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Host Immune Evasion by Trypanosoma Brucei, the Causative Agent of African Sleeping Sickness

Jack Dazley is a researcher in environmental science and biology.

SEM image of trypanosoma cells next to host immune cells

SEM image of trypanosoma cells next to host immune cells


The single celled protozoan Trypanosoma brucei is responsible for human African trypanosomiasis in sub-Saharan Africa, affecting some 65 million people in 36 countries. Carried by the tsetse fly (Glossina sp.) mammals are the definitive host. The pathology associated with T. brucei is notoriously difficult to treat, and this is due to the fact that the parasite uses a number of molecules and proteins to not only evade detection and elimination of the parasite by the host immune system, but is also capable of manipulating the host’s own biological molecules in order to promote growth of the parasite.

Here we will see the molecular mechanisms employed by T. brucei in order to evade detection and destruction by immune cells of the host organism, and how this parasite can use the host’s immune system to its own advantage in order to proliferate in the host both the mammalian host and the tsetse fly vector.

Inoculation into Mammalian Host

Unlike some species of protozoon parasites, such as Plasmodium, the causative agent of malaria which inhabits the erythrocytes of the host, Trypanosoma brucei is an extracellular parasite, spending the some of its life cycle in the bloodstream of the host. As such, the parasite should be vulnerable to the innate immune defences of the host including phagocytes and lymphocytes. In order to evade detection by the immune system of the host, Trypanosoma has evolved several mechanisms which are able to manipulate the host’s immune system to both modulate host defences ensuring the parasite is not destroyed, and also to activate certain processes to stimulate growth and development of the parasite.

Once the trypanosomes have developed into metacyclic trypomastigotes in the salivary glands of the tsetse fly, they must enter the bloodstream of the mammalian host. The skin of the mammal represents a significant anatomical barrier to T. brucei, and in order to penetrate the skin’s defences Trypanosoma uses a combination of saliva components and trypanosome-derived factors to create a trypanosome-receptive microenvironment in the skin, allowing the parasite to enter the bloodstream undetected. When feeding, infected fly injects saliva and along with it the metacyclic trypomastigotes intradermally, and the saliva constituents TTI and Adenosine-Deaminase (ADA) related proteins prevent coagulation of blood and the aggregation of platelet cells to the site of penetration.

Also, the allergen TAg5 stimulates activation of the host’s mast cells, which causes degranulation of the mast cells. As a result the mast cells release histamine and TNF, and this causes vasodilation of the blood vessels and also increases membrane permeability of blood vessels, allowing Trypanosoma to enter the bloodstream. Simultaneously, the immunoregulatory peptide Gloss2 downregulates the mammalian inflammatory response which is triggered upon breaching of the skin by the proboscis of the tsetse fly and in response to metacyclic trypomastigotes.

As the tsetse fly bites a mammal, the trypanosomes migrate into the blood of the mammalian host

As the tsetse fly bites a mammal, the trypanosomes migrate into the blood of the mammalian host

In addition to tsetse salivary components trypanosome factors are also involved in the inoculation of Trypanosoma into the mammalian bloodstream. Before entering the bloodstream, the metacyclic trypomastigotes develop into bloodstream forms, however the pathogen associated molecular patterns (PAMP) of this form, particularly variant surface glycoproteins (VSG) and CpG oligodeoxynucleotides activate host T cells and keratinocytes, leading to an increased immune response.

Manipulation of Host Biological Molecules

T. brucei is able to evade the host’s immune system using a variety of different biological molecules. The T. brucei-derived kinesin heavy chain (TbKHC1) is one molecule deployed by T. brucei which is able to dampen the inflammatory response of host macrophages. When TbKHC1 binds to the SIGN-R1 molecule, arginase activity is favoured which leads to an increased production of L-ornithine and by extension polyamines by the host, which are required for the growth of trypanosomes within the host. This also compromises the ability of arginine-producing immune cells to destroy the trypanosomes, allowing the parasite to grow and establish itself in the bloodstream of the host.

Trypanosoma brucei is also able to utilise adenylate cyclases (AdCs), namely T. brucei adenylate cyclase (TbAdC), an enzyme which catalyses the conversion of ATP to cyclic adenosine monophosphate (cAMP). During situation of immunological stress, for example when phagocytosis is taking place, cAMP levels are elevated within phagocytes, and this activates protein kinase A, leading to the inhibition of TNF synthesis, enabling the parasites to establish whilst avoiding destruction by host organism phagocytes.

Some of the many cell-surface antigens of Trypanosoma; these are always changing due to antigenic variation, impeding the host's immune response

Some of the many cell-surface antigens of Trypanosoma; these are always changing due to antigenic variation, impeding the host's immune response

Considering that Trypanosoma brucei is an extracellular parasite, they are directly exposed to the humoral immune response of the host. Once the metacyclic form of the trypanosome is inoculated by the infected tsetse fly, it rapidly develops into a LS bloodstream form. This change involves the remodelling of the trypanosome cell surface, with a change in the structure of the VSG (variant surface glycoprotein) coat. The VSG coat has two main functions, which are to protect bloodstream parasites from complementary-mediated lysis by the host’s immune cells, and to prevent recognition of cell surface proteins on the trypanosome by the innate immune system of the host. This way the immune cells of the host are unable to attach to the antigens and other extramembranous proteins on the cell surface of the trypanosomes, and thus the innate immune defences of the host are compromised.

