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The impact of the MBL pathway on the outcome of infection with representative mycobacterial strains of the Mycobacterium tuberculosis complex

  • Full or part time
    Dr C Hölscher
    Prof S Niemann
  • Application Deadline
    Sunday, November 10, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

Tuberculosis (TB) is the leading cause of death from a single infectious agent which are strains of the Mycobacterium tuberculosis complex (Mtbc). After inhalation, mycobacteria are recognized by the innate immune system which initiates and shapes the adaptive immunity. In general, the immune response of the host is characterized by a balance between protection and pathology.

Complement evasion strategies of Mtbc strains have been inadequately investigated so far. Mannose binding lectin (MBL) recognizes specific cell surface carbohydrates such as mannosylated lipoarabinomannan of the mycobacterial cell wall. MBL can act as an opsonin or activate the lectin pathway of the complement cascade and thereby modulate the innate and adaptive immune response. Besides host factors that are important for the outcome of infection also the genetic diversity of mycobacteria has a significant influence on the pathogenesis of TB. The Hölscher lab could demonstrate that strains of the ancient Mtbc lineage M. africanum bind MBL to a higher extend than strains of modern lineages e.g. Euroamerican and that a specific human MBL2 variant confers protection against TB caused by M. africanum. In humans, several MBL2 gene polymorphisms exist which result in a great variation of circulating MBL levels. By exploiting MBL-null mice, host-pathogen interactions which are influenced by this receptor can be investigated in a controlled setting. So far, the role of MBL in TB infection has not been analyzed in the experimental mouse model of infection. Therefore, the aim of this PhD thesis project is the detailed characterization of the MBL mediated modulation of host-pathogen interaction during Mtb infection.

To achieve this goal, first, the binding of MBL to the cell wall of strains of different ancient and modern mycobacterial lineages will be determined in vitro (RCB). The interaction of different Mtbc complex proteins with MBL and other complement activating molecules will be explored at the University of Copenhagen. The impact of MBL on susceptibility to TB will be investigated in vivo by infecting Mbl1/2-deficient (-/-) mice infected with well characterized strains ofancient and modern mycobacterial lineages at the RCB. The course of infection will be compared with wild-type mice by analyzing the bacterial burden in different organs, histopathology, immunophenotyping and transcription profiling at defined time points after infection.

General description of your individual PhD-schedule:

• Your main university will be University of Lübeck (Germany). Supervision will be shared by Dr. Hölscher (RCB) and Prof. Niemann (University of Lübeck). You will mainly work at RCB.
• You will have a 6-months research secondment at University of Copenhagen (Denmark) with Prof. Garred as supervisor, where you continue to scientifically work on your thesis project.
• You will have a further 6-months research secondment at RCB (Germany) where you will investigate the impact of MBL on the course of experimental tuberculosis.
• You will have a 1-month clinical training at University Hospital Helsinki (Finland).
• You will have a 1-month entrepreneur training at RCB.
• You will finally receive a PhD issued by University of Lübeck and University of Copenhagen if you fulfil the respective requirements.

Application

Please visit http://www.corvos.eu for application and more information on the PhD program. You have to submit: Application Form (see http://www.corvos.eu), CV, Master/MD/Diploma document, Abstract of Master/MD/Diploma thesis. Selected candidates will be invited for a personal interview to Innsbruck on 03rd/04thJan or 09thJan2020.

Requirements:

We are looking for highly qualified and motivated aspiring PhD students from any nationality with an open-minded and very enterprising personality, capable of working in collaborative and integrated research groups. Ideal candidates should possess a good scientific drive and a strong motivation to succeed.

•You have a full study completing degree (Master, Magister, Diploma, MD) in medicine, natural sciences or related disciplines until March 2020
•You are an Early Stage Researcher (ESR) – you either just finished your studies, or you have worked less than 4 years as an employee in the biomedical sector after obtaining your degree
•You have to show academic excellence, scientific potential, flexibility, motivation and suitability for the research project
•You have the willingness to stay abroad for 3 years from your current residence and willingness to travel through Europe
•You comply with the mobility rule for Marie Sklodowska Curie ITN fellows – Researchers must not have resided or carried out their main activity (work, studies, etc.) in the country of the recruiting university for more than 12 months in the 3 years immediately before the recruitment date. This will be thouroughly checked.

Funding Notes

The Marie Sklodowska-Curie project CORVOS, for COmplement Regulation and Variations in Opportunistic infectionS, is funded as an Innovative Training Network (ITN) – European Joint Doctorate (EJD). Its focus lies on education of young scientists in the field of complement in opportunistic infections. This interdisciplinary doctoral program is supported by 10 European universities, 2 research institutes, 3 biomedical companies and 3 hospitals. The PhD students will have enhanced career perspectives in the academic and non-academic sectors through international, interdisciplinary and inter-sectoral mobility combined with an innovation-oriented mind-set. Visit View Website to see all the benefits that you will have as CORVOS PhDstudent.

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