Talundzic Eldin, Scott Stephen, Owino Simon O, Campo David S, Lucchi Naomi W, Udhayakumar Venkatachalam, Moore Julie M, Peterson David S
Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
Department of Infectious Diseases, University of Georgia, Athens, GA 30602, USA.
Pathogens. 2022 Apr 28;11(5):520. doi: 10.3390/pathogens11050520.
The protein VAR2CSA allows infected erythrocytes to accumulate within the placenta, inducing pathology and poor birth outcomes. Multiple exposures to placental malaria (PM) induce partial immunity against VAR2CSA, making it a promising vaccine candidate. However, the extent to which VAR2CSA genetic diversity contributes to immune evasion and virulence remains poorly understood. The deep sequencing of the DBL3X domain in placental blood from forty-nine primigravid and multigravid women living in malaria-endemic western Kenya revealed numerous unique sequences within individuals in association with chronic PM but not gravidity. Additional analysis unveiled four distinct sequence types that were variably present in mixed proportions amongst the study population. An analysis of the abundance of each of these sequence types revealed that one was inversely related to infant gestational age, another was inversely related to placental parasitemia, and a third was associated with chronic PM. The categorization of women according to the type to which their dominant sequence belonged resulted in the segregation of types as a function of gravidity: two types predominated in multigravidae whereas the other two predominated in primigravidae. The univariate logistic regression analysis of sequence type dominance further revealed that gravidity, maternal age, placental parasitemia, and hemozoin burden (within maternal leukocytes), reported a lack of antimalarial drug use, and infant gestational age and birth weight influenced the odds of membership in one or more of these sequence predominance groups. Cumulatively, these results show that unique sequences differentially appear in women with different PM exposure histories and segregate to types independently associated with maternal factors, infection parameters, and birth outcomes. The association of some sequence types with indicators of pathogenesis should motivate vaccine efforts to further identify and target VAR2CSA epitopes associated with maternal morbidity and poor birth outcomes.
VAR2CSA蛋白可使受感染的红细胞在胎盘内聚集，引发病变并导致不良分娩结局。多次接触胎盘疟疾（PM）可诱导机体产生针对VAR2CSA的部分免疫力，使其成为一种很有前景的疫苗候选物。然而，VAR2CSA基因多样性在免疫逃逸和毒力方面所起的作用仍知之甚少。对生活在肯尼亚西部疟疾流行地区的49名初产妇和经产妇胎盘血中的DBL3X结构域进行深度测序后发现，个体中存在许多独特序列，这些序列与慢性PM有关，但与妊娠次数无关。进一步分析发现了四种不同的序列类型，它们在研究人群中以不同比例混合存在。对这些序列类型各自丰度的分析表明，一种与婴儿孕周呈负相关，另一种与胎盘寄生虫血症呈负相关，第三种与慢性PM有关。根据女性优势序列所属类型进行分类，结果发现不同类型的分布与妊娠次数有关：两种类型在经产妇中占主导，而另外两种在初产妇中占主导。序列类型优势的单因素逻辑回归分析进一步显示，妊娠次数、产妇年龄、胎盘寄生虫血症、（母体白细胞内的）疟色素负荷、报告的抗疟药物使用情况，以及婴儿孕周和出生体重，都会影响个体属于这些序列优势组中一个或多个组的几率。总体而言，这些结果表明，独特序列在有不同PM暴露史的女性中差异出现，并独立分离为与母体因素、感染参数和分娩结局相关的类型。某些序列类型与发病机制指标之间的关联，应促使疫苗研发工作进一步识别并靶向与母体发病和不良分娩结局相关的VAR2CSA表位。
