Cryptosporidium parvum multidrug resistance protein confers resistance to toxic gut microbial metabolite

Cryptosporidium parvum subtypes differ in pathogenicity, but the genetic factors underlying these differences are largely unknown. Here, we show that two C. parvum isolates grow equally well in vitro but differ in pathogenicity in immunocompromised mice. Reduced oocyst shedding of the avirulent strain was restored by antibiotic treatment, suggesting susceptibility to colonization resistance imparted by the microbiota. To investigate the extent of genetic differences of the isolates, we comducted whole genome sequencing (WGS). To map significant associations between parasite genes and enhanced infectivity of the virulent strain, we performed genetic crosses followed by bulk segregant analysis (BSA) under permissive (antibiotic-treated) and restrictive (untreated) conditions. To evaluate the environmental differences between these conditions, we also profiled gut microbiota composition using 16S rRNA sequencing.微小隐孢子虫（Cryptosporidium parvum）的不同亚型具有不同的致病性，但介导此类致病性差异的遗传因素在很大程度上仍未明确。本研究显示，两株微小隐孢子虫分离株在体外培养时增殖能力相当，但在免疫缺陷小鼠体内表现出显著的致病性差异。无毒株的卵囊排出量降低的表型可通过抗生素处理得以恢复，这提示该毒株对微生物群介导的定殖抗性具有易感性。为探究两株分离株的遗传差异程度，我们对其进行了全基因组测序（whole genome sequencing, WGS）。为定位寄生虫基因与强毒株增强的感染性之间的显著关联，我们分别在容许性（抗生素处理）与限制性（未处理）条件下开展了遗传杂交实验，随后进行了集群分离分析（bulk segregant analysis, BSA）。为评估这两种实验条件下的肠道环境差异，我们还通过16S rRNA测序（16S rRNA sequencing）对肠道微生物群组成进行了分析。