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Front. Microbiol. | doi: 10.3389/fmicb.2018.02258

Heparin-binding Hemagglutinin Adhesin (HBHA) is involved in intracytosolic lipid inclusions formation in mycobacteria

 Dominique Raze1*, Claudie Verwaerde1, Gaspard Deloison1, Elisabeth Werkmeister1, Baptiste Coupin1, Marc Loyens1, Priscille Brodin1, Carine Rouanet1 and  Camille Locht1
  • 1INSERM U8204 Centre d'infection et d'immunité de Lille (CIIL), France

The heparin-binding hemagglutinin (HBHA) is an important virulence factor of Mycobacterium tuberculosis. It is a surface-displayed protein that serves as an adhesin for non-phagocytic cells and is involved in extra-pulmonary dissemination of the tubercle bacillus. It is also an important latency antigen useful for the diagnosis of latently M. tuberculosis-infected individuals. Using fluorescence time-lapse microscopy on mycobacteria that produce HBHA-green fluorescent protein chimera we show here that HBHA can be found at two different locations and dynamically alternates between the mycobacterial surface and the interior of the cell, where it participates in the formation of intracytosolic lipid inclusions (ILI). Compared to HBHA-producing mycobacteria, HBHA-deficient mutants contain significantly lower amounts of ILI when grown in vitro or within macrophages, and the sizes of their ILI are significantly smaller. Lipid-binding assays indicate that HBHA is able to specifically bind to phosphatidylinositol and in particular to 4,5 di-phosphorylated phosphatidylinositol, but not to neutral lipids, the main constituents of ILI. HBHA derivatives lacking the C-terminal methylated, lysine-rich repeat region fail to bind to these lipids and these derivatives also fail to complement the phenotype of HBHA-deficient mutants. These studies indicate that HBHA is a moonlighting protein that serves several functions depending on its location. When surface exposed, HBHA serves as an adhesin, and when intracellularly localized, it participates in the generation of ILI, possibly as a cargo to transport phospholipids from the plasmic membrane to the ILI in the process of being formed.

Keywords: Tuberculosis, Mycobacterium, Lipids, dormancy, Carbon Storage, HBHA

Received: 14 Jun 2018; Accepted: 05 Sep 2018.

Edited by:

Martin Koenneke, Zentrum für Marine Umweltwissenschaften, Universität Bremen, Germany

Reviewed by:

Michel DRANCOURT, Aix-Marseille Université, France
Giovanni Delogu, Università Cattolica del Sacro Cuore, Italy  

Copyright: © 2018 Raze, Verwaerde, Deloison, Werkmeister, Coupin, Loyens, Brodin, Rouanet and Locht. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Dominique Raze, INSERM U8204 Centre d'infection et d'immunité de Lille (CIIL), Lille, Nord-Pas-de-Calais, France, dominique.raze@ibl.cnrs.fr