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Role of pentraxin and interaction with complement in immune defence against opportunistic infections

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

Project Description

PTX3 is a soluble pattern recognition molecule which acts as a key component of humoral innate immunity in opportunistic infections of fungal and bacterial origin. PTX3 binds microbial structures and activates effector functions (complement, phagocytosis). Moreover, it has a complex regulatory role in inflammation and tissue remodeling. PTX3 allelic variants are associated with increased susceptibility to fungal as well as bacterial infections. PTX3 modulates all three complement pathways by interacting with key molecules involved in activation and/or regulation of the complement cascade. PTX3 interacts with ficolins and MBL, leading to enhanced complement deposition on the surface of fungi and phagocytosis of the pathogen. Finally, PTX3 interacts with complement negative regulators, such as FH and C4BP, modulating complement activation and preventing an excessive inflammatory response to tissue injury, while increasing the deposition of opsonic molecules. PTX3 also interacts with fibrinogen/fibrin and plasminogen at acidic pH, promoting fibrin degradation. Aspergillus fumigatus evades complement recognition and promote tissue damage by recruiting FH and plasminogen, respectively.

The major aim of this PhD thesis project is to investigate whether PTX3 interferes with the binding of FH and plasminogen to Aspergillus fumigatus, thereby affecting complement deposition, plasmin activation and fibrinogen degradation, thus counteracting Aspergillus complement evasion and tissue infiltration strategies. A second aim is to analyse the interaction between PTX3 and other fungal and bacterial microbes and to investigate the consequences on complement activation.

To achieve the goals, IT-1 will use recombinant molecules available in the consortium and in vitro approaches (IF, confocal microscopy, FACS, biochemical assays, phagocytosis assays, in vitro fibrinolysis assays). An in vivo Aspergillus infection model and treatment with PTX3 variants, domains and muteins will be used to validate the relevance of results obtained in vitro.

In Helsinki (FI), IT1 will analyze potential novel interactions of PTX3 with other microbes, like Candida, streptococci and staphylococci, plus the protozoan parasite Plasmodium falciparum and its individual surface components. Functional studies will include the effect of these interactions on the activation and regulation of the complement system. Moreover, respective individual binding sites on interacting molecules will be mapped, thus promoting the development of PTX3-based therapeutic strategies.

General description of your individual PhD-schedule:
• Your main university will be Humanitas University Milano (Italy) with Prof. Garlanda as supervisor.
• You will have a 6-months research secondment at University of Helsinki (Finland) with Prof. Meri as supervisor, where you continue to scientifically work on your thesis project.
• You will have a 1-month clinical training at Research Center Borstel Hospital (Germany).
• You will have a 1-month entrepreneur training at MSD Finland (Helsinki).
• You will finally receive a PhD issued by Humanitas University and Helsingin Yliopisto (FI) 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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