Analyse der immunsuppressiven Profile von MDSCs in chronischen Helmintheninfektionen
Parasitologie und Biologie der Erreger tropischer Infektionskrankheiten
Zusammenfassung der Projektergebnisse
Filarial-driven modulation of the host immunity is crucial for parasite survival. On the other hand, it dampens immune responses against concomitant infections and even worsens vaccination efficacy. Therefore, the mechanisms of how filariae induce and maintain immunomodulatory capacity remain uncertain. Investigation revealed that regulatory immune cell subsets play an important role for the immune modulation and over the last two decades myeloid‐ derived suppressor cells (MDSCs) have been described as potential immune cell subsets that can suppress T cell responses especially during cancer. Thus, this project aims to characterise developing myeloid‐derived suppressor cells (MDSCs) during filariasis and investigate the mechanisms involved in their suppression of filarial‐specific CD4+ T cell responses. Indeed, we could show that distinct monocytic (Mo‐MDSCs = Ly6C, CD11b+Ly6C+Ly6G) or polymorphonuclear (PMN‐MDSCs = Ly6G, CD11b+Ly6Cint/loLy6G+, labelled as Ly6G) MDSCs expand in the thoracic cavity (site of infection) of Litomosoides sigmodontis (a murine filarial)-infected mice. Moreover, the expansion of MDSC subsets was positively correlated with filarial life stages. Further analysis elucidated the signalling mechanisms of MDSC subsets and deciphered that only infection-derived Mo-MDSCs showed a suppressive nature by preventing IL-13 and IFN-γ secretion from filarial-specific CD4+ T cells. This suppression was not mediated by IL-10, IL-6 or TNF-α, and did not require cell-contact, nitric oxide (NO), IL-4/IL-5 signalling pathways or CCR2. The suppression ability could be blocked when TGF-β was neutralised. PCR array analysis further showed an overall down-regulation of inflammatory pathways in both infection-derived Mo-MDSCs and PMN-MDSCs and ongoing next-generation sequencing analysis of TC, bone marrow and spleen samples from latent (MF-) and patent (MF+) infected mice will reveal alteration of expression profile and function of MDSC subsets during the murine filarial infection. Analysis of MDSC subsets in human filarial infections, confirms the murine results showing that MDSC subsets expand only at the site of infection. Ongoing research continues the investigation of these distinct immunosuppressive cells to elucidate their potential and role for filarial-driven immune regulation.
Projektbezogene Publikationen (Auswahl)
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Infection-Derived Monocytic MDSCs Require TGF-β to Suppress Filarial-Specific IFN-γ But Not IL-13 Release by Filarial-Specific CD4+ T Cells In Vitro. Frontiers in Tropical Diseases, 2.
Tamadaho, Ruth S. E.; Ritter, Manuel; Wiszniewsky, Anna; Arndts, Kathrin; Mack, Matthias; Hoerauf, Achim & Layland, Laura E.
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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. Frontiers in Tropical Diseases, 4.
Karunakaran, Indulekha; Ritter, Manuel; Pfarr, Kenneth; Klarmann-Schulz, Ute; Debrah, Alexander Yaw; Debrah, Linda Batsa; Katawa, Gnatoulma; Wanji, Samuel; Specht, Sabine; Adjobimey, Tomabu; Hübner, Marc Peter & Hoerauf, Achim
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Reduced Type 2 Innate Lymphocyte Cell Frequencies in Patent Wuchereria bancrofti-Infected Individuals. Pathogens, 12(5), 665.
Tamadaho, Ruth S. E.; Osei-Mensah, Jubin; Arndts, Kathrin; Debrah, Linda Batsa; Debrah, Alexander Y.; Layland, Laura E.; Hoerauf, Achim; Pfarr, Kenneth & Ritter, Manuel
