African trypanosomes: the genome and adaptations for immune evasion

Abstract

The African trypanosome Trypanosoma brucei is a flagellated unicellular parasite transmitted by tsetse flies that causes African sleeping sickness in sub-Saharan Africa. Trypanosomes are highly adapted for life in the hostile environment of the mammalian bloodstream, and have various adaptations to their cell biology that facilitate immune evasion. These include a specialized morphology, with most nutrient uptake occurring in the privileged location of the flagellar pocket. In addition, trypanosomes show extremely high rates of recycling of a protective VSG (variant surface glycoprotein) coat, whereby host antibodies are stripped off of the VSG before it is re-used. VSG recycling therefore functions as a mechanism for cleaning the VSG coat, allowing trypanosomes to survive in low titres of anti-VSG antibodies. Lastly, T. brucei has developed an extremely sophisticated strategy of antigenic variation of its VSG coat allowing it to evade host antibodies. A single trypanosome has more than 1500 VSG genes, most of which are located in extensive silent arrays. Strikingly, most of these silent VSGs are pseudogenes, and we are still in the process of trying to understand how non-intact VSGs are recombined to produce genes encoding functional coats. Only one VSG is expressed at a time from one of approximately 15 telomeric VSG ES (expression site) transcription units. It is becoming increasingly clear that chromatin remodelling must play a critical role in ES control. Hopefully, a better understanding of these unique trypanosome adaptations will eventually allow us to disrupt their ability to multiply in the mammalian bloodstream.

Conference Scene: Understanding Pathogen Evasion of Host Immunity

“…In effect, Rudenko concluded that the extensive potential for VSG switching gives T. brucei gambiense a modifiable patchwork surface, with the H1 histone reflecting a checkpoint mechanism to T. brucei gambiense chronicity [1,2]. Increased research into antigen switching in T. brucei gambiense may assist in understanding the mechanisms underlying other pathogen antigen switch strategies and hopefully stimulate therapeutic design to overcome this strategy of host immune evasion.…”

“…In collaboration, Rudenko's group determined that H1 knockdown effected a more open T. brucei gambiense chromatin structure, leading to increased VSG switching, with normally silent VSG expression sites particularly sensitive [1,2].…”

“…Rudenko reminded the conference that clinical features occur in a cyclical pattern, with characteristic fever 'spikes' throughout the course of infection. This underpinned Rudenko's investigation of the effect of mosaic pattern switching of VSG localized on the T. brucei gambiense membrane as an effective coat [1].…”

Inhibition of Nucleotide Sugar Transport in Trypanosoma brucei Alters Surface Glycosylation

“…Each has a glycoprotein coat composed of a stage-specific major surface glycoprotein: procyclins in the PCF stage (7) and variant surface glycoproteins (VSGs) in the BSF stage (8). Both VSGs and procyclins play pivotal roles in pathogenesis, VSG as the lynchpin of antigenic variation in the mammalian bloodstream (9) and procyclin as a critical component facilitating colonization in the tsetse midgut (10). In addition, there are many less abundant surface glycoproteins including invariant surface antigens, transferrin receptor, and other nutrient transporters that are critical to the success of these important human pathogens (11).…”

“…Both are glycosylphosphatidylinositol (GPI) anchored and N-glycosylated, and there are distinct stage-specific variations for each class of glycomodification (12). In PCF cells only oligomannose N-glycans (Man 9 GlcNAc 2 ) are transferred to nascent glycoproteins, and these are typically trimmed to small triantennary (Man 5 GlcNAc 2 ) structures (13,14); subsequent extension by addition of other hexose units in the Golgi apparatus has not been found. In addition to this kind of N-glycosylation, BSF cells are also capable of transferring abbreviated biantennary paucimannose structures (Man 5 GlcNAc 2 ), and these can be trimmed and extended in the Golgi apparatus by addition of N-acetyllactosamine (LacNAc, Gal␤1-4GlcNAc) units (15,16).…”