DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

Abstract

Survival of the African trypanosome in its mammalian hosts has led to the evolution of antigenic variation, a process for evasion of adaptive immunity that has independently evolved in many other viral, bacterial and eukaryotic pathogens. The essential features of trypanosome antigenic variation have been understood for many years and comprise a dense, protective Variant Surface Glycoprotein (VSG) coat, which can be changed by recombination-based and transcription-based processes that focus on telomeric VSG gene transcription sites. However, it is only recently that the scale of this process has been truly appreciated. Genome sequencing of Trypanosoma brucei has revealed a massive archive of >1000 VSG genes, the huge majority of which are functionally impaired but are used to generate far greater numbers of VSG coats through segmental gene conversion. This chapter will discuss the implications of such VSG diversity for immune evasion by antigenic variation, and will consider how this expressed diversity can arise, drawing on a growing body of work that has begun to examine the proteins and sequences through which VSG switching is catalyzed. Most studies of trypanosome antigenic variation have focused on T. brucei , the causative agent of human sleeping sickness. Other work has begun to look at antigenic variation in animal-infective trypanosomes, and we will compare the findings that are emerging, as well as consider how antigenic variation relates to the dynamics of host–trypanosome interaction.

Genome-wide and protein kinase-focused RNAi screens reveal conserved and novel damage response pathways in Trypanosoma brucei

“…Furthermore, homologous recombination (HR) not only provides for DNA break repair genome-wide, but also catalyses the locus-directed movement of Variant Surface Glycoprotein (VSG) genes that underpins immune evasion by antigenic variation in T . brucei [10]. The above knowledge has been accrued through homology-informed candidate gene studies, meaning several DDR activities have not been functionally tested and potentially kinetoplastid-specific activities may have escaped detection.…”

Post-meiotic DNA double-strand breaks occur in Tetrahymena, and require Topoisomerase II and Spo11

“…In fact, self-inflicted DSBs are essential for a wide range of processes, such as TOP2-dependent DNA disentangling (Champoux, 2001), V(D)J recombination (Stavnezer et al, 2008), chromatin diminution (Wang and Davis, 2014), Saccharomyces cerevisiae mating-type switching (Haber, 2012), antigenic variation in Trypanosoma (McCulloch et al, 2015), and, most prominently, meiosis (Keeney et al, 1997). They may also be essential for chromatin remodeling.…”

“…Nevertheless, deliberate DSB induction is necessary for reshuffling genes or DNA sequences. The most common example in eukaryotes is the induction of meiotic DSBs (Keeney et al, 1997), and others include the somatic recombination of immunoglobulin genes (Stavnezer et al, 2008), mating-type switching in yeast (Haber, 2012), and inducing antigenic variation in Trypanosoma (McCulloch et al, 2015). Post-meiotic DSBs (PM-DSBs) are a novel type of programmed DSBs that are claimed to occur during spermiogenesis in animals, including humans (Marcon and Boissonneault, 2004) and Drosophila (Rathke et al, 2007).…”

Transcriptional initiation of a small RNA, not R‐loop stability, dictates the frequency of pilin antigenic variation in Neisseria gonorrhoeae

“…There is evidence that RNase H controls the R-loop formation, and thereby affecting Av in the eukaryotic parasite, Trypanosoma brucei. Trypanosoma brucei is the causative agent of African sleeping sickness and utilizes Av to alter a variable surface glycoprotein (VSG) (McCulloch et al, 2015). R-loops form near VSG switch regions and upon deletion of the gene encoding RNase HI, R-loops near VSG are increased and VSG variation is increased (Briggs et al, 2018;Prister and Seifert, 2018).…”