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Tropical Medicine Section The Major Surface Protein of Wolbachia Endosymbionts in Filarial Nematodes Elicits Immune Responses through Toll-like Receptors 2 and 4 Zusammenfassung Das Oberflächenprotein von Wolbachien (WSP) wirkt als Stimulans des natürlichen Abwehrsystems. (i) WSP induziert die Freisetzung inflammatorischer Zytokine aus Monozyten, (ii) die inflammatorische Antwort ist Toll-like Rezeptor (TLR)2- und TLR4-abhängig, (iii) Onchocerca volvulus-infizierte Personen bilden IgG1- aber nicht IgG4- und IgE-Antikörper gegen WSP. WSP lässt sich in Mikrofilarien und in Gewebsmakrophagen nachweisen, die Mikrofilarienfragmente aufgenommen haben. Filarien können daher durch WSP der Endobakterien Charakteristika mikrobieller Pathogene annehmen. Introduction Immunopathological reactions are thought to play a major role in the development of filarial diseases. Thus, clinical symptoms of chronic infection by O. volvulus appear to result from the cumulative effects of inflammation evoked mainly by the microfilarial stage of the worms. Wolbachia are endosymbionts in filariae and essential for worm fertility and have been suggested to contribute to the pathogenesis of filarial disease. Adverse reactions following microfilaricidal therapy are associated with innate responses including the release of inflammatory mediators tightly correlating with the presence of circulating Wolbachia DNA, liberated from degenerating microfilariae. Figure 1: NF-kB dependent reporter gene activation upon challenge with WSP using TLR2 or TLR4 transiently overexpressing human fibroblastoid cells. Luciferase was quantified 24 h after exposure to WSP (grey) or lipopolysaccharide (open). 84 Project Description and Results Purified major Wolbachia surface protein (WSP) was shown to stimulate monocytes of both, O. volvulusinfected and of uninfected persons to release TNF-α, IL-12 and IL-8. The inflammatory response to WSP was TLR2 and TLR4 dependent as demonstrated with TLRtransfected fibroblasts (Figure), as well as macrophages and dendritic cells from functional TLR deficient mice. The dependence of the TLR engagement on WSP protein was shown by the treatment with protease and polymyxin B. WSP reactive IgG1 antibodies were present in sera of the O. volvulus-infected persons but not in those of the uninfected Europeans. Antibodies against WSP stained endobacteria in living and degenerating tissue microfilariae and host tissue macrophages that had engulfed microfilariae. Thus, filarial helminths, through products of their endobacteria such as WSP, acquire characteristics of a typical microbial pathogen inducing immune responses through TLR2 and TLR4. Selected Publications • Brattig NW, Bazzocchi C, Kirschning CJ, Reiling N, Büttner DW, Ceciliani F, Geisinger F, Hochrein H, Ernst M, Wagner H, Bandi C, Hoerauf A. (2004) The major surface protein of Wolbachia endosymbionts in filarial nematodes elicits immune responses through Toll-like receptor 2 and TLR4. J Immunol (accepted). • Bandi C, Trees AJ, Brattig NW. (2001). Wolbachia in filarial nematodes: evolutionary aspects and implications for the pathogenesis and treatment of filarial diseases. Vet Parasitol 98:215-238 • Brattig NW. (2004). Pathogenesis and host responses in human onchocerciasis: impact of Onchocerca filariae and Wolbachia endo-bacteria. Microbes Infect 6: 113–128 Cooperating Partners • A. Hoerauf, D.W. Büttner, BNI • C. Bazzocchi, C. Bandi University of Milan, Italy • C.J. Kirschning, Max von Pettenkofer-<strong>Institut</strong>e for Hygiene and Medical Microbiology, Munich • N. Reiling, M. Ernst, <strong>Research</strong> Center Borstel Investigators • Nobert W. Brattig • Frank Geisinger
Zusammenfassung In einer Studie an 458 Afrikanern, die der Filarie Onchocerca volvulus exponiert sind, wurde IL-5 in O. volvulus-Antigen (OvAg)-stimulierten Vollblutkulturen bestimmt. O. volvulus-reaktives IL-5 korrelierte quantitativ mit der peripheren Eosinophilie und erklärte 13.7% der Variabilität der Eosinophilenzahl. Die Korrelation wurde nur festgestellt, wenn die Mikrofilarienzahl in einer multiplen Regressionsanalyse mit einbezogen wurde. Die Ergebnisse zeigen, dass in-vitro-Tests mit sehr kleinen Blutvolumina die Aktivität der gesamten Lymphozytenpopulation in vivo quantitativ reflektieren können. Introduction Determinations of in-vitro proliferative and secretory activities of peripheral blood cells are widely used for research in clinical immunology but have not been evaluated as to their power to reflect in-vivo activities quantitatively. IL-5 and IL-4 are important cytokines of T-helper 2 lymphocytes and as such relevant to the immune response towards helminths. IL-5 has been shown to be the key regulator of eosinophil production and IL-5 production of lymphocytes in vitro is supposed to reflect the in-vivo situation and should correlate to in-vivo eosinophilia. 