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Lipidomics of host-pathogen interactions: human macrophage as a cellular system to study functional implications of lipid metabolism during infection

Applicant Guan Xueli
Number 136738
Funding scheme Ambizione
Research institution Swiss Tropical and Public Health Institute
Institution of higher education Institution abroad - IACH
Main discipline Biochemistry
Start/End 01.10.2011 - 30.06.2016
Approved amount 585'508.00
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All Disciplines (2)

Discipline
Biochemistry
Medical Microbiology

Keywords (9)

Lipidomics; Host-pathogen interactions; Macrophage; Protozoan parasite; Mycobacterium; Lipids; Systems Biology; Metabolism; Molecular Epidemiology

Lay Summary (English)

Lead
Lay summary

The cell biology of intracellular pathogens (viruses, bacteria, eukaryotic parasites) has provided us with molecular information of host–pathogen interactions. As a result it is becoming increasingly evident that lipids play important roles at various stages of this intricate interaction between the pathogens and their hosts. Being positioned at the cell surface, lipids contribute to the interplay between host and pathogen, acting in first line recognition and host cell signaling during pathogen docking, invasion and intracellular trafficking. Serving as a basic building block of membranes and as an energy source, lipids are critical for the growth and replication of a pathogen.

Despite the growing appreciation of the relevance of lipids in infectious diseases, many gaps remain to be filled. Combining novel lipidomics approaches with synthetic chemistry, infection biology and molecular epidemiology, we aim to link changes in macrophage lipid metabolism, membrane trafficking and immunomodulation to  defined pathogens including Mycobacterium spp., as well as microbial lipids. An in vitro cellular system using the human macrophage will be complemented with in vivo models of infection as well as clinical and/or field research to establish the functional roles of lipids in mycobacteriosis and parasitic infection.

 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Match-making for Posaconazole through systems-thinking.
Fugi Matthias, Kaiser Marcel, Tanner Marcel, Schneiter Roger, Maser Pascal, Guan Xue Li (2015), Match-making for Posaconazole through systems-thinking., in Trends in Parasitology, 46.
Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack
Fügi M Gunasekera K Ochsenreiter T Guan XL Wenk MR Mäser P (2014), Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack, in Journal of lipid research, 929.
Lipidomics and genomics of M. tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis
Portevin D Sukumar S Coscolla M Shui G Li B Guan XL Bendt AK Young D. Gagneux S Wenk MR. (2014), Lipidomics and genomics of M. tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis, in Microbiology open, TBD.
Lipidomics identifies a requirement of host cell choline lipid metabolism for influenza virus replication.
Tanner LB Chng C Guan XL Lei Z Rozen SG. Wenk MR (2014), Lipidomics identifies a requirement of host cell choline lipid metabolism for influenza virus replication., in Journal of Lipid Research, 1357.
NICELips: A computational framework for reconstructing lipid metabolism.
Hadidi N Soh KC Pedarsani P Seijo M Guan XL Wenk MR Hatzimanikatis V (2014), NICELips: A computational framework for reconstructing lipid metabolism., in Metabolic engineering, 1.
Biochemical membrane lipidomics during Drosophila development
Guan Xueli, Cestra Gianluca, Shui Guanghou, Kuhrs Antje, Schittenhelm Ralf, van der Goot Gisou Francoise, Robinett Carmen, Gatti Maurizio, Gonzalez-Gaitan Marcos, Wenk Markus (2013), Biochemical membrane lipidomics during Drosophila development, in Developmental Cell, 24(1), 98-111.

