Department of Zoology, University of Oxford, Oxford, United Kingdom.
PLoS Pathog. 2011 Mar;7(3):e1001306. doi: 10.1371/journal.ppat.1001306. Epub 2011 Mar 3.
Many pathogenic bacteria, fungi, and protozoa achieve chronic infection through an immune evasion strategy known as antigenic variation. In the human malaria parasite Plasmodium falciparum, this involves transcriptional switching among members of the var gene family, causing parasites with different antigenic and phenotypic characteristics to appear at different times within a population. Here we use a genome-wide approach to explore this process in vitro within a set of cloned parasite populations. Our analyses reveal a non-random, highly structured switch pathway where an initially dominant transcript switches via a set of switch-intermediates either to a new dominant transcript, or back to the original. We show that this specific pathway can arise through an evolutionary conflict in which the pathogen has to optimise between safeguarding its limited antigenic repertoire and remaining capable of establishing infections in non-naïve individuals. Our results thus demonstrate a crucial role for structured switching during the early phases of infections and provide a unifying theory of antigenic variation in P. falciparum malaria as a balanced process of parasite-intrinsic switching and immune-mediated selection.
许多致病性细菌、真菌和原生动物通过一种被称为抗原变异的免疫逃避策略实现慢性感染。在人类疟疾寄生虫疟原虫中，这涉及到 var 基因家族成员之间的转录切换，导致具有不同抗原和表型特征的寄生虫在群体中不同时间出现。在这里，我们使用全基因组方法在一组克隆寄生虫群体中在体外探索这一过程。我们的分析揭示了一种非随机的、高度结构化的开关途径，其中最初占主导地位的转录物通过一组开关中间物切换到新的主导转录物，或者返回到原始转录物。我们表明，这种特定的途径可以通过病原体在保护其有限的抗原库和保持在非幼稚个体中建立感染能力之间的一种进化冲突而产生。因此，我们的结果表明在感染的早期阶段结构转换起着至关重要的作用，并为疟原虫疟疾中的抗原变异提供了一个统一的理论，即寄生虫内在转换和免疫介导选择之间的平衡过程。