85 Tropical Medicine Section Relevance of ex-vivo Blood Lymphocyte Assay for in-vivo Lymphocyte Function Figure: Multiple regression analysis between in-vitro IL-5 secretion by blood lymphocytes in response to O. volvulus antigen, microfilarial counts and blood eosinophil counts. The regression plane is indicated. The coefficient of determination is r 2 = 0.14, p < 10 -15 . Project Description and Results We studied 458 individuals heavily exposed to the tissue nematode O. volvulus but void of other worm disease except for low-level infection with intestinal helminths. Cell proliferation and cytokine secretion were studied in whole blood cultures upon stimulation with OvAg or the mitogen PHA. No correlation was found between IL-5 secretion and eosinophil counts, neither for PHA-stimulated nor for OvAg-reactive blood cells. Therefore, we performed a multiple regression analysis which included the variation in microfilarial counts. It showed a greater than additive increase in the coefficient of determination for eosinophil counts when both, OvAg-reactive IL-5 and microfilarial counts, were included (Figure). Selected Publications • Timmann C et al. (2003). Br J Dermatol 149: 782-787 • Brattig NW et al. (2002). J Infect Dis 185: 1148-1154 Funding • Deutsche Forschungsgemeinschaft Cooperating Partners • RD Horstmann, C Timmann C, B Müller-Myhsok, BNI Investigators • Norbert W. Brattig • Frank Geisinger • Wilfried Groenwoldt
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BERNHARD NOCHT INSTITUTE FOR TROPIC
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Human genetic variants influencing
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Research Funding / Haushaltsmittel
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Introduction The appearance of SARS
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tive project with the Faculty of Me
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since this group headed by Dr. Chri
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Vorwort Das Erscheinen der schweren
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AIDS-Forschung hat eine lange zurü
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europäisches Konsortium mit 8 Part
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Parasitology Section Selected Scien
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Zusammenfassung des Sprechers Die S
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Research Group Clos (Leishmaniasis
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Figure 2: Incidence of ALA in Hué
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jects were assigned to receive dilo
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is increased in the first 24 h of h
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Symposia and Meetings 2002 Symposia
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Symposia and Meetings 2003 May 13 t
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Staff Activities Staff Activities A
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Staff Activities PD Dr. Joachim Clo
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Staff Activities Editorial Activiti
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Staff Activities Prof. Dr. Rolf Hor
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Staff Activities Prof. Dr. Christia
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Staff Activities Prof. Dr. Egbert T
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Publications Book chapters and Mono
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Publications Herbst R, Ott C, Jacob
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Publications Supali T, Wibowo H, Ru
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Publications Scholze H and Tannich
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Publications Graefe SE, Meyer BS, M
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Publications Schulz A, Mellenthin K
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Appendix 01. Januar 2002 Das BNI wi
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Appendix 01. Oktober 2002 Gemeinsam
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Appendix 01. April 2003 Ergebnis de
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Appendix 01. Juni 2003 Fernsehrepor
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Appendix November 2003 Inauguration
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Appendix red by solar energy could
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Appendix Ansprache von Dr. Thomas F
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Diary 2004/2005 12.-14. November 20
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