DNA Double-Strand Breaks and Telomeres Play Important Roles in Trypanosoma brucei Antigenic Variation

Abstract

Human-infecting microbial pathogens all face a serious problem of elimination by the host immune response. Antigenic variation is an effective immune evasion mechanism where the pathogen regularly switches its major surface antigen. In many cases, the major surface antigen is encoded by genes from the same gene family, and its expression is strictly monoallelic. Among pathogens that undergo antigenic variation, Trypanosoma brucei (a kinetoplastid), which causes human African trypanosomiasis, Plasmodium falciparum (an apicomplexan), which causes malaria, Pneumocystis jirovecii (a fungus), which causes pneumonia, and Borrelia burgdorferi (a bacterium), which causes Lyme disease, also express their major surface antigens from loci next to the telomere. Except for Plasmodium, DNA recombination-mediated gene conversion is a major pathway for surface antigen switching in these pathogens. In the last decade, more sophisticated molecular and genetic tools have been developed in T. brucei, and our knowledge of functions of DNA recombination in antigenic variation has been greatly advanced. VSG is the major surface antigen in T. brucei. In subtelomeric VSG expression sites (ESs), VSG genes invariably are flanked by a long stretch of upstream 70-bp repeats. Recent studies have shown that DNA double-strand breaks (DSBs), particularly those in 70-bp repeats in the active ES, are a natural potent trigger for antigenic variation in T. brucei. In addition, telomere proteins can influence VSG switching by reducing the DSB amount at subtelomeric regions. These findings will be summarized and their implications will be discussed in this review.

Subtelomeric I-SceI-Mediated Double-Strand Breaks Are Repaired by Homologous Recombination in Trypanosoma cruzi

“…The switch of one VSG in the ES in T. brucei telomeres can be determined by telomere exchange/crossover or gene conversion mechanisms. Therefore, HR plays a role in the antigenic variation undergone by this parasite to evade the vertebrate host immune response (Li, 2015). In addition, spontaneous DSBs can activate VSG switching by HR-mediated DSB repair mechanisms (Boothroyd et al, 2009).…”

“…These (70-bp) repetitions are involved in recombination mechanisms responsible for antigenic variation in the African trypanosome (Boothroyd et al, 2009; Glover et al, 2013; Li, 2015). …”

“…Spontaneous DSBs in 70-bp repetitive regions, particularly in the active expression site (ES), can promote DNA recombination-mediated VSG switching involved in T. brucei antigenic variability (Glover et al, 2013; Li, 2015). The location of the DSB in the ES determines the type of VSG switching mechanism that will take place (Glover et al, 2013).…”

A Borrelia burgdorferi mini‐vls system that undergoes antigenic switching in mice: investigation of the role of plasmid topology and the long inverted repeat

“…Long IRs of similar size have been found in the same position in other B. burgdorferi strains: PAbe plasmid lp28‐1, Accession CP019923; 297 lp28‐1, Accession AB041949; JD1 lp28‐1, and BL206 lp28‐1, (unpublished results) and even other Borrelia species ( B. garinii lp28‐1, unpublished results) suggesting a possible role in the mechanism of antigenic variation. However, IRs have not been reported in other antigenic variation systems (Vink et al, ; Li, ).…”

Evidence for regulated expression of Telomeric Repeat-containing RNAs (TERRA) in parasitic trypanosomatids

“…Similar to other eukaryotes, the linear chromosomes of trypanosomatids are capped by telomeres composed of TTAGGG repeats and participate not only in protection of chromosome ends, but also in the control of expression of subtelomeric genes (ElSayed et al 2005, Glover et al 2007). Subtelomeric and telomeric regions are pivotal for antigenic variation in Trypanosoma brucei, a process that allows evasion from the host immune system during infection (Li 2015). Despite the growing body of information on trypanosomatid telomere biology (Janzen et al 2004, Jehi et al 2014, Devlin et al 2016, our knowledge of TERRA transcription and function in these early-branching eukaryotes remains limited.…”