Chapter 4 : Invasion of the Mammalian Host: Early Events at the Cellular and Molecular Levels

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The majority of species belonging to the genus are divided into two groups, the spotted fever group rickettsiae (SFGR) and typhus group rickettsiae (TGR), based on the diseases that they cause, the presence of major surface antigens, and the ability to promote intracellular actin-based motility. This chapter focuses on the cell biology involved in the internalization of SFGR into nonphagocytic mammalian cells using as a model organism. It highlights the current knowledge regarding the bacterial proteins and cognate host cell receptors involved in initiating this process. Early studies on the mechanism(s) utilized by rickettsiae to invade nonphagocytic mammalian cells identified cellular actin dynamics as playing an important role. In some invasive pathogens, depletion of membrane cholesterol using methyl-β-cyclodextrin disrupts the composition of lipid rafts and inhibits invasion of nonphagocytic cells, suggesting that the presence of Ku70 within these microdomains is important for efficient bacterial entry. Mechanistic similarities to the invasion pathways utilized by zippering pathogens suggested that also usurps these types of signaling events. Bioinformatic analyses of sequenced rickettsial genomes revealed the presence of a gene family. Four genes in this family, namely , , , and , are present as intact open reading frames in the genomes of the majority of SFGR. The signals involved in rickettsial outer membrane protein B (rompB)-dependent invasion closely resemble those observed during the invasion of into Vero cells and include the activation of actin and microtubule dynamics and the stimulation of protein tyrosine kinase and PI-kinase activities.

Citation: Martinez J. 2012. Invasion of the Mammalian Host: Early Events at the Cellular and Molecular Levels, p 142-153. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch4
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Image of FIGURE 1

recruits actin to site of entry on mammalian cells. Fluorescence microscopy of infected mammalian cells reveals colocalization of actin-rich structures (green) with invading bacteria (red). Arrows indicate areas of colocalization (yellow). White scale bar represents 2 μm. Stimulation of actin dynamics is critical to the rickettsial invasion of mammalian cells. (Reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch4.f1

Citation: Martinez J. 2012. Invasion of the Mammalian Host: Early Events at the Cellular and Molecular Levels, p 142-153. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch4
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Image of FIGURE 2

Model of -induced signaling pathways in mammalian cells. The interaction of with Ku70 and other mammalian receptors initiates signaling events that are coordinated to ultimately recruit actin and components of the endocytic machinery to localized areas of the membrane. These pathways include the activation of protein tyrosine kinases, PI3-kinase, Cdc42, Src, FAK, and cortactin, which are likely involved in Arp2/3-mediated actin polymerization at entry sites. c-Cbl-mediated ubiquitination (Ub) of Ku70 and the involvement of clathrin and caveolin-2 implicate the host endocytic machinery in the invasion pathway. Pathways involved in the Ku70-rOmpB invasion pathway are highlighted in light blue boxes. Putative protein-protein interactions and pathways involved in rickettsial invasion are demarcated by dashed arrows and questions marks. (Reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch4.f 2

Citation: Martinez J. 2012. Invasion of the Mammalian Host: Early Events at the Cellular and Molecular Levels, p 142-153. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch4
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