Chapter 4 Lipid Raft-Mediated Entry of Bacteria into Host Cells

Many bacterial pathogens are known to enter into host cells, either as a means of avoiding the host immune system or as an integral part of their replicative cycle. One major hurdle intracellular pathogens must overcome is degradation in the classical endosomal/lysosomal fusion pathway. Some pathogens avoid this by escaping from their phagosomes before lysosomal fusion occurs, others actively modify their compartment to prevent lysosomal fusion, while still others have evolved defenses that allow them to survive in the harsh lysosomal environment (Small et al., 1994). Recent work has demonstrated that some pathogens have evolved a means of entering cells in a way that completely sidesteps the endosomal/lysosomal pathway altogether by utilizing discrete plasma membrane microdomains located on the host cell surface. These microdomains, commonly referred to as caveolae or lipid rafts, are enriched in cholesterol, glycosphingolipids, and glycosylphosphatidylinosotol (GPI)-anchored molecules (Anderson, 1998; Kurzchalia and Parton, 1999). Caveolae were initially described as cave-like invaginations of the plasma membrane, 50-100 nm in diameter, which contained a distinctive protein, caveolin. Since the protein caveolin is not found in all microdomains with the biochemical properties of caveolae, and not all domains with these properties have the distinctive shape of caveolae, we will define caveolae as pleomorphic lateral assemblies containing the protein caveolin-1 that are enriched in cholesterol, glycosphingolipids, and GPI-anchored molecules and that have the distinct morphological appearance of cave-like invaginations by electron microscopy (EM). Microdomains with the same biochemical properties that do not exhibit the cave-like structure of caveolae will be referred to as lipid rafts, regardless of the presence or absence of caveolin-1 within these microdomains (Harder and Simons, 1997; Simons and Ikonen, 1997; Kurzchalia and Parton, 1999). For ease of reading, except when it is necessary to make a clear distinction between caveolae and lipid rafts, the term lipid raft will be used. Most of the microbes that are utilizing lipid rafts for entry into cells bind distinct receptors on the host cell surface, which could lead one to envision multiple endocytic mechanisms for the various microbes. Another explanation for this conserved mechanism of entry is that the various receptors can all lead to the same endocytic pathway. This would imply that the various microbial receptors are located within lipid rafts or move into lipid rafts after microbial contact, as has been found to be the case for the receptors of many of the microbes and bacterial toxins that use lipid rafts (Lencer et al., 1999; Shin et al., 2000; Duncan et al., 2004). Many different signaling molecules are concentrated within lipid rafts (Anderson, 1998; Okamoto et al., 1998), including all the machinery necessary for vesicle budding, docking, and fusion (Schnitzer et al., 1995), making this an ideal pathway for microbial entry. Lipid rafts also seem to be linked to the actin cytoskeleton based on the localization of actin mobilizing/modulating molecules to lipid rafts and the recent report that the F-actin cross-linking protein filamin is a ligand for the protein caveolin-1 (Rozelle et al., 2000; Stahlhut and van Deurs, 2000). The idea that such vastly different bacterial pathogens such as FimH-expressing Escherichia coli (Baorto et al., 1997; Shin et al., 2000; Duncan et al., 2004), Salmonella typhimurium (Catron et al., 2002; Garner et al., 2002), and Chlamydia trachomatis (Norkin et al., 2001) can gain entry into host cells through a pathway involving lipid rafts, or use these structures to aid in intracellular survival, could be thought to indicate a high degree of similarity in their mechanism of entry. The fact that FimH-expressing E. coli and the infectious form of C. trachomatis (the metabolically inert elementary body) enter in a passive manner while S. typhimurium enters by actively secreting effector proteins into the cytoplasm of the host cell via a type III secretion system, thereby inducing uptake (Collazo and Galan, 1997; Suarez and Russmann, 1998), indicates that, though similarities in their mechanism of entry exist, there are distinct differences as well. Regardless, it is becoming clear that several pathogenic bacteria have recognized the endocytic functions of lipid rafts as a means of gaining entry into host cells in a manner that aids in the avoidance of lysosomal fusion and have evolved to fully exploit this mechanism of entry. © 2005 Elsevier Inc. All rights reserved.

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Author Soman Ninan Abraham Pathology