Conclusions and Proposals for Future Work

While there have been a lot of studies done in the past to attempt elucidate the mechanism of infection of Rocky Mountain spotted fever there is still a lot of work that needs to be done. Additionally, the scientific literature seems to be lacking in treatment methods due to the fact that Doxycycline has really been the only antibiotic to positively treat infected patients with significant results. After thoroughly investigating Rocky Mountain spotted fever from a variety of angles, it is clear that there are definitely places where future studies need to be done to uncover more about the disease and its bacterial pathogen.

In the current literature, there are many studies shown uncovering new surface proteins that play a role in binding of rickettsia to target host cells; however, most of these studies conclude by stating that although there are other proteins involved, the exact function is unknown (Gong et al 2014). The fact that there are so many proteins covering the surface of these bacterial species makes it very difficult to understand exactly how R. rickettsii is able to enter endothelial cells. Studies similar to the one mentioned above that uncovered five novel surface proteins, need to be examined from a different view point to understand the exact interactions between receptors and ligands of rickettsia infection. OmpB is essentially the only target of research for the mechanism of binding to endothelial cells by the bacteria, and even this interaction is not that well known. The scientists studying the surface proteins of R. rickettsii should attempt to compare the bacterial surface proteins that are known to be involved in binding with proteins present already in the human body that bind to similar receptors based on structure. Because of the fact that little is known about the bacterial surface protein interactions apart from OmpB, a lot of studies have only attempted to create vaccines using a recombinant form of OmpB (Gong et al. 2015). If more information were obtained about the other proteins, it is possible that another protein could be necessary for bacterial invasion that has not been seen before. This new protein could potentially be a drug that inhibits binding of R. rickettsii to human cells so that the bacteria are unable to enter cells and replicate in the first place.

Even more so than the fact that more research needs to be done on the surface proteins on rickettsia species, the mechanism of exactly how the bacteria is able to enter endothelial cells needs to be elucidated much more. Although the mechanism of how R. rickettsii infects host endothelial cells is generally shown in the literature, there are many pieces of it that could benefit from future research. Even though there are crystal structures of bacterial OmpB and the receptor to which it binds, Ku70, it is disconcerting that the exact way rickettsia species interact and enter the cells here is still unclear. Studies done by Martinez et al. even attempt to describe the mechanism by which the OmpB-Ku70 complex facilitates the invasion of R. rickettsii into the cell, but show that the exact path is unclear. A possible way to investigate this problem could be through a series of tests, such as cross-linking and/or pull-down assays, that could isolate OmpB and Ku70 so their interactions could be studied. If more information could be obtained about the exact structural interactions between both rickettsia and human surface cells, it is possible that a drug could be created to inhibit this binding without altering the expression of Ku70 and its role in healthy cell function. 

cross link
Figure 1: Possible depiction of cross-linking experiment that could produce better results for the interaction between OmpB and Ku70. http://www.nature.com/nprot/journal/v9/n1/images/nprot.2013.168-F1.jpg

Another area of study that could benefit from future research is the use preventative measures prior to infection with R. rickettsii and prior to bite of infected tick. While there have been studies done on the feeding period required for transmission of R. rickettsii from vector to host (Saraiva et al. 2014), there is no significant research available on how to prevent the tick from staying attached in the first place. While any generic bug spray product may prevent ticks from coming into contact with the shielded skin, it is not possible to consider this viable protection. It would not only be too inconvenient to put on bug spray every day, but also the current products available on the market are not 100 percent effective. Future research could potentially be done to consider a drug administered that would prevent ticks from staying attached long enough to transfer the infective agent. It would be interesting to see if a drug has the potential to be toxic for ticks but still able to circulate in our body. The possibility of a chemical manifesting itself in our skin cells that would be released upon puncture of the skin by tick bite, which would in turn either kill the tick or simply cause it to detach itself from the host is something that is very intriguing.

