scholarly journals A Genetic Screen for Mycobacterium tuberculosis Mutants Defective for Phagosome Maturation Arrest Identifies Components of the ESX-1 Secretion System

2007 ◽  
Vol 75 (6) ◽  
pp. 2668-2678 ◽  
Author(s):  
Jason A. MacGurn ◽  
Jeffery S. Cox
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Mechanisms ◽  
Lipid Synthesis ◽  
Secretion System ◽  
Growth Defect ◽  
Phagosome Maturation ◽  
Macrophage Infection ◽  
Maturation Arrest ◽  
System A ◽  
Early Endosomes

ABSTRACT After phagocytosis, the intracellular pathogen Mycobacterium tuberculosis arrests the progression of the nascent phagosome into a phagolysosome, allowing for replication in a compartment that resembles early endosomes. To better understand the molecular mechanisms that govern phagosome maturation arrest, we performed a visual screen on a set of M. tuberculosis mutants specifically attenuated for growth in mice to identify strains that failed to arrest phagosome maturation and trafficked to late phagosomal compartments. We identified 10 such mutants that could be partitioned into two classes based on the kinetics of trafficking. Importantly, four of these mutants harbor mutations in genes that encode components of the ESX-1 secretion system, a pathway critical for M. tuberculosis virulence. Although ESX-1 is required, the known ESX-1 secreted proteins are dispensable for phagosome maturation arrest, suggesting that a novel effector required for phagosome maturation arrest is secreted by ESX-1. Other mutants identified in this screen had mutations in genes involved in lipid synthesis and secretion and in molybdopterin biosynthesis, as well as in genes with unknown functions. Most of these trafficking mutants exhibited a corresponding growth defect during macrophage infection, but two mutants grew like wild-type M. tuberculosis during macrophage infection. Our results support the emerging consensus that multiple factors from M. tuberculosis, including the ESX-1 secretion system, are involved in modulating trafficking within the host.

scholarly journals The Mycobacterium tuberculosis SecA2 System Subverts Phagosome Maturation To Promote Growth in Macrophages

2012 ◽  
Vol 80 (3) ◽  
pp. 996-1006 ◽  
Author(s):  
Jonathan Tabb Sullivan ◽  
Ellen F. Young ◽  
Jessica R. McCann ◽  
Miriam Braunstein
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Protein Export ◽  
Growth Defect ◽  
Phagosome Maturation ◽  
Wild Type ◽  
Intracellular Growth ◽  
Maturation Arrest ◽  
Content Type ◽  
Late Endosomes ◽  
Export System

The ability ofMycobacterium tuberculosisto grow in macrophages is critical to the virulence of this important pathogen. One wayM. tuberculosisis thought to maintain a hospitable niche in macrophages is by arresting the normal process of phagosomes maturing into acidified phagolysosomes. The process of phagosome maturation arrest byM. tuberculosisis not fully understood, and there has remained a need to firmly establish a requirement for phagosome maturation arrest forM. tuberculosisgrowth in macrophages. Other intracellular pathogens that control the phagosomal environment use specialized protein export systems to deliver effectors of phagosome trafficking to the host cell. InM. tuberculosis, the accessory SecA2 system is a specialized protein export system that is required for intracellular growth in macrophages. In studying the importance of the SecA2 system in macrophages, we discovered that SecA2 is required for phagosome maturation arrest. Shortly after infection, phagosomes containing a ΔsecA2mutant ofM. tuberculosiswere more acidified and showed greater association with markers of late endosomes than phagosomes containing wild-typeM. tuberculosis. We further showed that inhibitors of phagosome acidification rescued the intracellular growth defect of the ΔsecA2mutant, which demonstrated that the phagosome maturation arrest defect of the ΔsecA2mutant is responsible for the intracellular growth defect. This study demonstrates the importance of phagosome maturation arrest forM. tuberculosisgrowth in macrophages, and it suggests there are effectors of phagosome maturation that are exported into the host environment by the accessory SecA2 system.

scholarly journals Tuberculosis: New Aspects of an Old Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Luisa Jordao ◽  
Otilia V. Vieira
Keyword(s):  
Public Health ◽  
Nitric Oxide ◽  
Infectious Disease ◽  
Innate Immunity ◽  
Mycobacterium Tuberculosis ◽  
Host Defense ◽  
Molecular Mechanisms ◽  
Nitric Oxide Production ◽  
Phagosome Maturation ◽  
The World

