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You are here: Home / Health / Introduction to the evasive world of trypanosomes

Introduction to the evasive world of trypanosomes

Transmitted by the tsetse fly, Trypanosoma brucei, the African Trypanosome is a single-celled parasite that can cause African sleeping sickness.

Both sexes of the tsetse fly can transmit the parasite and it can be found in rural areas and woodlands and bites during the day.

African sleeping sickness is split into two forms, East African and West African, dependant on the subspecies of T. brucei that infects the host. Their name, quite concisely, reflects their geographical distribution. The disease progression varies between the two, with East African being the more rapid. Ultimately though, if untreated, both will lead to coma and death.

Figure 1 | The sleeping sickness life cycle in humans | Courtesy of DPDx (www.cdc.gov/dpdx)

What’s interesting is that the parasite spends quite some time exposed in the human bloodstream, which is important, as the mammalian bloodstream is a hostile environment. For example, Plasmodium, the parasite that causes Malaria, is well-adapted to spending time inside our host cells to evade our immune response.

The mammalian bloodstream

Trypanosomes, whilst being extracellular parasites, can evade the mammalian bloodstream’s host defences, whilst maintaining chronic infections and multiplying. It is because of this that they are useful models for investigating host-pathogen interactions and evasion of the immune response. This is achieved in a neat way, analogous to a shapeshifter.

Loosely speaking, the immune response works as such: The host creates Y-shaped antibodies – also known as immunoglobulins. A common analogy used to illustrate this is that the Y-shape is a ‘lock’. The ‘key’ is the antigen, which is a unique molecule of the pathogen. The role of the antibody is to lock on to or bind and label the antigen. This label identifies the antigen and allows the rest of the immune system to know where to target its response.

Whilst simplified, this sounds elegant and effective, so how do Trypanosomes evade the host’s immune response? They have developed a variable surface glycoprotein (VSG) coat. Variable is the key word here, as the VSG changes so that even if antibodies are raised to a certain VSG variant, new variants are generated, which evade the immune response.

Let’s say the host raises antibodies against the predominant trypanosome population, which we’ll say has a blue coat. Within that population, some may have switched their coats to red, which as yet, is not recognised by the host. These have a temporary advantage and may proliferate. There are many coat ‘colour’ genes to choose from, and by switching regularly, the trypanosome can evade the host’s immune response and mount a chronic infection for a sustained period.

The VSG coat doesn’t cover the whole trypanosome, and there are some surface proteins that do not vary, making them vulnerable to host recognition. These cells, however, are in a sheltered location near the base of the flagellum (the tail bit – see Figure 2).

Fig 2 | Trypanosoma brucei | By Zephyris [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], from Wikimedia Commons
Trypanosomes have a huge array of VSG genes that code for different VSG coats, or continuing the analogy, coat colours. Only one coat colour can be expressed at a time, which happens at the expression site (ES). There are many mechanisms to change the coat colour. Some are as simple as just activating a new ES and silencing the old one, but there’s one mechanism that is worth mentioning, as it shows us why the trypanosome is so adept at evading the host’s immune response.

Imagine each VSG gene codes for a colour, and in theory, you can only express one colour at a time. What if you expressed small segments of multiple VSGs? Red and blue? Sure! Now the coat is purple. In this way, the trypanosome can cycle through endless permutations of VSG, evading the immune response for a sustained period.

The mechanisms for changing the VSG aren’t fully understood. The VSG is transcribed from a finite amount of expression sites (ESs). The mechanisms behind changing the VSG allow for an almost endless amount of mosaic VSG coats to be produced.

That is not all though, the coat ‘recycles’ itself approximately every twelve minutes, whilst also being cleansed of any host molecules, including importantly any of the host’s antibodies. It is only effective when the immune system is being launched, and few antibodies are present.

We can see now why the trypanosome is so adept at evading the immune response in the mammalian bloodstream, an environment known for its hostility. The trypanosome can not only recycle and clean its coat but almost infinitely vary it.

Evolutionarily-speaking, an ancestor of trypanosomes diverged from the eukaryote family tree (which includes us) relatively early on. As such, their biology is distinct from the standard eukaryotic model organisms that we study today. Understanding the underlying functions and pathways that keep them ticking may be crucial to treating disease. Additionally, they may have evolved distinct pathways to solving a problem that we can learn from and manipulate.

Ultimately, if we can understand and impede the trypanosomes’ host-evasion strategies, we can look to finding an effective way to end African sleeping sickness. In the process, we learn about a sophisticated and elegant parasite and how it avoids host detection. This may inform how we deal with other parasite-borne diseases in the future.

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