Intracellular Bacteria
Bacterial Specificity

Macrophages serve as the first line of defence by eliminating indesirable microorganisms. These professional phagocytic cells engulf bacteria within phagosomes that rapidly evolve into bactericidal organelles termed phagolysosomes. As they mature into digestive organelles, phagosomes progressively acidify and interact with the endosomal network and/or the biosynthetic pathway (Endosomal membrane traffic: convergence point targeted by Mycobacterium tuberculosis and HIV. 2004) (Desjardins et al., 1994; Desjardins, 1995; Claus et al., 1998; Ullrich et al., 1999; Deretic et al., 2004; Becker et al., 2005). Two predominant models exist to explain the biogenesis of phagolysosomes: the ‘vesicle shuttle’ model, which supports that transport intermediates deriving from endocytic organelles are targeted to phagosomes, and the ‘kiss and run’ model, which proposes that phagosomes undergo transient and partial fusion with endocytic organelles (Desjardins et al., 1994; Desjardins, 1995; Gu and Gruenberg, 1999; Gruenberg, 2001; Harrison et al., 2003).

This dynamic process is modulated by the sequential appearance and disappearance of proteins on the membrane.

1. plasma membrane proteins, including the transferrin receptor (TfR), which initially compose the phagosome, disappear and are replaced sequentially by proteins present in early endosomes (e.g. early endosomes antigen 1 or EEA1, and Rab5 GTPase).
2. The following event leads to the late endosome stage of maturation, characterized by the acquisition of specific markers such as the Rab7 GTPase and peripheral transmembrane glycoproteins Lamps.
3. as the phagosomes continue to acidify and accumulate different Rabs, more Lamps, cathepsin D and other acid hydrolases, they develop lysosomal traits.

In addition to this well-characterized endocytic pathway, cells possess another defensive mechanism against invading pathogens, the autophagic pathway (Mizushima et al., 2002; Reggiori and Klionsky, 2002; Yoshimori, 2004).

Inside host cells, certain intracellular pathogens control the fate of their membrane-bound compartments, and escape host degradation by interfering with the endocytic pathway or by infiltrating the autophagic route (Meresse et al., 1999; Dorn et al., 2002).

Parasite tools against acidification

Inhibition of Rab7 etc

Intravacuolar pathogens have evolved several different strategies of finding a successful intracellular replication niche. One strategy developed by Mycobacteria and Salmonella enterica serovar Typhimurium within phagocytic cells is the establishment of vacuoles specifically retaining or excluding proteins that govern phagosome maturation. Indeed, aberrant distribution of the EEA1/Rab5 and Rab7 GTPases has been correlated with virulence for these pathogens (Clemens and Horwitz, 1995; Via et al., 1997; Hashim et al., 2000; Knodler and Steele-Mortimer, 2003). A second strategy used by a subgroup of vacuolar pathogens such as Brucella abortus (Pizarro-Cerda et al., 1998a,b), Coxiella burnetii (Beron et al., 2002) and Porphyromonas gingivalis (Dorn et al., 2001) is to infiltrate the autophagic pathway of host cells. The transit through autophagic pathway allows B. abortus and Legionella pneumophila to gain access to the endoplasmic reticulum (ER) (Pizarro-Cerda et al., 1998a,b; Amer and Swanson, 2005). AIEC LF82 E. Coli are able to survive and to replicate within a compartment harbouring hostile features of mature phagolysosomes including acid pH and active cathepsin D. Moreover, the acidic vacuolar environment is necessary for replication of AIEC LF82 bacteria within J774 macrophages.

Phagosomes Fuse with Late Endosomes and/or Lysosomes by Extension of Membrane Protrusions along Microtubules: Role of Rab7 and RILP

Autophagy: a regulated bulk degradation process inside cells.

Bacterial interactions with the autophagic pathway.

Taking possession: biogenesis of the Salmonella-containing vacuole.

Brucella abortus Transits through the Autophagic Pathway and Replicates in the Endoplasmic Reticulum of Nonprofessional Phagocytes

Coxiella burnetii Localizes in a Rab7-Labeled Compartment with Autophagic Characteristics

Porphyromonas gingivalis Traffics to Autophagosomes in Human Coronary Artery Endothelial Cells

Macrophages Rapidly Transfer Pathogens from Lipid Raft Vacuoles to Autophagosomes

The Crohn's disease-associated adherent-invasive Escherichia coli strain LF82 replicates in mature phagolysosomes within J774 macrophages.