Tuberculosis is an ancient infectious disease that remains a threat for public health around the world. Although the etiological agent as well as tuberculosis pathogenesis is well known, the molecular mechanisms underlying the host defense to the bacilli remain elusive. In this paper we focus on the innate immunity of this disease reviewing well-established and consensual mechanisms likeMycobacterium tuberculosisinterference with phagosome maturation, less consensual mechanism like nitric oxide production, and new mechanisms, such as mycobacteria translocation to the cytosol, autophagy, and apoptosis/necrosis proposed mainly during the last decade.

scholarly journals Tuberculosis Toxin Blocking Phagosome Maturation Inhibits a Novel Ca2+/Calmodulin-PI3K hVPS34 Cascade

2003 ◽  
Vol 198 (4) ◽  
pp. 653-659 ◽  
Author(s):  
Isabelle Vergne ◽  
Jennifer Chua ◽  
Vojo Deretic
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Membrane Trafficking ◽  
Intracellular Signaling ◽  
Antigen Processing ◽  
Phagosome Maturation ◽  
Maturation Arrest ◽  
Phagosomal Maturation

The capacity of Mycobacterium tuberculosis to infect latently over one billion people and cause two million fatalities annually rests with its ability to block phagosomal maturation into the phagolysosome in infected macrophages. Here we describe how M. tuberculosis toxin lipoarabinomannan (LAM) causes phagosome maturation arrest, interfering with a new pathway connecting intracellular signaling and membrane trafficking. LAM from virulent M. tuberculosis, but not from avirulent mycobacteria, blocked cytosolic Ca2+ increase. Ca2+ and calmodulin were required for a newly uncovered Ca2+/calmodulin phosphatidylinositol (PI)3 kinase hVPS34 cascade, essential for production of PI 3 phosphate (PI3P) on liposomes in vitro and on phagosomes in vivo. The interference of the trafficking toxin LAM with the calmodulin-dependent production of PI3P described here ensures long-term M. tuberculosis residence in vacuoles sequestered away from the bactericidal and antigen-processing organelles in infected macrophages.

scholarly journals Rab14 is critical for maintenance of Mycobacterium tuberculosis phagosome maturation arrest

2006 ◽  
Vol 25 (22) ◽  
pp. 5250-5259 ◽  
Author(s):  
George B Kyei ◽  
Isabelle Vergne ◽  
Jennifer Chua ◽  
Esteban Roberts ◽  
James Harris ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Phagosome Maturation ◽  
Maturation Arrest

scholarly journals Modeling Tubercular ESX-1 Secretion Using Mycobacterium marinum

2020 ◽  
Vol 84 (4) ◽  
Author(s):  
Alexandra E. Chirakos ◽  
Ariane Balaram ◽  
William Conrad ◽  
Patricia A. Champion
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Chronic Disease ◽  
Protein Secretion ◽  
Molecular Mechanisms ◽  
Salt Water ◽  
Secretion System ◽  
Mycobacterium Marinum ◽  
Content Type

SUMMARY Pathogenic mycobacteria cause chronic and acute diseases ranging from human tuberculosis (TB) to nontubercular infections. Mycobacterium tuberculosis causes both acute and chronic human tuberculosis. Environmentally acquired nontubercular mycobacteria (NTM) cause chronic disease in humans and animals. Not surprisingly, NTM and M. tuberculosis often use shared molecular mechanisms to survive within the host. The ESX-1 system is a specialized secretion system that is essential for virulence and is functionally conserved between M. tuberculosis and Mycobacterium marinum. M. marinum is an NTM found in both salt water and freshwater that is often used to study mycobacterial virulence. Since the discovery of the secretion system in 2003, the use of both M. tuberculosis and M. marinum has defined the conserved molecular mechanisms underlying protein secretion and the lytic and regulatory activities of the ESX-1 system. Here, we review the trajectory of the field, including key discoveries regarding the ESX-1 system. We highlight the contributions of M. marinum studies and the conserved and unique aspects of the ESX-1 secretion system.

scholarly journals Cellubrevin Alterations and Mycobacterium tuberculosis Phagosome Maturation Arrest

2002 ◽  
Vol 277 (19) ◽  
pp. 17320-17326 ◽  
Author(s):  
Rutilio A. Fratti ◽  
Jennifer Chua ◽  
Vojo Deretic
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Phagosome Maturation ◽  
Maturation Arrest
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