Current information at the cellular level of the disease state focuses on the effect of the bacterial pathogen on cell surface receptors and the downstream effects within the host; however, it seems that the field is lacking a lot of knowledge on many of these specific interactions. Additionally, most of the information obtained regarding the disease mechanism for R. rickettsii is based on experiments using a very similar bacteria R. conorii. Regardless, because of the major similarity between the two species, it is viable to consider the mechanism of infection of R. conorii as being generally identical to that of R. rickettsii. This statement is supported by the fact that OmpB is potentially conserved functionally across all rickettsia species due to the large degree of shared sequence identity and homology of the specific protein (Chan et al. 2009).
Due to the fact that Rocky Mountain spotted fever is characterized by the effects of R. rickettsii on endothelial cells, it is important to consider the mechanism of binding between the host cells and bacteria cells as it is what controls for the disease state. The most important surface protein for the mechanism of infection of R. rickettsii is OmpB, as it is what allows for the bacteria to bind and enter endothelial cells through the Ku70 receptor (Chan et al. 2009). This study indicates that although very little is known about the specific interactions of the complex, OmpB is sufficient to mediate invasion of host endothelial cells via attachment to Ku70 on the surface (Chan et al. 2009). OmpA also has a role in this process, but what it binds and how it helps to mediate invasion of the host cell is not clear. Additionally, a recent study shows that knockdown of OmpA does not have a significant effect on the virulence of R. rickettsii because OmpB is what is paramount (Noriea et al 2015).
The landmark experiment that established Ku70 as the receptor for OmpB was carried out approximately ten years ago and was the first study that showed the receptor-ligand interaction allowing for the entry of rickettsial species into the cells (Martinez et al. 2005). Studies done by this group showed that upon the binding of OmpB to Ku70, the E3 ubiquitin ligase, Cbl, ubiquitinates Ku70 and the rickettsia present is phagocytosed as a result of a different signal-transduction pathway that uses Cdc42 (Martinez et al. 2005 and Chan et al 2009). However, the exact mechanism of how the structure of Ku70 facilitates the invasion of the rickettsial species using OmpB is still unclear. This is surprising due to the fact that the crystal structure of Ku70 has been uncovered; however, because OmpB is present on the outside of the bacteria along with numerous other unknown strucutres, it is very difficult to isolate a crystal strucutre of the protein by itself (Walker and Ismail 2008).After phagocytosis, R. rickettsii is shown to cause the lysis of the phagosome, which is then followed by the use of the Arp2/3 complex to polymerize actin monomers that function to push the bacteria through the cytoplasm and into the filopodia (Martinez and Cossart 2004). After this process, R. rickettsii are able to leave the cell and enter adjacent cells by pushing through the filopodia and into an adjacent endothelial cell to continue to replicate and infect more and more epithelial cells.
The binding of OmpB to Ku70 produces downstream effects that can be used to explain some of the negative symptoms of Rocky Mountain spotted fever. In addition to the fact that endothelial cells are disrupted upon invasion of the bacteria, the expression of two major enzymes involved in inflammatory response are affected. One of these enzymes, p38 MAP kinase, is activated by the binding of OmpB to Ku70 and causes for an increased inflammatory response in the body (Rydkina et al. 2005). The next enzyme, cyclooxygenase-2, is activated at the transcriptional level by signaling of p38 MAP kinase, which in turn causes for the release of prostaglandins (Rydkina et al 2009). The activation and stimulation of these enzymes via infection serve to alter the inflammatory response in infected humans to contribute to the symptoms of the disease. Pro-inflammatory response is also induced by infection of the bacteria as it causes increased expression of cytokines and chemokines (Rydkina et al. 2005). The increased production of chemokines is intriguing as to whether it benefits or hinders the disease due to the fact that they stimulate T cell movement to the site of infection (Walker and Ismail 2008). Additionally, R. rickettsii plays a role in altering cell apoptosis, which allows for the bacteria to manipulate cell death in order to be able to survive for longer periods of time in infected cells (Bechelli et al. 2009). While there is still a lot that is unclear regarding the infection with this bacteria, studies are continuously done to uncover more about the mechanisms of R. rickettsii as they pertain to Rocky Mountain spotted fever.