Molecular Basis of Disease State
Treatment and Disease Management
Conclusions and Proposals for Future Work
Human African trypanosomiasis, also known as “African sleeping sickness,” is an affliction endemic to sub-Saharan African (Stich, Abel, & Krishna, 2002). It is caused by trypanosomes, a type of parasite. The specific etiological agent that is responsible for most cases of African sleeping sickness is Trypanosoma brucei gambiense, although the disease can also be caused by Trypanosoma brucei rhodesiense. Trypanosoma brucei rhodesiense causes a rarer, acute form of the illness that kills over a few months. Trypanosoma brucei gambiense causes a chronic form of the illness that can take up to a few years to kill.
Trypanosomes have a complicated life cycle, part of which takes place within an insect called the tsetse fly (Stich, Abel, & Krishna, 2002). When an infected tsetse fly bites a human, the parasites are transmitted from the fly to the victim. A more detailed view of the tsetse fly life cycle can be seen in the image below.
The human immune system is naturally immune to attack from most trypanosomes (Vanhollebeke et al., 2008). During the first stage of disease, trypanosomes live in the bloodstream, where they reproduce and scavenge heme, a compound that is part of hemoglobin (the protein in red blood cells that transports oxygen between tissues) from red blood cells. Heme binds to a specific receptor on the trypanosome surface, and is then taken in by the parasite. The human immune system can usually kill trypanosomes by binding a compound called Hrp to heme (Pays et al., 2014). When this Hrp-heme complex is taken up by the trypanosome (which thinks that it is merely heme), Hrp enters the parasite and kills it from within.
If humans are usually naturally immune to trypanosomes, why do Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause disease? The answer lies in the trypanosome’s heme receptor. As previously mentioned, the immune system can bind a compound called Hrp to heme. This Hrp/heme complex binds to the trypanosome heme receptor, and Hrp can cause the death of the trypanosome. Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense have a single amino acid mutation in their heme receptors which prevents heme from binding when it is complexed with Hrp (Uzureau et al., 2013). Since it is the Hrp/heme complex that is deadly to trypanosomes, if its binding is blocked, the trypanosome can continue to thrive.
The stage of disease in which trypanosomes are multiplying in the circulatory system is known as the hemolymphatic stage (Lundkvist, 2004). When the trypanosomes have finished obtaining heme in the bloodstream, they cross over the blood-brain barrier and begin to attack the central nervous system (Mogk et al., 2014). This marks the beginning of the second stage of the disease, during which it is harder to treat. Potentially the most obvious effect of this infiltration is a significant disturbance of the sleep-wake cycle, caused by a release of tryptophol, a compound that is associated with proper circadian rhythms (Cornford et al., 1979). This sleep disturbance is where African sleeping sickness gets its name. The disease is eventually fatal if not treated. There are therapies available, but any treatment for second-stage African trypanosomiasis has a risk for severe side effects.
Lundkvist, G.B. (2004). Why Trypanosomes Cause Sleeping Sickness. Physiology 19, 198–206.
Stich, A., Abel, P.M., and Krishna, S. (2002). Human African trypanosomiasis. BMJ 325, 203–206.
Very interesting topic! The terminology for the acute and chronic versions of the disease was a bit confusing. Perhaps an explanation of the phases in disease progression would help. Interesting that it presents as an anemia.
Thanks for your comment! I can definitely clarify the terminology, and explain the disease progression a bit better.
This article is very clear and informative. I thought that the chart at the top of the page was useful, and I was wondering if there would be any way to reference it in the article.
Thank you for your comment Natalie! I agree, I think that the chart should be referenced.
As a non scientist, I would like to know:
1. What is Chagas disease?
2. What makes the human system susceptible if it is usually naturally immune?
3. Is the disease treatable, and if so, how is it treated?
Additionally, the part of how the disease reacts in the human system is a little confusing.
The topic was very interesting and informative.
Hi Barbara! Thank you for your feedback-I appreciate it. To answer your questions, 1) Chagas disease is a trypanosomal infection similar to African sleeping sickness, but is found in Latin and South America as opposed to Africa. 2) I brought mentioned this in my article, but I’m glad you brought it up, because it’s important! Trypanosomes thrive in the bloodstream by obtaining heme, which binds to a receptor on the outer surface of the parasite. Normally, the immune system can bind a compound called Hrp to heme. This Hrp/heme complex can bind the the trypanosome receptor, and Hrp can cause the death of the trypanosome. Trypanosomes that cause disease have a single mutation in their heme receptors that makes the immune Hrp/heme complex unable to bind, which means the immune system doesn’t have an “in” to the trypanosome. 3) There are several treatment options, depending on the stage of the disease. If the disease is still in its first stage (i.e., within the circulatory system), the disease can be treated with a drug called pentamidine, which has some side effects. If the disease has reached the central nervous system, then a drug called melarsoprol is implemented. Derived from arsenic, this drug can have serious side effects, including permanent brain damage. There is a newer drug available called eflornithine as well, that has less adverse effects than melarsoprol.
Also, I agree, I think that I could make the description of what the disease does within humans a little more clear!