Adherence to and invasion of host cells by spotted Fever group rickettsia species

Abstract

The pathogenic lifecycle of obligate intracellular bacteria presents a superb opportunity to develop understanding of the interaction between the bacteria and host under the pretext that disruption of these processes will likely lead to death of the pathogen and prevention of associated disease. Species of the genus Rickettsia contain some of the most hazardous of the obligate intracellular bacteria, including Rickettsia rickettsii and R. conorii the causative agents of Rocky Mountain and Mediterranean spotted fevers, respectively. Spotted fever group Rickettsia species commonly invade and thrive within cells of the host circulatory system whereby the endothelial cells are severely perturbed. The subsequent disruption of circulatory continuity results in much of the severe morbidity and mortality associated with these diseases, including macropapular dermal rash, interstitial pneumonia, acute renal failure, pulmonary edema, and other multisystem manifestations. This review describes current knowledge of the essential pathogenic processes of adherence to and invasion of host cells, efforts to disrupt these processes, and potential for disease prevention through vaccination with recently identified bacterial adherence and invasion proteins. A more complete understanding of these bacterial proteins will provide an opportunity for prevention and treatment of spotted fever group Rickettsia infections.

Keywords: Rickettsia; adherence; invasion.

Figure 1

Autotransporter protein structure and secretion. Autotransporter proteins have modular structures, including an N-terminal signal peptide (SP, red), a central passenger domain (green), and a C-terminal translocation module called a β-peptide (blue). Following translation, the polypeptide is secreted across the inner membrane (IM) through the Sec translocon into the periplasmic space using information encoded in the N-terminal signal sequence. Through an undefined mechanism, the β-peptide next inserts into the bacterial outer membrane (OM) to form a β-barrel-rich transmembrane pore for the secretion of the central passenger domain into the extracellular space. In the case of some proteins, such as rOmpB, the passenger domain is subsequently proteolyzed from the β-peptide portion of the protein, but may remain associated with the outer leaflet of the bacterial outer membrane.

Figure 2

rOmpB-mediated bacterial invasion. Pseudo-colored scanning electron micrographs of a rOmpB-expressing Escherichia coli (yellow) inducing host membrane rearrangements during infection of a mammalian HeLa cell (blue).

Figure 3

Model of Rickettsia conorii invasion of non-phagocytic mammalian cells. R. conorii interaction with host receptors, including Ku70, activates numerous signaling pathways whose coordinated activities lead to modulation of the actin cytoskeleton and predicted localized recruitment of endocytic players including clathrin and caveolin 2. R. conorii internalization depends on the stimulation of multiple pathways involving PTKs, Cdc42, PI 3-kinase, Src, FAK, c-Cbl, and cortactin, which ultimately result in Arp2/3 dependent actin polymerization at the bacterial entry foci. Pathways and proteins involved in rOmpB–Ku70-mediated bacterial invasion have been highlighted in light blue boxes. Dashed arrows and question marks indicate putative protein interplay during the invasion process.