, J.J., Yazdanbakhsh, M., and Sartono, E. (2008). Doxycycline treatment of Brugia malayi-infected persons reduces microfilaremia and adverse reactions after diethylcarbamazine and albendazole treatment. Clin Infect Dis46, 1385-1393.

Debrah, A.Y., Mand, S., Marfo-Debrekyei, Y., Batsa, L., Pfarr, K., Buttner, M., Adjei, O., Buttner, D., and Hoerauf, A. (2007). Macrofilaricidal effect of 4 weeks of treatment with doxycycline on Wuchereria bancrofti. Trop Med Int Health12, 1433-1441.

Debrah, A.Y., Mand, S., Toliat, M.R., Marfo-Debrekyei, Y., Batsa, L., Nurnberg, P., Lawson, B., Adjei, O., Hoerauf, A., and Pfarr, K. (2007). Plasma vascular endothelial growth Factor-A (VEGF-A) and VEGF-A gene polymorphism are associated with hydrocele development in lymphatic filariasis. Am J Trop Med Hyg77, 601-608.

Pfarr, K., Foster, J., Slatko, B., Hoerauf, A., and Eisen, J.A. (2007). On the taxonomic status of the intracellular bacterium Wolbachia pipientis: should this species name include the intracellular bacteria of filarial nematodes? Int J Syst Evol Microbiol57, 1677-1678.

Pfarr, K.M., and Hoerauf, A. (2007). A niche for Wolbachia. Trends Parasitol23, 5-7.

Debrah, A.Y., Mand, S., Specht, S., Marfo-Debrekyei, Y., Batsa, L., Pfarr, K., Larbi, J., Lawson, B., Taylor, M., Adjei, O., et al. (2006). Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog2, e92.

Heider, U., Blaxter, M., Hoerauf, A., and Pfarr, K.M. (2006). Differential display of genes expressed in the filarial nematode Litomosoides sigmodontis reveals a putative phosphate permease up-regulated after depletion of Wolbachia endobacteria. Int J Med Microbiol296, 287-299.

Pfarr, K., Heider, U., and Hoerauf, A. (2006). RNAi mediated silencing of actin expression in adultLitomosoides sigmodontis is specific, persistent and results in a phenotype. Int J Parasitol36, 661-669.

Pfarr, K.M., and Hoerauf, A.M. (2006). Antibiotics which target the Wolbachia endosymbionts of filarial parasites: a new strategy for control of filariasis and amelioration of pathology. Mini Rev Med Chem6, 203-210.

Turner, J.D., Mand, S., Debrah, A.Y., Muehlfeld, J., Pfarr, K., McGarry, H.F., Adjei, O., Taylor, M.J., and Hoerauf, A. (2006). A randomized, double-blind clinical trial of a 3-week course of doxycycline plus albendazole and ivermectin for the treatment of Wuchereria bancrofti infection. Clin Infect Dis42, 1081-1089.

Gilbert, J., Nfon, C.K., Makepeace, B.L., Njongmeta, L.M., Hastings, I.M., Pfarr, K.M., Renz, A., Tanya, V.N., and Trees, A.J. (2005). Antibiotic chemotherapy of onchocerciasis: in a bovine model, killing of adult parasites requires a sustained depletion of endosymbiotic bacteria (Wolbachia species). J Infect Dis192, 1483-1493.

Mand, S., Marfo-Debrekyei, Y., Debrah, A., Buettner, M., Batsa, L., Pfarr, K., Adjei, O., and Hoerauf, A. (2005). Frequent detection of worm movements in onchocercal nodules by ultrasonography. Filaria J4, 1.

Pfarr, K., and Hoerauf, A. (2005). The annotated genome of Wolbachia from the filarial nematode Brugia malayi: what it means for progress in antifilarial medicine. PLoS Med2, e110.

Hoerauf, A., Mand, S., Fischer, K., Kruppa, T., Marfo-Debrekyei, Y., Debrah, A.Y., Pfarr, K.M., Adjei, O., and Buttner, D.W. (2003). Doxycycline as a novel strategy against bancroftian filariasis-depletion of Wolbachia endosymbionts from Wuchereria bancrofti and stop of microfilaria production. Med Microbiol Immunol192, 211-216.

McGarry, H.F., Pfarr, K., Egerton, G., Hoerauf, A., Akue, J.P., Enyong, P., Wanji, S., Klager, S.L., Bianco, A.E., Beeching, N.J., et al. (2003). Evidence against Wolbachia symbiosis in Loa loa. Filaria J2, 9.

Pfarr, K.M., Fischer, K., and Hoerauf, A. (2003). Involvement of Toll-like receptor 4 in the embryogenesis of the rodent filaria Litomosoides sigmodontis. Med Microbiol Immunol192, 53-56.

Pfarr, K.M., Qazi, S., and Fuhrman, J.A. (2001). Nitric oxide synthase in filariae: demonstration of nitric oxide production by embryos in Brugia malayi and Acanthocheilonema viteae. Exp Parasitol97, 205-214.

Pfarr, K.M., and Fuhrman, J.A. (2000). Brugia malayi: localization of nitric oxide synthase in a lymphatic filariid. Exp Parasitol94, 92-98.

Soltysik-Espanola, M., Klinzing, D.C., Pfarr, K., Burke, R.D., and Ernst, S.G. (1994). Endo16, a large multidomain protein found on the surface and ECM of endodermal cells during sea urchin gastrulation, binds calcium. Dev Biol165, 73-85.

 

Date: 
Friday, April 4, 2014 - 16:00 - Tuesday, January 3, 2017 - 12:00

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