Collaboration

Group / person Country
Types of collaboration
National University of Singapore (NUS), Singapore Singapore (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
UCSD United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
6th International Phospholipase A and Lipid Mediator Conference. 10-12th February 2015. Tokyo, Japan. Talk given at a conference Decrypting sphingolipids structures and functions – from bench to clinic 10.02.2015 Singapore, Singapore Guan Xueli;
Systems Biology@Systems Medicine Workshop Talk given at a conference Systems biology of lipid metabolism and function in real life Tuberculosis 26.11.2014 singapore, Singapore Guan Xueli;
DBS Seminar Talk given at a conference Systems biology of lipid metabolism and function in infectious diseases 17.10.2014 Singapore, Singapore Guan Xueli;
Lee Kong Chian School of Medicine Seminar Talk given at a conference Systems biology of lipid metabolism and functions – from model organisms to medically relevant systems 14.10.2014 Singapore, Singapore Guan Xueli;
Trends in metabolomics 2014 Talk given at a conference Lipidomics of host-pathogen interactions – a systems-based approach from the bench to field 03.06.2014 Frankfurt, Germany Guan Xueli;
5th International Singapore Lipid Symposium Talk given at a conference Systems biology of lipid metabolism and functions: from model organisms to medically relevant pathogens 18.03.2014 singapore, Singapore Guan Xueli;
Symposium on Lipid Signaling and Functions Talk given at a conference Lipidomics and its contributions towards systems biology of lipid metabolism and functions 06.03.2014 Zurich, Switzerland Guan Xueli;
Gordon Research Conference on Glycolipid and Sphingolipid Biology Talk given at a conference Sphingolipidomics and Genomics of Medically Relevant Pathogens - A Novel Pathway and Biomarker Discovery Tool For Infectious Diseases 12.01.2014 Ventura, United States of America Guan Xueli;
Swiss TPH Symposium - Mycobacterial diseases and co-morbidities Talk given at a conference Lipidomics of host-pathogen interactions– Novel tools and applications for mycobacteriosis 05.12.2013 switzerland, Switzerland Guan Xueli;
Singapore Lipidomics Incubator Group Seminar Talk given at a conference Decrypting sphingolipids structures and functions – from bench to clinic 20.09.2013 Singapore, Singapore Guan Xueli;
3rd European lipidomics meeting Talk given at a conference Lipidomics:from model organisms to medically relevant pathogens 02.07.2013 pardubice, Czech Republic Guan Xueli;
Systems Biology of Infection Poster Lipidomics of host-pathogen interactions 23.06.2013 Ascona, Switzerland Guan Xueli;
All SystemsX.ch Day Poster Lipidomics of host-pathogen interactions 13.05.2013 Bern, Switzerland Guan Xueli;
LS2 2013 Talk given at a conference Lipidomices of host-pathogen interactions 31.01.2013 Zurich, Switzerland Guan Xueli;
EPFL LSS 2012 Poster lipidomics of host-pathogen interactions 29.08.2012 Lausanne, Switzerland, Switzerland Guan Xueli;
FEBS-lipids workshop: From lipidomics to disease and green energy Poster lipidomics of host pathogen interactions 23.08.2012 Spetses, Greece, Greece Guan Xueli;
Membrane Dynamics in Physiology and Diseases Talk given at a conference Lipidomics of host-pathogen interactions 05.06.2012 Basel, Switzerland, Switzerland Guan Xueli;
FEBS Workshop on Microbial Lipids Talk given at a conference Lipidomics of host-pathogen interactions 16.05.2012 Bern, Switzerland, Switzerland Guan Xueli;
4th International Singapore Lipids Symposium Talk given at a conference lipidomics of host-pathogen interactions 13.03.2012 Singapore, Singapore Guan Xueli;


Abstract

Infectious diseases continue to threat to global health and economy. The cell biology of intracellular pathogens (viruses, bacteria, eukaryotic parasites) has provided us with molecular information of host-pathogen interactions. As a result it is becoming increasingly evident that lipids play important roles at various stages of this intricate interaction between the pathogens and their hosts. Being positioned at the cell surface, lipids contribute to the interplay between host and pathogen, acting in first line recognition and host cell signaling during pathogen docking, invasion and intracellular trafficking. Serving as a basic building block of membranes and as an energy source, lipids are critical for the growth and replication of a pathogen. Furthermore, a number of lipids contribute to the outcome of an infection due to their immunomodulatory functions. In fact the importance of lipid metabolism in pathogens has long been recognized and the variation in the lipid repertoire and enzymatic machinery found in different organisms make targeting microbial lipid metabolism a highly attractive approach for therapeutic intervention. For instance, one of the first line drugs for tuberculosis, isoniazid, targets biosynthesis of a major cell wall lipid component, mycolic acid, of Mycobacterium tuberculosis. Despite the growing appreciation of the relevance of lipids in infectious diseases, many gaps remain to be filled. Here I propose to establish the human macrophage as a cellular system to interrogate the functions of lipids during the complex host-pathogen relationship. Combining novel lipidomics approaches (which have been and will be continued to be developed) with synthetic chemistry, infection biology and molecular epidemiology, I will1)Systematically profile lipids (using liquid chromatography and mass spectrometry) of human macrophages infected with clinical isolates of various Mycobacterium species to identify host lipids and/or pathways relevant to the pathogenesis of mycobacterial infection.2)Compare the human macrophage response to defined mixtures of different classes and chemical species of mycobacterial lipids (rather than a single chemical species) which are representative of the lipid signatures of Mycobacterium isolates to revisit the contribution of mycobacterial lipids as multiple components (rather than single chemical species) to the various stages of infection as well as to elucidate the structure-function relationship of these lipids.These will link changes in macrophage lipid metabolism, membrane trafficking and immunomodulation to defined genetic variations in pathogens, and well-characterized compositional and structural variations of microbial lipids. These variations have been observed during microbial adaptations and evolution and are potential determinants of infection outcomes. The in vitro cellular system using the human macrophage will be complemented with in vivo models of infection as well as clinical and/or field research to establish the functional roles of lipids in mycobacteriosis. In the second phase of the project, the study will be extended to infection caused by protozoan parasites.The proposed platform using the human macrophage will allow future investigation of host-pathogen interactions for other infectious diseases, as well as an integration of other experimental readouts such as transcriptomics and theoretical modeling for systems biology research in infection biology. In addition, a fixed asset of this proposed research is that the lipidomics approaches developed will be an invaluable tool with widespread applications in basic, clinical and molecular epidemiology research in infectious diseases and other fields.This proposal is very interdisciplinary and bridges in a well defined format various disciplines in biomedical research (basic cell and biochemical research, epidemiology and clinical research). It aims at detailed characterization on both biochemical and molecular levels of microbial and host lipid diversity in association with the etiology of infectious diseases, thus making this work particularly relevant for basic research and public health both within Switzerland and worldwide.
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