Project 26
XIAP-mediated cell-autonomous immune reaction against Shigella flexneri
Institute for Medial Microbiology, Immunology and Hygiene, University of Cologne
Brief description in German:
Dieses Projekt untersucht die Rolle von XIAP (X-linked inhibitor of apoptosis) in der zellautonomen Immunabwehr gegen Bakterien am Beispiel von Shigella flexneri. In den eigenen Vorarbeiten wurde gezeigt, dass die S. flexneri–induzierte zellautonome Immunreaktion (NF-κB-Aktivierung und Produktion von IL-8) durch XIAP vermittelt wrrd. Detaillierte Analysen, die die Regulation und Funktion von XIAP während einer S. flexneri-Infektion aufklären, werden wertvolle Erkenntnisse über die Physiologie intrazellulärer Infektionen liefern und zum besseren Verständnis von Immunität gegen infektiöse Erreger beitragen.
This project aims to understand the role of XIAP (X-linked inhibitor of apoptosis) in the cell-autonomous immune response to Shigella flexneri infection.
Preliminary work of the applicant showed that the S. flexneri-induced NF-κB activation and production of IL-8 is dependent on XIAP action. The mechanistic details how XIAP modulates the cellular responses to S. flexneri infection and how XIAP function is regulated during the cell-autonomous immune response will be scrutinized. These investigations will contribute to a better understanding of the physiology of intracellular infections and will increase our knowledge about immunity in infectious diseases.
The most intensively studied IAP family member, XIAP, is a 57 kDa protein which appears to be ubiquitously expressed in all adult and fetal tissues. Given its role in apoptosis and its frequently elevated expression in malignant cells, XIAP has previously garnered the most attention in mammalian cancer. Although the initial presumption was that XIAP functions mainly by antagonizing cell death pathways, there is a rapidly growing body of evidence arguing that XIAP modulates a variety of cellular functions including immune regulation.
Our own recent in vitro analyses show that XIAP is involved in cell-autonomous immune response to S. flexneri, a Gram-negative invasive enteropathogenic bacterium causing severe bacillary dysentery (Shigellosis) in humans by inflammatory destruction of the human colonic epithelium.
A crucial aspect of the propensity of Shigella for causing disease lies in its ability to invade the cytosol of epithelial cells and macrophages. Intracellular S. flexneri activates the NF-κB pathway and caspase-1 activity in epithelial cells and macrophages, respectively, and triggers the up-regulation and the secretion of proinflammatory cytokines. Our results show that XIAP is indispensible for NF-κB activation and IL-8 production/secretion in response to S. flexneri infection.
The objective of this project is
- to understand the mechanistic details how XIAP modulates the cell-autonomous immune response to intracellular S. flexneri,
- to investigate the involvement of mitochondria in the cell-autonomous immune reaction to cytosolic S. flexneri as the central regulatory machinery controlling XIAP function and expression, and
- to characterize the physiologic role of XIAP in the context of immune regulation and immune resolution of S. flexneri infection using mice with tissue specific deletion or over-expression of XIAP.
These investigations will delineate the role of XIAP in cell-autonomous immune response and will provide important clues to design new anti-inflammatory treatment protocols by targeting XIAP.
List of relevant publications
Peer-reviewed publications:
Yazdanpanah, B., Wiegmann, K., Tchikov, V., Krut, O., Pongratz, C., Schramm, M., Kleinridders, A., Wunderlich, T., Kashkar, H., Utermöhlen, O., et al. (2009). Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 460, 1159-1163.
Herz, J., Pardo, J., Kashkar, H., Schramm, M., Kuzmenkina, E., Bos, E., Wiegmann, K., Wallich, R., Peters, P.J., Herzig, S., et al. (2009). Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nature Immunology 10, 761-768.
Meemboor, S., Mertens, J., Flenner, E., Groneck, L., Zingarelli, A., Gamstätter, T., Bessler, M., Seeger, J.M., Kashkar, H., Odenthal, M., Kalka-Moll, W.M. (2009). Interleukin 6 is essential for zwitterionic polysaccharide-mediated abscess formation. Innate Immunity 2009 Nov 6. [Epub ahead of print]
Mertens, J., Fabri, M., Zingarelli, A., Kubacki, T., Meemboor, S., Groneck, L., Seeger, J., Bessler, M., Hafke, H., Odenthal, M., Bieler, J.G., Kalka, C., Schneck, J.P., Kashkar, H., Kalka-Moll, W.M. (2009). Streptococcus pneumoniae serotype 1 capsular polysaccharide induces CD8CD28 regulatory T lymphocytes by TCR crosslinking. PLoS Pathogens 5, e1000596.
Kashkar, H., Deggerich, A., Seeger, J.M., Yazdanpanah, B., Wiegmann, K., Haubert, D., Pongratz, C., and Krönke, M. (2007). NF-kappaB-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs. Blood 109, 3982-3988.
Schnaith, A., Kashkar, H., Leggio, S.A., Addicks, K., Krönke, M., and Krut, O. (2007). Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death. J Biol Chem 282, 2695-2706.
Abdullah, Z., Saric, T., Kashkar, H., Baschuk, N., Yazdanpanah, B., Fleischmann, B.K., Hescheler, J., Krönke, M., and Utermöhlen, O. (2007). Serpin-6 expression protects embryonic stem cells from lysis by antigen-specific CTL. J Immunol 178, 3390-3399.
Haubert, D., Gharib, N., Rivero, F., Wiegmann, K., Hösel, M., Krönke, M., and Kashkar, H. (2007). PtdIns(4,5)P-restricted plasma membrane localization of FAN is involved in TNF-induced actin reorganization. EMBO Journal 26, 3308-3321.
Kashkar, H., Seeger, J.M., Hombach, A., Deggerich, A., Yazdanpanah, B., Utermohlen, O., Heimlich, G., Abken, H., and Krönke, M. (2006). XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack. Blood 108, 3434-3440.
Kashkar, H., Wiegmann, K., Yazdanpanah, B., Haubert, D., and Krönke, M. (2005). Acid sphingomyelinase is indispensable for UV light-induced Bax conformational change at the mitochondrial membrane. J Biol Chem 280, 20804-20813.
Kashkar, H., Haefs, C., Shin, H., Hamilton-Dutoit, S.J., Salvesen, G.S., Krönke, M., and Jürgensmeier, J.M. (2003). XIAP-mediated caspase inhibition in Hodgkin's lymphoma-derived B cells. J Exp Med 198, 341-347.
Kashkar, H., Krönke, M., and Jürgensmeier, J.M. (2002). Defective Bax activation in Hodgkin B-cell lines confers resistance to staurosporine-induced apoptosis. Cell death and differentiation 9, 750-757.
