Molecular signalling in the spontaneous cell death pathway of granulocytes

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April 25, 2008

Molecular signalling in the spontaneous cell death pathway of granulocytes

In contrast to all other haematopoietic cells neutrophil granulocytes (PMN) are destined to die by a spontaneous apoptotic process. This program is controlled by a complex network of signalling pathways that regulate the turnover of the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1).

PMN and their apoptotic system are a primary target for obligate intracellular pathogens such as Leishmania. This prototype intracellular parasite manipulates the signalling program in PMN thereby interfering with the apoptotic machinery. We found that in the very early course of disease apoptotic Leishmania enable viable parasites to enter PMN and survive intracellularly (1). The infected apoptotic PMN is misused by Leishmania as a Trojan horse to recruit and invade macrophages, the optimal host cell for survival and multiplication (2). The key molecules enabling Leishmania this delicate regulation of PMN signalling and survival are still unknown. We hypothesize that Mcl-1 is a key regulator of Leishmania dependent regulation of the spontaneous cell death pathway.

Methoden:
Cell culture, culture of Leishmania parasites, isolation of human granulocytes, in vitro infection models. Apoptosis assays, protein analysis (western blot, fluorescence microscopy, laser scanning microscopy),
RT-PCR (LightCycler).

Anfangsdatum: 24. April 2008

geschätzte Dauer: 3 years

Bezahlung: TvL 13, 50%

Veröffentlichungen:
1. van Zandbergen, G., et.al. 2006. Apoptotic Leishmania promastigotes in the virulent inoculum enable disease development. Proc. Natl. Acad. Sci. U S A. 103(37):13837-42.
2. van Zandbergen, G., et.al. 2004. Cutting edge: Neutrophil granulocyte serves as a vector for leishmania entry into macrophages. J. Immunol., 173:6521-6525.

Homepage: http://www.uniklinik-ulm.de/struktur/institute/medizinische-mikrobiologie-und-hygiene/home/forschung/tvl-lab.html

In unserem Labor sind Erregertricks im Focus: Tod versus Leben-Labor (TvL Lab)

Die Infektion des menschlichen Organismus durch intrazelluläre Erreger macht das Umgehen von phagocytären Abwehrmechanismen erforderlich. An Parasiten (Leishmania major) und Bakterien (Chlamydia pneumonia) konnten wir zeigen, dass diese anti-inflammatorische Apoptosemerkmale auf unterschiedliche Weise anwenden und daher unbemerkt in Phagocyten überleben können.

Das Aufdecken dieser unterschiedlichen Evasionsstrategien ist für das Verständnis des Krankheitsbeginns wesentlich und könnte eine Beeinflussung der Krankheitsentwicklung ermöglichen.

Daher arbeiten wir mit frisch isolierten humanen Phagocyten und untersuchen die Interaktion mit toten/ lebenden Erregern und apoptotischen Neutrophilen.

Fachgebiet: Infektionsbiologie
Kontakt: Ger.Zandbergen@Uniklinik-Ulm

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Scholarship Tags: cell death, granulocytes, Molecular, pathway, signalling, spontaneous