Identification of Loci Controlling Restriction of Parasite Growth in Experimental Taenia crassiceps Cysticercosis

Human neurocysticercosis (NC) caused by Taenia solium is a parasitic disease of the central nervous system that is endemic in many developing countries. In this study, a genetic approach using the murine intraperitoneal cysticercosis caused by the related cestode Taenia crassiceps was employed to identify host factors that regulate the establishment and proliferation of the parasite. A/J mice are permissive to T. crassiceps infection while C57BL/6J mice (B6) are comparatively restrictive, with a 10-fold difference in numbers of peritoneal cysticerci recovered 30 days after infection. The genetic basis of this inter-strain difference was explored using 34 AcB/BcA recombinant congenic strains derived from A/J and B6 progenitors, that were phenotyped for T. crassiceps replication. In agreement with their genetic background, most AcB strains (A/J-derived) were found to be permissive to infection while most BcA strains (B6-derived) were restrictive with the exception of a few discordant strains, together suggesting a possible simple genetic control. Initial haplotype association mapping using >1200 informative SNPs pointed to linkages on chromosomes 2 (proximal) and 6 as controlling parasite replication in the AcB/BcA panel. Additional linkage analysis by genome scan in informative [AcB55xDBA/2]F1 and F2 mice (derived from the discordant AcB55 strain), confirmed the effect of chromosome 2 on parasite replication, and further delineated a major locus (LOD = 4.76, pD2Mit295, 29.7 Mb) that we designate Tccr1 (T. crassiceps cysticercosis restrictive locus 1). Resistance alleles at Tccr1 are derived from AcB55 and are inherited in a dominant fashion. Scrutiny of the minimal genetic interval reveals overlap of Tccr1 with other host resistance loci mapped to this region, most notably the defective Hc/C5 allele which segregates both in the AcB/BcA set and in the AcB55xDBA/2 cross. These results strongly suggest that the complement component 5 (C5) plays a critical role in early protective inflammatory response to infection with T. crassiceps.由猪带绦虫（Taenia solium）引发的人类神经囊尾蚴病（NC）是一种中枢神经系统寄生虫病，在众多发展中国家呈地方性流行态势。本研究采用基于粗带绦虫（Taenia crassiceps）所致小鼠腹腔囊尾蚴病的遗传学策略，旨在筛选调控寄生虫定植与增殖的宿主因子。A/J小鼠对粗带绦虫感染呈易感表型，而C57BL/6J小鼠（简称B6）则相对抵抗；感染30天后回收的腹腔囊尾蚴数量二者相差可达10倍。本研究以源自A/J与B6亲本的34个AcB/BcA重组同类系菌株为材料，对其进行粗带绦虫复制水平的表型分型，以探究该品系间差异的遗传学基础。与其遗传背景相符，大多数AcB菌株（源自A/J小鼠）呈现易感表型，而多数BcA菌株（源自B6小鼠）则表现为抵抗，仅少数品系表型与遗传背景不符，这提示该性状可能受简单遗传机制调控。基于超过1200个信息性单核苷酸多态性（SNPs）的初始单倍型关联定位分析显示，在AcB/BcA重组同类系群体中，2号染色体（近端区域）与6号染色体上的位点与寄生虫复制调控相关。针对源自表型不符的AcB55菌株的信息性[AcB55×DBA/2]F1及F2小鼠进行全基因组扫描的连锁分析，进一步验证了2号染色体对寄生虫复制的调控作用，并精确定位了一个主效位点（LOD值=4.76，标记位点pD2Mit295，区间29.7 Mb），我们将其命名为Tccr1（粗带绦虫囊尾蚴病抵抗位点1，T. crassiceps cysticercosis restrictive locus 1）。Tccr1位点的抵抗等位基因源自AcB55小鼠，且以显性方式遗传。对该最小遗传区间的精细分析显示，Tccr1与定位于该区域的其他宿主抵抗位点存在重叠，其中最值得关注的是缺陷型Hc/C5等位基因，该等位基因在AcB/BcA群体及AcB55×DBA/2杂交群体中均存在分离现象。上述结果强烈提示，补体成分5（C5）在宿主针对粗带绦虫感染的早期保护性炎症应答中发挥关键作用。