Lipidomics; Host-pathogen interactions; Macrophage; Protozoan parasite; Mycobacterium; Lipids; Systems Biology; Metabolism; Molecular Epidemiology
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, 24(1), 98-111.
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.