Figure 2: Photograph of Dermacentor variabilis attached to and feeding on a human host. http://www.pestworld.org/media/561776/american-dog-tick.jpg
Figure 2: Photograph of Dermacentor variabilis attached to and feeding on a human host. http://www.pestworld.org/media/561776/american-dog-tick.jpg

6 Replies to “Conclusions and Proposals for Future Work”

  1. Hi Tyler,

    Great job on your blog, this is an interesting disease and I’m glad I now know the symptoms just incase!

    My questions are regarding the transmission of the bacteria. One of your proposals is regarding the development of protection against tick bites. While this may sound a little funny, I know that there are well developed tick repellent products that we use for our dogs and cats. Has anyone tested these types of products as a way of preventing tick bites in humans? Also, since transmission occurs within a tick borne vector are there typically co-infections that occur? I know in the case of Lyme disease which is another tick borne illness, often patients can develop other infections such as babesia or bartonella in addition.

    1. Hey Elaine thanks for the interesting questions! While I have not come across the use of animal tick repellants for the protection of humans against tick bites, I am sure that the animal repellants are very similar is chemical make up to the bug sprays that we typically use. In terms of co-infections with the bacteria, I have not seen any studies specifically mentioning other infections as a result of Rocky Mountain spotted fever other than those that develop as symptoms, like conjunctival infection. However, due to the nature of the infection and its effect on the endothelial cells, it would not surprise me if patients infected are more susceptible to developing some type of skin infection in addition to the rash.

  2. Great job on your explanations and I like your suggested cross-linking experiment. Above you mention that furthering our understanding of how rickettsia binds and enters host cells is an important next step. This is an interesting point to make as blocking such fusion interactions is currently used a strategy for treatment of viruses, such as HIV, even resulting in an entire class of drugs used for treatment (search for fusion and entry inhibitors if you want more info.) Have you come across any information in the literature where a similar strategy has been tried/used to treat infections with intracellular pathogenic bacteria? What is know about how other intracellular bacteria enter their host cells, i.e. are those pathways better elucidated?

    1. Hey Matt thank you for great comments and questions! I think the idea of inhibiting the binding of this specific complex would be a great strategy and cross-linking may show some helpful results. I do not have a lot of information on other pathogenic bacteria apart from R. rickettsii in terms of treatment of their infections due to the fact that the topic of my project focused specifically on Rocky Mountain spotted fever. Additionally, I have not seen much research on my particular proposed strategy in general, which is why I definitely think a lot of studies need to be done in the future to improve what is known about this area of the disease and with infections that result from other bacterial pathogens that have similar mechanisms of infection.

  3. Nice work Tyler! To be honest the giant picture of the tick really freaked me out! They are so gross. Anyway, I was curious about your proposal of investigating the interaction between OmpB and Ku70 in order to create a drug that would inhibit this binding without altering the expression of Ku70. Did you get a sense from your research that a drug could be used to target and bind to OmpB on the bacterium instead of Ku70 so this wouldn’t be a problem? What else binds to Ku70 that would cause problems if the receptor of Ku70 was inhibited? Could it be inhibited for a short amount of time just until the bacterium was destroyed, and then could the inhibitor be knocked out? I’m curious about your thoughts on this since there seems to be a lot left to be discovered when it comes to this disease!

    1. Hey Nikki thank you for your questions and I am sorry that the tick scared you, but that’s one of the effects I was hoping to have on readers due to how scary of a disease the tick could actually cause! In terms of the development of a drug that can target OmpB on the bacteria, there are no specific antibiotics available yet that is able to do so. In the literature, however, there have been studies showing the use of recombinant OmpB as a treatment for the symptoms through the development of antibodies as a response by Gong et al 2015. Another study by Riley et al. 2015 actually showed the failure of a creation of a vaccine via this route. I have not seen a study in terms of a specific inhibitor of OmpB being developed, but inhibiting Ku70 could potentially result in a lot of damage to the host due to the fact that Ku70 plays a large role in many nuclear functions like DNA repair, V(D)J recombination, transcription regulation and many more (Martinez et al. 2005). I think that because all of these functions rely on Ku70 that it would be difficult to inhibit it even for a short period of time.

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