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However, as mentioned previously, VSGs are susceptible to detection and activation of T cells which can initiate antibody-mediated lysis of the trypanosome cell (trypanolysis). In order to prevent this from occurring, T. brucei has evolved to frequently change the gene expression and by extension structure, of VSGs, meaning that the cell-surface antigens of the trypanosome are frequently mutating, much like the surface proteins of a virus. Again, this causes complications for the host immune system, as host antibodies are unable to bind to the cell surface antigens of the trypanosome. In addition, premature host B-cell expansion triggered by VSGs and non-mammalian CpG DNA causing the B-cells to differentiate into short-lived plasmablasts results in the production of non-specific IgM antibodies, which eventually leads to a decline in the population of host B-cells as cell death (apoptosis) occurs.

Another trypanosome-derived factor which is linked to promotion of parasite growth is the trypanosome-derived lymphocyte-triggering factor (TLTF). This secreted glycoprotein plays an important role in host-parasite interactions by stimulating the production of interferon gamma (IFN-γ), a type of cytokine produced by T-cells. Although IFN-γ is associated with a reduction in TLTF in the presence of anti-TLTF antibodies, in vitro studies have shown that IFN-γ is actually able to trigger TLTF secretion, promoting growth of the parasite. This shows that both TLTF and IFN-γ are critical molecules for bidirectional cellular communication between T. brucei trypomastigotes and host T-lymphocytes, and highlights the regulatory function of these molecules in the host-parasite interactions in T. brucei.

Immunological Suppression of Hosts

The T. brucei-derived trypanosome suppression immunological factor (TbTSIF) is another key molecule produced by Trypanosoma brucei which is known to initiate NO-dependent suppression of T-cell populations by stimulating macrophage activity. TbTSIF has two main routes of action against the immune response of the host. First, the molecule is able to inhibit proliferation of host T-lymphocytes by utilising IFN-γ dependent pathways, and secondly TbTSIF is able to down regulate the secretion of interleukin 10 (IL-10), an anti-inflammatory cytokine which plays a key role in immunological defence against pathogens. This is done by activating M2 macrophages, which reduce the effects of M1 macrophages. The overall effect of this is the suppression of the action of both M1 macrophages and T-lymphocytes, resulting in establishment of T. brucei and suppression of the host immune response. By this effect, it can be considered that TbTSIF is an essential molecule for parasite proliferation in the mammalian host.

Alongside host immune system evasion, trypanosome-derived factors are also capable of actively impairing healthy functioning and development of B-lymphocytes. The high antigenic variability and constant mutation of VSG proteins mean result in a loss of humoral immune function against the parasite, until a new set of antigen-specific antibodies are produced, a process which can take up to 10 days post-immunisation. In addition, VSGs have two direct effects on B-lymphocyte growth and development. Firstly, VSGs stimulate the production of non-specific polyclonal B-lymphocytes which leads to polyclonal exhaustion, leading to a failed immune response. Secondly, the VSGs are able to destroy the splenic B-lymphocyte compartment, resulting in massive depletion of B-cell proliferation and development. This results in a complete compromise of B-cell mediated immune response by the host, alleviating antibody-related pressures from the parasite and allowing T. brucei to successfully establish itself within the host, further resulting in trypanosome-related pathogenicity.


To conclude, over the course of evolution, Trypanosoma brucei has evolved many mechanisms for not only evading detection by the immune system of the host, for example by using tsetse salivary components to establish a trypanosome-tolerant microenvironment and escape detection by mast cells, but also to avoid elimination by host immune cells such as B-lymphocytes, achieved by manipulating immune cells and using the host’s own immunological molecules, such as INF-γ, to not only supress B- and T-lymphocytes, and to stimulate production of growth-promoting molecules such as TNF and TLTF. In addition, the constant mutation and structural changes of VSGs due to morphological changes in the lifecycle of T. brucei mean that there is a constant ‘arms race’ between parasite and host, as each time the surface antigens of the parasite change, the host’s immune system produces complimentary antibodies exerting an antibody-mediated pressure on the parasite.

Trypanosoma brucei is a perfect example of a parasite which, although simple in body structure, being a microbial eukaryote, has incredibly complex molecular mechanism involved in interactions with the hosts, demonstrating a specialisation to mammalian definitive hosts.


- Cnops, J., De Trez, C., Bulte, D., Radwanska, M., Ryffel, B. and Magez, S., 2015. IFN-γ mediates early B-cell loss in experimental African trypanosomiasis. Parasite Immunology, 37 (9), 479-484.

- Hutchinson, O. C., Picozzi, K., Jones, N. G., Mott, H., Sharma, R., Welburn, S. C. and Carrington, M., 2007. Variant surface glycoprotein gene repertoires in Trypanosoma brucei have diverged to become strain-specific. BMC Genomics, 8 (234), 1-10.

- Kim, H-S. and Cross, G. A., 2010. TOPO3α influences antigenic variation by monitoring expression-site-associated VSGF switching in Trypanosoma brucei. PLOS Pathogens, 6 (7), 1-14.

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- Radwanska, M., Guirnalda, P., De Trez, C., Ryffel, B., Black, S. and Magez, S., 2008. Trypanosomiasis-induced B cell apoptosis results in loss of protective anti-parasite antibody responses and abolishment of vaccine-induced memory responses. PLOS Pathogens, 4 (5).

© 2018 Jack Dazley

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