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Rickettsia rickettsii Infectious Cycle

Rickettsia rickettsii is an obligately intracellular bacterium that is spread to human beings by ticks.^[1] This bacterium has been previously characterized as the causal agent of Rocky Mountain spotted fever (RMSF). RMSF is endemic to many woodland areas of the United States as well as parts of Central and South America ^[2]. RMSF is the most severe of the spotted fevers with increasing prevalence in the United States. ^[3]. According to current data, the majority of rickettsial infections can be controlled by appropriate broad-spectrum antibiotic therapy if diagnosed early; however, up to 20% of misdiagnosed or untreated cases result in a fatal outcome caused by acute disseminated vascular endothelial infection and damage. ^[4] Now, more 100 years later the disease itself remains a dangerous threat to even the healthiest individuals due to difficulties of diagnosis. Furthermore, it has been predicted that temperature increases attributable to global climate change will lead to more widespread distribution of rickettsioses in addition to RMSF^[4].

Rickettsia rickettsii can be transmitted to human hosts through the bite of an infected tick. As with other bacterium transmitted via ticks, the process generally requires a period of attachment of 4 to 6h^[1]. However, in some cases a Rickettsia rickettsii infection has been contracted by contact with tick tissues or fluids^[1]. Then, the bacteria induce their internalization into host cells via a receptor-mediated invasion mechanism.

Researchers believe that this mechanism is similar to that of Rickettsia conorii. This species of Rickettsia uses an abundant cell surface protein called OmpB to attach to a host cell membrane protein called Ku70. It has previously been reported that Ku70 migrates to the host cell surface in the presence of "Rickettsia". ^[5] Then, Ku70 is ubiquitinated by c-Cbl, an E3 ubiquitin ligase. This triggers a cascade of signal transduction events resulting in the recruitment of Arp2/3 complex. Cdc42, protein tyrosine kinase, phosphoinositide 3-kinase, and Src-family kinases then activate Arp2/3. This causes the alteration of local host cytoskeletal actin at the entry site as part of a zipper mechanism. ^[6]. Then, the bacteria is phagocytosized by the host cell and enveloped by a phagosome.^[5]

Studies have suggested that rOmpB is involved in this process of adhesion and invasion. Both rOmpA and rOmpB are members of a family of surface cell antigens (Sca) which are autotransporter proteins; they act as ligands for the Omp proteins and are found throughout the rickettsiae. ^[3]

The cytosol of the host cell contains nutrients, adenosine triphosphate, amino acids, and nucleotides which are used by the bacteria for growth. For this reason, as well as to avoid phagolysosomal fusion and death, rickettsiae must escape from the phagosome. To escape from the phagosome, the bacteria secrete phospholipase D and hemolysin C. This causes disruption of the phagosomal membrane and and allows the bacteria to escape. Following generation time in the cytoplasm of the host cells, the bacteria utilizes actin based motility to move through the cytosol. ^[5]

RickA, expressed on the rickettsial surface—activates Arp2/3 and causes actin polymerization. The rickettsiae use the actin to propel themselves throughout the cytosol to the surface of the host cell. This causes the host cell membrane to be deformed outward and then it invaginates into the adjacent cell. ^[6]. The bacteria are then able to spread from cell to cell.

Rickettsia rickettsii migrate to vital organs such as the brain, skin, and the heart following infection. The subsequent binary replication causes perforation of the vessel walls within the host cells. The damage inflicted by the bacteria often results hyperplasia and then apoptosis of the infected cell. ^[5]