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Mycobacterial lipids at the host/pathogen interface

macrophage myco membrane.jpg

Biphoton imaging of the interaction between mycobacteria  (pink) and plasma membrane (blue) of human macrophages  (Photo credit: © J. Augenstreich (IPBS/CNRS-UPS)).

Principal Investigator: Catherine Astarie-Dequeker (CR-CNRS)

 

Our global objective is to explore the pathophysiological implication of lipids exposed at the cell surface of major mycobacterial pathogens and to go beyond a phenomenological description by deciphering their molecular mechanisms.

We have contributed to demonstrate that complex specific lipids (amphiphilic glycolipids and hydrophobic compounds) that are loosely associated with the outermost bilayer of the bacterial cell wall modulate the protective host immune responses, specifically during the early steps of infection when the bacilli encounter macrophages. We are also interested in elucidating how these lipids interact with the host at the molecular level. One originality of our strategy is to target specifically the lipid motifs to understand how they impair the biophysical properties of host cell membranes and collaborate with cell membrane partners to the pathogen’s advantage.

We have developed a multidisciplinary and a multi-scale approach that helps us:

- At the molecular level, to characterize the impact of lipids on host cell membranes and on membrane-associated effectors involved in crucial steps of the dialog between mycobacterial pathogens and host macrophages, namely phagocytosis, intracellular bacterial trafficking and induction of membrane damage.

- At the cellular level, to assess the role of lipids in the fate of intracellular bacteria and infected cells. We go on exploring the functional role of lipids in the dialog between mycobacteria and macrophages, and the consequences on bacterial propagation to neighboring immune cells. We are also interested in highlighting a potential synergy with other virulence factors.

- At the animal level, to examine the impact of mycobacterial lipids on the physiopathology in mouse models of infection.  We examine whether the effect of lipids, established at the early stage of infection when the bacteria encounter macrophages has a physiological relevance and a pathological impact at the level of whole animal infection models

 

Designed to generate new insight into a complex phenomenon, our data may open new ways to attack mycobacterial infection and, importantly, should have an impact beyond the field of mycobacteria with a possible application to cell wall lipids of Gram-negative bacterial

macrophage 2.jpg

Visualization by confocal microscopy of mycobacteria (green filaments) infected macrophages (red) phagocytosed by naïve macrophages (green) (Photo credit: © I. Vergne (IPBS/CNRS-UPS)).

 

 

Persons involved: 

Christophe Guilhot (DR-CNRS)

Delphine Payros (Post-Doc)

Jacques Augenstreich (PhD-UPS)

Céline Berrone (AI-CDD).

Collaborations:

E. Hanaapel & L. Salomé (IPBS, Toulouse), A. Milon (IPBS, Toulouse), I. Vergne & J. Nigou (IPBS, Toulouse), R. Brosch (Institut Pasteur, Paris), C. Demangel (Institut Pasteur, Paris), F. Lafont (Institut Pasteur, Lille), N. Winter (INRA, Tours), M. C. Vidal-Pessolani (Institudo Oswaldo Cruz, Brazil).

Main publications:

  • Augenstreich et al. (2017) ESX-1 and phthiocerol dimycocerosates of Mycobacterium tuberculosis act in concert to cause phagosomal rupture and host cell apoptosis. Cell. Microbiol. Jan 17. doi: 10.1111/cmi.12726.
  • Arbués et al. (2016) Trisaccharides of Phenolic Glycolipids Confer Advantages to Pathogenic Mycobacteria through Manipulation of Host-Cell Pattern-Recognition Receptors. ACS Chem. Biol. 11:2865
  • Arbués et al. (2014) Playing hide and seek with host macrophages through the use of mycobacterial cell envelope phthiocerol dimycocerosates and phenolic glycolipids. Front. Cell. Infect. Microbiol. 4:173
  • Passemar et al. (2014)  Multiple deletions in the polyketide synthase gene repertoire of Mycobacterium tuberculosis reveal functional overlap of cell envelope lipids in host-pathogen interactions. Cell. Microbiol. 16: 195.
  • Tabouret et al. (2010) Mycobacterium leprae phenolglycolipid-1 expressed by engineered M. bovis BCG modulates early interaction with human phagocytes. PLOS Pathog. 6:e1001159
  • Astarie-Dequeker et al. (2009) Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids. PLOS Pathog. 5 : e1000289.