Malaria Immunology and Pathogenesis in Pregnant Women and Young Children

在2019财年，我们进行了人体和动物研究，以调查孕妇和儿童的疟疾免疫学和发病机制。在这几年的总结中重点介绍了我们出版物的成果。 1.Attaher O，et al.季节性疟疾化学预防对耗竭和调节免疫标志物的影响。2019年。传染病杂志。在媒体上。 季节性疟疾化学预防(SMC)是一种减少儿童疟疾感染的新策略。在这项研究中，季节性疟疾化学预防对疟疾引起的免疫功能障碍的影响，通过与耗竭和调节T细胞相关的标记物来衡量，通过流式细胞术进行了探索。与没有接受SMC的儿童相比，接受季节性疟疾化学预防的儿童疟疾发作更少，CD4PD1和CD4PD1 LAG3的变化显著降低，SMC儿童的CD4FOXP3T调节细胞比SMC儿童增加得更多。因此，通过季节性疟疾化学预防减少疟疾感染可能会预防免疫功能障碍。 2.朴智星、S等人。母源恶性疟原虫裂殖子抗原-1抗体对子代内源性抗PfSEA-1产生的影响。2019年。疫苗。14；37(35)：5044-5050。 使用我们出生队列研究的样本和数据，我们在Brown和我们的合作者评估了脐带血中针对疟疾候选疫苗候选恶性疟原虫裂谷蛋白-1(PfSEA-1)的母源抗体是否干扰了婴儿对自然暴露的抗PfSEA-1抗体的产生。我们发现脐带血中母源抗PfSEA-1A抗体并不能阻止寄生虫病驱动的婴儿抗PfSEA-1A抗体的发生：在出生时母源抗PfSEA-1A抗体水平低的新生儿中，6月龄时的寄生虫血症与抗PfSEA-1A抗体水平显著相关，而在出生时中、高水平的新生儿中，母源抗PfSEA-1A抗体水平较低的新生儿的寄生虫血症与抗PfSEA-1A抗体水平显著相关。母体接种PfSEA-1a不太可能干扰婴儿时期暴露后自然获得的抗PfSEA-1a免疫反应的发展。 3.DoritChamou J，et al.针对胎盘疟疾寄生虫的功能性抗体是变种依赖的，并因地理区域而异。2019年。感染和免疫力。6月20日；87(7)。 在这里，我们使用两个CsA结合的实验室分离株(FCR3和NF54)检测了分娩时从不同胎次的马里和坦桑尼亚妇女采集的血浆中抗重组VAR2CSA抗原(FCR3等位基因)的总抗体水平，以及对IE的表面反应性和结合抑制和优化功能活性。马里孕妇的血浆与FCR3反应更强烈，而坦桑尼亚的血浆优先与NF54反应。此外，功能性抗体(结合抑制或调理)的获得依赖于变异。因此，参与每种功能活性的IE表面表达的表位可能在不同的恶性疟原虫株之间有所不同。因此，流行毒株的地理差异可能会影响抗体功能，这应该被考虑到PM疫苗的开发，目的是实现对各种寄生虫毒株的广泛保护。

In FY 2019, we conducted human and animal studies to investigate malaria immunology and pathogenesis in pregnant women and children. Highlighted in this years summary are results from our publications. 1. Attaher O, et al. Effect of seasonal malaria chemoprevention on immune markers of exhaustion and regulation. 2019. Journal of Infectious Diseases. In press. Seasonal malaria chemoprevention (SMC) is a novel strategy to reduce malaria infections in children. In this study, the impact of seasonal malaria chemoprevention on malaria-induced immune dysfunction, as measured by markers associated with exhaustion and regulatory T cells, was explored by flow cytometry. Children that received seasonal malaria chemoprevention had fewer malaria episodes and showed significantly lower fold changes in CD4+PD1+ and CD4+PD1+LAG3+ compared to those that did not receive SMC, and SMC+ children showed greater increases in CD4+FOXP3+ T regulatory cells compared to SMC- children. Thus, reduction of malaria infections due to seasonal malaria chemoprevention may prevent immune dysfunction. 2. Park S, et al. Impact of maternally derived antibodies to Plasmodium falciparum Schizont Egress Antigen-1 on the endogenous production of anti-PfSEA-1 in offspring. 2019. Vaccine. 14;37(35):5044-5050. Using samples and data from our birth cohort studies, our collaborators at brown and we evaluated whether maternally-derived antibodies to a malarial vaccine candidate, Plasmodium falciparum Schizont Egress Antigen-1 (PfSEA-1), in cord blood interfered with the development of infant anti-PfSEA-1 antibodies in response to natural exposure. We found that maternally-derived anti-PfSEA-1A antibodies in cord blood did not abrogate the parasitemia driven development of infant anti-PfSEA-1A: parasitemia were significantly correlated with anti-PfSEA-1A antibody levels at 6months of age in the infants born with low maternally-derived anti-PfSEA-1A antibody levels in cord blood and borderline significantly correlated in those infants born with middle and high levels. Maternal vaccination with PfSEA-1A is unlikely to interfere with the development of naturally acquired anti-PfSEA-1A immune responses following exposure during infancy. 3. Doritchamou J, et al. Functional antibodies against placental malaria parasites are variant-dependent and differ by geographic region. 2019. Infection and Immunity. Jun 20;87(7). Here, we assayed plasma collected at delivery from Malian and Tanzanian women of different parities for total antibody levels against recombinant VAR2CSA antigens (FCR3 allele), and for surface reactivity and binding inhibition and opsonizing functional activities against IE using two CSA-binding laboratory isolates (FCR3 and NF54). Plasma from Malian gravid women reacted more strongly with FCR3 whereas Tanzanian plasma preferentially reacted with NF54. Further, acquisition of functional antibodies (binding-inhibitory or opsonizing) was variant dependent. Thus, IE surface-expressed epitopes involved in each functional activity may differ among P. falciparum strains. Consequently, geographic bias in circulating strains may impact antibody functions, and this should be considered for the development of PM vaccines aiming to achieve broad protection against various parasite strains.