History and Metabolic Context

Rocky Mountain spotted fever is a tick-borne illness that could possibly become fatal after infection of the host with the bacteria Rickettsia rickettsii.  Rocky Mountain spotted fever is also the deadliest and most severe form of any Rickettsia infection. Some symptoms of the disease include but are not limited to: a full-body rash, fever, nausea, headache, vomiting, muscle and abdominal pain, conjunctival infection and loss of appetite. Diagnosis of the disease is only possible through identifying the above symptoms of Rocky Mountain spotted fever in a patient followed by blood tests to check for any of the specific microorganisms known to be responsible for infection (Choi et al. 2016).

Figure 1: Diagram of symptoms of Rocky Mountain spotted fever after infection. TG
Figure 1: Diagram of symptoms of Rocky Mountain spotted fever after infection. (TG)

Even though the first case of Rocky Mountain spotted fever was identified in 1896, it was not for another decade that scientists were able to uncover the causative agent (Dantas-Torres 2007). Howard Taylor Ricketts is the scientist who is credited with the discovery of the microorganism that leads to Rocky Mountain spotted fever. In a series of studies done at the beginning of the 20th century, Ricketts was able to discover R. rickettsii, as the bacteria present in the blood of both infected humans and their tick vectors. His preliminary studies on the disease were inconclusive in terms of finding the specific bacteria that is the causative agent of Rocky Mountain fever through the successful inoculation of various mammalian species (Ricketts 1906). It was not until his experimental paper produced two months later that he was able to identify that a guinea pig was able to become infected and display the symptoms of Rocky Mountain spotted fever through placement of a tick on its ear (Ricketts 1906). His landmark paper that established the role of the wood-tick as the vector for the disease was not published until the following year after Ricketts was able to perform more experiments with a greater sample size to obtain significant results. (Ricketts 1907). However, even in this experiment Ricketts did not come to the final conclusion that a microorganism within the tick is what is truly responsible for the manifestation of the disease. Ricketts was aware that some intracellular parasite caused the symptoms of the disease to occur in a host after bite of a tick, but it was not for another two years that he produced a paper stating that the “bacillus” of Rocky Mountain fever had been connected to the disease (Ricketts 1909). Through testing the blood of infected ticks, guinea pigs, and humans, Ricketts was able to find a small microorganism present that he was unable to isolate previously. He identified this as the pathogen responsible for Rocky Mountain spotted fever; however, Ricketts died the following year after getting typhus while studying the disease itself. His research specifically set the stage for other scientists to continue work with the bacteria in an attempt to develop some preventative measures for infection.

Figure 2: Transmission electron micrograph of the bacteria Rickettsia rickettsii.  https://cdn.superstock.com/4269/Download/4269-27720.jpg

To identify the disease in an infected patient, doctors primarily rely on seeing if the symptoms present correlate with Rocky Mountain spotted fever. However, after this, it is important for a series of blood tests to be done because of the difficulty of clinically identifying this specific virulent form of Rickettsia due to its similarity with other infections of the same genus. A recent study conducted on various R. rickettsii carrying ticks showed that isolation of the bacteria was possible through centrifugation of the blood and egg masses of infected ticks (Dzul-Rosado et al. 2013). Another way scientists have been able to identify the disease is shown in a skin biopsy experiment carried out that used real time PCR isolate the infectious microorganism from the rash of patients with Rocky Mountain spotted fever (Denison et al. 2014). Clinical testing using the skin and blood of infected patients has proven to be the most effective method done to isolate the the bacteria causing Rocky Mountain spotted fever so that a diagnosis can be properly obtained.

The cellular context of Rocky Mountain spotted fever can be essentially simplified down to R. Rickettsii being transmitted to the host via infected tick bite and traveling through the blood in an attempt to ultimately bind to and enter host endothelial cells. The exact way that R. rickettsii is able to infect the host is through the binding of its outer membrane proteins to receptors present on endothelial cells. The two major surface proteins identified to participate in this reaction are bacterial OmpA and OmpB, with OmpB being identified as the necessary surface protein that is required for the bacteria to be able to infect host cells (Policastro and Hackstadt 1994). However, recent studies show that new surface proteins have been identified as having an unknown role in the facilitation of this binding reaction in an attempt to further understand the mechanism behind infection (Gong et al. 2014). Binding of these outer membrane proteins to the Ku70 receptor protein on host cells would result in the the replication of the bacteria and eventual phagocytosis, but in a healthy state endothelial cells are able to proliferate normally. Ku70 is an integral part of the DNA-dependent protein kinase that plays a role in DNA repair, V(D)J recombination, and immune response (Martinez et al. 2005). Inhibition of Ku70 function and expression is very significant due to the roles that it plays in healthy cells, and it is perhaps the most important receptor to investigate in terms of the molecular context of Rocky Mountain spotted fever. In a disease-free state, Ku70 is able to continue to function for its role in DNA maintenance, and endothelial cells are able to proliferate and continue to play a role in inflammatory response, barrier regulation, and blood cell maintenance.

2 Replies to “History and Metabolic Context”

  1. Great Work, very well written review! I was wondering for the diagnosis of Rocky Mountain Spotted Fever, do they ever test the tick for R. rickettsii carrying the disease, prior to the when symptoms appear? If a tick is found on a person in an area where Rocky Mountain fever is prevalent, would physicians begin treatment with Doxycycline (also used for lyme disease) before symptoms; in a similar way that lyme disease is treated in this area?

    1. Hey Zach thank you very much for your input. Your question is difficult to give a yes or no response to due to the fact that not everyone who finds ticks on themselves actually keeps the tick to get it tested, especially given how often ticks are found on people in the Rocky Mountain area that consists of a lot of woodland. Given the information as provided by the CDC, diagnosis of the disease is normally based on clinical signs and symptoms, so it is difficult to even determine if someone has the disease, let alone treat them until symptoms are shown. However, I would assume that in areas where Rocky Mountain spotted fever is prevalent, it would not be abnormal to treat with low doses of the antibiotic before symtpoms are shown. Additionally, there are many studies shown to identify for the presence of R. rickettsii in ticks as evident in some of the literature I have provided by H. T. Ricketts and Dzul-Rosado et. al. if you are curious for more information.

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