Telomere components as potential therapeutic targets for treating microbial pathogen infections

Abstract

In a number of microbial pathogens that undergoes antigenic variation to evade the host’s immune attack, genes encoding surface antigens are located at subtelomeric loci, and recent studies have revealed that telomere components play important roles in regulation of surface antigen expression in several of these pathogens, indicating that telomeres play critical roles in microbial pathogen virulence regulation. Importantly, although telomere protein components and their functions are largely conserved from protozoa to mammals, telomere protein homologs in microbial pathogens and humans have low sequence homology. Therefore, pathogen telomere components are potential drug targets for therapeutic approaches because first, most telomere proteins are essential for pathogens’ survival, and second, disruption of pathogens’ antigenic variation mechanism would facilitate host’s immune system to clear the infection.

Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids

“…Many pathogens that undergo antigenic variation express their major surface antigens from subtelomeric regions, as subtelomere plasticity would facilitate antigen switching ( 2 ). Indeed, T. brucei subtelomeres are fragile ( 3 ), which presumably facilitates DNA recombination-mediated VSG switching ( 42 ).…”

“…Subtelomeres are regions immediately upstream of telomeres at chromosome ends. The relatively plastic and fragile environment at subtelomeres allows more frequent DNA rearrangements ( 1 ) and facilitates gene conversion-mediated antigenic variation in microbial pathogens such as Trypanosoma brucei that causes human African trypanosomiasis, Pneumocystis jerovecii that causes pneumonia, and Borrelia burgdorferi that causes Lyme disease, as the major surface antigens are transcribed from subtelomeric expression sites in these pathogens ( 2 ). However, introduction of a single DNA double strand break (DSB) at certain subtelomeric loci results in lethality in >90% of T. brucei cells ( 3 ), underlying the importance of subtelomere integrity.…”

The Fun30 Chromatin Remodeler Fft3 Controls Nuclear Organization and Chromatin Structure of Insulators and Subtelomeres in Fission Yeast

“…Beyond yeasts, subtelomeres are important in several other eukaryotic systems. In parasites such as Trypanosoma brucei and Plasmodium falciparum , the subtelomeres habor genes encoding surface markers that can be varied through recombination [ 48 ] and contribute to antigen variation. In T .…”

Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity

“…These pathogens regularly switch their major surface antigen to evade the host immune response, and genes encoding variant surface antigens are expressed exclusively (or sometimes in P. falciparum) from subtelomeric regions in a strictly monoallelic fashion [6]. Therefore, plasticity at subtelomeric regions is necessary for these microbial pathogens.…”

“…npg of microbial pathogens that undergo antigenic variation, including T. brucei that causes human African trypanosomiasis, Plasmodium falciparum that causes malaria, Pneumocystis jirovecii that causes pneumonia, and Borrelia burgdorferi that causes Lyme disease [6]. These pathogens regularly switch their major surface antigen to evade the host immune response, and genes encoding variant surface antigens are expressed exclusively (or sometimes in P. falciparum) from subtelomeric regions in a strictly monoallelic fashion [6].…”