Final Report Summary - PGLMP (Deciphering the role of phenolic glycolipids in mycobacterial pathogenesis)
Mycobacterial diseases (such as tuberculosis, leprosy and Buruli ulcer) remain major public health problems throughout the world causing not only death, but also suffering, economic losses and poverty on endemic countries. Although antibiotics and a vaccine currently exist, they have failed to control these diseases. It is hence crucial to improve our knowledge of the factors and mechanisms involved in mycobacterial pathogenicity in order to identify new ways to fight mycobacterial infections.
The hallmark of mycobacterial pathogens is their ability to persist for decades in the infected individuals, and there is mounting evidence that they have evolved mechanisms to suppress host immune response. Among the factors suspected to play a role are phenolic glycolipids (PGL), which are produced notably by the major pathogenic mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae, and possess a common lipid core and species-specific sugar domains.
The aim of our project PGLMP was to decipher the role of PGL in mycobacterial pathogenesis and the molecular mechanisms involved in their interaction with the host. To answer this question, a cross-disciplinary approach to compare the biological activities of various PGL was implemented. On the one hand, a novel strategy based on the genetic reprogramming of the vaccine strain to make it synthesize the species-specific PGL of other mycobacterial pathogens was developed. On the other hand, a chemistry approach in which the various species-specific sugar domains were synthesized was used to get insight into the structural basis. Using these tools, we found that PGL-1 from M. leprae is unique in conferring increased capacity to exploit the carbohydrate-binding domain of complement receptor type 3 (CR3) for efficient invasion of human macrophages. We next explored the mechanism involved in the immunomodulation by PGL, focusing on toll-like receptors (TLR) which recognize structurally conserved molecules produced by microbes and then activate immune responses. Trisaccharide epitopes of PGL from M. tuberculosis and M. leprae showed to share the capacity to inhibit TLR-2-triggered inflammatory response. Consistently, purified PGL-1 was found to bind both isolated CR3 and TLR-2. Taken together, these results show that trisaccharide-containing PGL confers an advantage to mycobacterial producing-species in terms of infectivity and evasion of host immune responses (Summary Figure).
A worldwide effort is focused on the development of new strategies to fight against mycobacterial diseases, in particular tuberculosis, covering both basic and applied research. Besides to advance our understanding of the pathogenesis of major human diseases, we expect that the basic knowledge about mycobacteria-host interaction acquired through this project may open avenues for the development of new, more efficient therapies against mycobacterial diseases, and therefore contributing to enhance European competitiveness in this issue of extreme relevance.
Contact details:
Scientist in charge:
Catherine Astarie-Dequeker PhD, CR1 CNRS
Institute of Pharmacology and Structural Biology, CNRS-UPS UMR 5089
Team "Molecular Mycobacterial Pathogenesis"
205, Route de Narbonne - BP64182
31077 Toulouse Cedex
Phone: (+33) 5 61 17 54 55
E-mail: catherine.astarie-dequeker@ipbs.fr
http://www.ipbs.fr/?lang=en(odnośnik otworzy się w nowym oknie)
http://www.ipbs.fr/?-Molecular-Mycobacterial-&lang=en(odnośnik otworzy się w nowym oknie)
IEF Marie Curie Fellow:
Ainhoa Arbués Arribas PhD
Institute of Pharmacology and Structural Biology, CNRS-UPS UMR 5089
Team "Molecular Mycobacterial Pathogenesis"
205, Route de Narbonne - BP64182
31077 Toulouse Cedex
Phone: (+33) 5 61 17 58 29
E-mail: ainhoa.arbues@ipbs.fr
http://www.ipbs.fr/?lang=en(odnośnik otworzy się w nowym oknie)
http://www.ipbs.fr/?-Molecular-Mycobacterial-&lang=en(odnośnik otworzy się w nowym oknie)
The hallmark of mycobacterial pathogens is their ability to persist for decades in the infected individuals, and there is mounting evidence that they have evolved mechanisms to suppress host immune response. Among the factors suspected to play a role are phenolic glycolipids (PGL), which are produced notably by the major pathogenic mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae, and possess a common lipid core and species-specific sugar domains.
The aim of our project PGLMP was to decipher the role of PGL in mycobacterial pathogenesis and the molecular mechanisms involved in their interaction with the host. To answer this question, a cross-disciplinary approach to compare the biological activities of various PGL was implemented. On the one hand, a novel strategy based on the genetic reprogramming of the vaccine strain to make it synthesize the species-specific PGL of other mycobacterial pathogens was developed. On the other hand, a chemistry approach in which the various species-specific sugar domains were synthesized was used to get insight into the structural basis. Using these tools, we found that PGL-1 from M. leprae is unique in conferring increased capacity to exploit the carbohydrate-binding domain of complement receptor type 3 (CR3) for efficient invasion of human macrophages. We next explored the mechanism involved in the immunomodulation by PGL, focusing on toll-like receptors (TLR) which recognize structurally conserved molecules produced by microbes and then activate immune responses. Trisaccharide epitopes of PGL from M. tuberculosis and M. leprae showed to share the capacity to inhibit TLR-2-triggered inflammatory response. Consistently, purified PGL-1 was found to bind both isolated CR3 and TLR-2. Taken together, these results show that trisaccharide-containing PGL confers an advantage to mycobacterial producing-species in terms of infectivity and evasion of host immune responses (Summary Figure).
A worldwide effort is focused on the development of new strategies to fight against mycobacterial diseases, in particular tuberculosis, covering both basic and applied research. Besides to advance our understanding of the pathogenesis of major human diseases, we expect that the basic knowledge about mycobacteria-host interaction acquired through this project may open avenues for the development of new, more efficient therapies against mycobacterial diseases, and therefore contributing to enhance European competitiveness in this issue of extreme relevance.
Contact details:
Scientist in charge:
Catherine Astarie-Dequeker PhD, CR1 CNRS
Institute of Pharmacology and Structural Biology, CNRS-UPS UMR 5089
Team "Molecular Mycobacterial Pathogenesis"
205, Route de Narbonne - BP64182
31077 Toulouse Cedex
Phone: (+33) 5 61 17 54 55
E-mail: catherine.astarie-dequeker@ipbs.fr
http://www.ipbs.fr/?lang=en(odnośnik otworzy się w nowym oknie)
http://www.ipbs.fr/?-Molecular-Mycobacterial-&lang=en(odnośnik otworzy się w nowym oknie)
IEF Marie Curie Fellow:
Ainhoa Arbués Arribas PhD
Institute of Pharmacology and Structural Biology, CNRS-UPS UMR 5089
Team "Molecular Mycobacterial Pathogenesis"
205, Route de Narbonne - BP64182
31077 Toulouse Cedex
Phone: (+33) 5 61 17 58 29
E-mail: ainhoa.arbues@ipbs.fr
http://www.ipbs.fr/?lang=en(odnośnik otworzy się w nowym oknie)
http://www.ipbs.fr/?-Molecular-Mycobacterial-&lang=en(odnośnik otworzy się w nowym oknie)