Fungal antigenic variation using mosaicism and reassortment of subtelomeric genes' repertoires, potentially mediated by DNA triplexes

Surface antigenic variation is crucial for major pathogens that infect humans, e.g. Plasmodium 1, Trypanosoma 2, Giardia 3. In order to escape the immune system, they exploit various mechanisms in order to modify or exchange the protein that is exposed on the cell surface, at the genetic, expressional, and/or epigenetic level 4. Understanding these mechanisms is important to better prevent and fight the deadly diseases caused. However, those used by the fungus Pneumocystis jirovecii that causes life-threatening pneumonia in immunocompromised individuals remain poorly understood. Here, though this fungus is currently not cultivable 5, our detailed analysis of the subtelomeric sequence motifs and genes encoding surface proteins suggest that the system involves mediation of homologous recombinations during meiosis by DNA triplexes. This leads to the reassortment of the repertoire of ca. 80 non-expressed genes present in each strain, from which single genes are retrieved for mutually exclusive expression within subpopulations of cells 6. The recombinations generates also constantly new mosaic genes. Dispersion of the new alleles and repertoires, supposedly by healthy carrier individuals, appears very efficient because identical alleles are observed in patients from all over the world. Our observations reveal a unique strategy of antigenic variation allowing colonization of the non-sterile niche corresponding to lungs of healthy humans. They also highlight the possible role in genome rearrangements of small imperfect mirror sequences forming DNA triplexes 7. Such mirror sequences are widespread in eukaryotic genomes 8, as well as in HIV virus 9, but remain poorly understood so far.