LAUSR

Antigenic variation is a successful strategy employed by numerous pathogens to evade the host immune system. It describes the frequent exchange of antigens, which prevents detection and elimination by the host immune system. Strikingly, pathogens from diverse phyla undergo antigenic variation, thereby underlining the efficiency of this strategy for pathogen survival (Deitsch et al., 2009). While the underlying molecular mechanisms are most likely different for each pathogen species, identifying the common principles of antigenic variation may open up new avenues to combat infectious diseases. African trypanosomes are commonly used model organisms to study antigenic variation due to their large antigen repertoire of more than 2000 antigen-coding genes (Horn, 2014) as well as their great compatibility with different experimental setups. It is important to note that trypanosomes are evolutionarily distant from other commonly used eukaryotic model organisms and exhibit a particular organization of transcription: Protein-coding genes are organized in long polycistronic transcription units (PTUs), each containing hundreds of genes. Transcription initiation occurs in a rather unregulated manner at transcription start sites of those PTUs and pre-mRNA maturation is mediated by trans—splicing of a common spliced leader RNA to the 5 ́end of each mRNA. Due to the unregulated nature of transcription, transcript levels are mainly regulated on the post-transcriptional level in the parasite. To establish long-lasting infections in the mammalian blood stream, two requirements have to be met: (1) each trypanosome selectively expresses one antigen and only few different antigens are expressed in the population at any time; (2) the expressed antigen is frequently exchanged. Notably, antigen expression is governed in a specific manner which differs from other protein-coding genes in the parasite: An antigen-coding gene can only be expressed when located in one of fifteen polycistronic expression sites (ESs), of which only one is active in each cell. To ensure stable levels of antigen mRNA, the active ES is expressed by highly processive RNA polymerase I (Pol I) within a nuclear body referred to as expression site body (ESB) (Navarro and Gull, 2001). Trans-splicing ensures maturation of the polycistronic pre-mRNA and mature antigen mRNA is additionally stabilized by mA RNA modifications in the poly-A tail (Viegas et al., 2022). Taken together,