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Medical Microbiology Section Immunpathways in filarial infection in mice: old Acquaintances and Surprises Zusammenfassung: Verschiedene immunologische Parameter sind für die Abwehr von Filarienematoden von großer Bedeutung. Das Zusammenspiel dieser Parameter wurde in Studien an gentechnisch veränderten Mäusen durchgeführt, die zum Teil einen doppelten Defekt in zwei Genen aufwiesen. Es zeigte sich, dass Zytokine synergistisch zusammenwirken, die bisher allgemein nicht im Verdacht standen Synergien miteinander zu bilden. Auch Immunzellen, von denen bekannt war, dass sie gegen Viren, Bakterien und Protozoen wirken, wurden in Zusammenhang mit der Abwehr von Filarien gebracht. Wichtige Erkenntnisse wurden über die Rolle der Wolbachien und deren freigesetzte LPS-ähnliche Produkte für den Verlauf der Immunabwehr gewonnen. Summary Different immunological parameters are of great importance for the defence against filarial infections. The interaction of these parameters was analysed in studies with genetic deficient mice. It was shown that cytokines that were thought to be antagonistic in the mode of action, rather interact synergistically with each other. Also immune cells, which are known to be involved in the defence against viruses, bacteria and protozoa were demonstrated to be important for defence against filarial infections. Important results were collected about Wolbachia and their released LPS-like products for the immune reaction. Introduction Filarial infections are a great problem in tropical countries. Over 180 million persons are infected with filarial worms. The immunological defence mechanisms are not understood in detail, which leads to the survival of worms for more than 20 years in the host. Our studies focus on the better understanding of these immune reactions. Experiments were done with mice which had a double deficiency of IL-5 and interferon-γ. These mice were analysed to see if this double deficiency had a synergistic or antagonistic effect on the course of the immune reaction. The role of IL-4, IL-4 receptor-α and IL-5 was analysed in knockout mice in the course of a filarial infection. Further studies of our group focused on the role of NK cells, as no role for NK cells was yet known in the defence against helminth infections. The important role of endosymbiotic Wolbachia bacteria for the defence against filarial infections was shown in animal models. 60 Project Description and Results Natural killer cells are known to be important for the defence against virus, bacteria and protozoa. In vivo depletion of NK cells led to a significantly higher worm load in mice. These data demonstrated for the first time that NK cells were involved in the defence mechanism against helminth parasites (Korten et al., 2002). Comparison of the immune reaction in IL-4, IL-4 receptor-α and IL-5 deficient mice demonstrated that IL-5 in contrast to IL-4 is important for the defence against adult worms. Only IL-5 KO mice had up to 200 times more adult worms and a longer persistence of worms during the chronic phase of the infection. In contrast, no significant differences in adult worm survival were observed between IL-4, IL-4 receptor-α and BALB/c wild-type mice. Both IL-5 and IL-4 knockout mice show a greatly enhanced microfilaremia and prolonged susceptibility. These data demonstrate that IL-5 and IL-4 effector pathways act against different stages of filarial worms. Deficiency of IL-5 results in effects on the adult worms and microfilariae, while deficiency of IL-4 and IL- 4 receptor-α has only effects on the microfilariae (Volkmann et al., 2003). A prevailing perception is that Th1 and Th2 immune reactions induce antagonistic immune effector mechanisms. IL-5 and IFN-γ knockout mice both show a higher worm load compared to the wild-type. The question was if IFN-γ/IL-5 double knockout mice have a significantly higher worm load compared to each single knockout mice. The results indicate that double deficiency of IFN-γ and IL-5 act synergistically and leads to a higher worm load compared to each single knockout. Our results show that these synergistic effects of these two cytokines were mediated in part by neutrophils. Neutrophils are important cells for the containment and encapsulation process of the worms. An important cytokine for neurophil activation is TNF-α, which was reduced in macrophages of KO mice. Furthermore, neutrophils of IL-5 KO, IFN-γ KO and double deficient mice were significantly decreased in their chemotactic activity compared to controls and double deficient mice show the lowest phagocytic activity (Saeftel et al., 2003). Wolbachia are intracellular endobacteria of filarial worms and their released LPS-like molecules might play a role in the induction of immune response. By using the LPS-nonresponsive C3H/HeJ mouse strain it was shown that these mice develop a higher fertility of adult worms. This experiment indicates that TLR4 signaling is involved in the immune reaction that controls worm fertility and embryogenesis (Pfarr et al., 2003).
Selected Publications • Korten S, Volkmann L, Saeftel M, Fischer K, Taniguchi M, Fleischer B, Hoerauf A. (2002). Expansion of NK cells with reduction of their inhibitory Ly-49A, Ly-49C, and Ly-49G2 receptorexpressing subsets in a murine helminth infection: contribution to parasite control. J. Immunol. 168(10): 5199-5206 • Pfarr KM, Fischer K, Hoerauf A. (2003). Involvment of Toll-like receptor 4 in the embryogenesis of the rodent filaria Litomosoides sigmodontis. Med. Microbiol. Immunol. (Berl). 192(1): 53-56. • Saeftel M, Arndt M, Specht S, Volkmann L, Hoerauf A. (2003). Synergism of gamma interferon and interleukin-5 in the control of murine filariasis. Infect. Immun. 71(12): 6978-6985. • Volkmann L, Bain O, Saeftel M, Specht S, Fischer K, Brombacher F, Matthaei KI, Hoerauf A. (2003). Murine filariasis: interleukin 4 and interleukin 5 lead to containment of different worm developmental stages. Med. Microbiol. Immunol. 192(1): 23-31. 61 Funding • These studies received financial support by the German Research Foundation Ho 2009/1-3; and Ho 2009/5-1. Cooperating Partners • O. Bain; Museum National d’Histore Naturelle et Ecole Pratique des Hautes Etudes, Paris, France • F. Brombacher; Groote Schuur Hospital, University of Cape Town, Kapstadt, Süd Afrika • K. Matthaei; John Curtin School of Medical Research, Australien National University Canberra, Australien • M. Taylor; Liverpool School of Tropical Medicine, Liverpool, U.K. • M. Taniguchi; The Institute of Physical and Chemical Research, and Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan Investigators • Achim Hoerauf • Manuela Arndt • Kerstin Fischer • Simone Korten • Kenneth Pfarr • Michael Saeftel • Sabine Specht • Lars Volkmann Medical Microbiology Section
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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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Education and Teaching Diploma Thes
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Education and Teaching Parasitology
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Education and Teaching Lars Volkman
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Education and Teaching The objectiv
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Education and Teaching Ziel des Kur
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Education and Teaching Institute Fa
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Education and Teaching Training for
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Seminar Programme 2002 Prof. Aileen
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Seminar Programme Dr. Stefan Martin
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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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Publications Book chapters and Mono
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Publications Herbst R, Ott C, Jacob
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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. Juni 2003 Fernsehrepor
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Appendix November 2003 Inauguration
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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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