Malaria Immunology and Pathogenesis in Pregnant Women and Young Children

2019财年，我们进行了人类和动物研究，以调查孕妇和儿童的疟疾免疫学和发病机制。本年度总结中突出强调的是我们出版物的结果。 1. Attaher O等人，季节性疟疾化学预防对衰竭和调节的免疫标志物的影响。2019.传染病杂志.在印刷中。 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诱导的免疫功能障碍的影响，通过与耗竭和调节性T细胞相关的标志物进行测量，通过流式细胞术进行了探讨。与未接受SMC的儿童相比，接受季节性疟疾化学预防的儿童的疟疾发作较少，并且CD 4 + PD 1+和CD 4 + PD 1 + LAG 3+的倍数变化显著较低，与SMC-儿童相比，SMC+儿童的CD 4 + FOXP 3 + T调节细胞增加更大。 因此，由于季节性疟疾化学预防而减少疟疾感染可以防止免疫功能障碍。 2. Park S等人，Impact of maternally derived antibodies to Plasmodium falciparum Schizont Egress Antigen-1 on the endogenous production of anti-PfSEA-1 in children. 2019.疫苗14;37（35）：5044-5050. 利用我们出生队列研究的样本和数据，我们和布朗大学的合作者评估了脐带血中针对疟疾候选疫苗恶性疟原虫裂殖子出口抗原-1（PfSEA-1）的母体来源抗体是否会干扰婴儿抗PfSEA-1抗体的产生自然暴露。我们发现，脐带血中母亲来源的抗PfSEA-1A抗体并不能消除婴儿抗PfSEA-1A的寄生虫血症驱动的发展：在脐带血中母亲来源的抗PfSEA-1A抗体水平低的婴儿中，寄生虫血症与6个月龄时的抗PfSEA-1A抗体水平显著相关，而在出生时具有中等和高水平的婴儿中，寄生虫血症与抗PfSEA-1A抗体水平显著相关。母亲接种PfSEA-1A疫苗不太可能干扰婴儿期暴露后自然获得的抗PfSEA-1A免疫应答的发展。 3. Doritchamou J等人，针对胎盘疟疾寄生虫的功能性抗体是变异依赖性的，并因地理区域而异。2019.感染与免疫Jun 20;87（7）. 在这里，我们分析了从不同产次的马里和坦桑尼亚妇女分娩时收集的血浆，用于检测针对重组VAR 2CSA抗原（FCR 3等位基因）的总抗体水平，以及使用两种CSA结合实验室分离株（FCR 3和NF 54）检测针对IE的表面反应性和结合抑制和调理功能活性。来自马里孕妇的血浆与FCR 3反应更强烈，而坦桑尼亚血浆优先与NF 54反应。此外，功能性抗体（结合抑制或调理）的获得是变体依赖性的。因此，参与每种功能活性的IE表面表达表位在恶性疟原虫菌株之间可能不同。因此，流行菌株的地理偏倚可能会影响抗体功能，这应该考虑到PM疫苗的开发，旨在实现对各种寄生虫菌株的广泛保护。

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.