Can complement fix placental malaria?,BMC Medicine

当前位置： X-MOL 学术 › BMC Med. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Can complement fix placental malaria?
BMC Medicine ( IF 9.3 ) Pub Date : 2021-09-10 , DOI: 10.1186/s12916-021-02083-5
Justin Y A Doritchamou ₁ , Patrick E Duffy ₁

Affiliation

Placental malaria (PM) is a deadly public health problem caused by the human parasite Plasmodium falciparum, and this scourge will get worse as existing control measures lose potency. Our understanding of PM pathogenesis suggests a vaccine is feasible, but first-generation candidates yielded only modest variant-specific activity in early trials. In this issue of BMC Medicine, Opi and colleagues provide evidence for a heretofore unrecognized mechanism of protective immunity, whereby the neutralizing activity of antibody against PM parasites is enhanced by fixing the complement component C1q [1].

Recent estimates [2] hold that up to 50,000 maternal deaths and 200,000 stillbirths result from PM in Africa annually, with additional mortality during infancy related to preterm and low birthweight deliveries. Despite public health advances including chemoprevention using intermittent sulfadoxine-pyrimethamine (SP) treatments, as well as insecticide-treated bednets, the terrible toll on mothers and their offspring continues. Deaths will increase as parasite resistance to SP intensifies and spreads.

The underlying cause of PM is well-established: P. falciparum-infected erythrocytes (IEs) adhere to receptors, mainly chondroitin sulfate A (CSA), and sequester in intervillous spaces (maternal blood) of the placenta, eliciting an inflammatory response associated with poor maternal and fetal outcomes. The parasite ligand for CSA, VAR2CSA, is a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of variant surface antigens. Its large size and extensive sequence variation make VAR2CSA a challenging target for vaccine developers, and insights into protective antibodies and epitopes are needed to focus immunogen design.

Nature suggests the solution to the PM problem. Over successive pregnancies, pregnant women in areas of endemicity develop resistance and simultaneously acquire antibodies against placental IEs, including antibody that blocks IE binding to CSA [3] or mediates IE opsonization/phagocytosis [4]. These functional antibodies are believed to target VAR2CSA, and antibodies to VAR2CSA increase over successive pregnancies, but the association of VAR2CSA antibodies to improved clinical outcomes has been inconsistent [5].

In their study, Opi and colleagues examine additional antibody mechanisms that might contribute to PM immunity. The immunoglobulins IgG1 and IgG3 dominate the naturally acquired response to placental IEs and to VAR2CSA, and both subclasses fix complement, which prompted the authors to examine antibody for complement-dependent functional activities [1]. Using samples from a longitudinal cohort of pregnant women in Papua New Guinea, the authors first demonstrated that serum antibodies fix complement on the IE surface of CSA-binding parasites. Levels of antibody-mediated complement fixation increased with gravidity and also predicted lower risk of PM at delivery among the subset of women who were infected at enrollment. This seroepidemiology suggests complement fixation might play a role in protective immunity.

The team examined possible mechanisms by which complement might neutralize parasites. They found that serum antibodies that bound recombinant VAR2CSA domains can fix the complement components C1q and C3. Using the CSA-binding laboratory isolate CS2 that maintains VAR2CSA on its IE surface, however, the group observed no evidence that complement fixation led to the formation of membrane attack complex or to inhibition of growth in vitro. These findings echo earlier studies with IEs from non-pregnant individuals, where the absence of complement activity was attributed to complement regulatory protein on the red cell surface [6, 7]. Instead, and surprisingly, fixation of C1q enhanced serum anti-adhesion activity against CSA-binding IEs.

Levels of complement on IE were reduced after CS2 was engineered to block PfEMP-1 surface expression, further implicating VAR2CSA as a target. Taken together, the data support the idea that VAR2CSA antibodies fix complement which enhances their anti-adhesion activity against CSA-binding IE and thereby might prevent placental sequestration. Of note, modest levels of complement were still detected on IEs without surface PfEMP1, and therefore, other surface antigens may also be targets of complement-fixing antibody.

In contrast to these new findings, a recent study of Ghanaian gravidae [8] observed complement fixation by serum antibody on recombinant VAR2CSA but not on the IE surface of CSA-binding IT4/FCR3 parasites (that are isogenic to the CS2 parasite studied here). Opi and colleagues confirmed C3 fixation on the IE surface of an additional maternal isolate from Papua New Guinea and also showed that serum antibody bound to recombinant VAR2CSA fragments from different alleles fixed C1q or C3. Nevertheless, studies are warranted in different geographical regions using diverse parasites to understand how host or parasite heterogeneity impacts complement-dependent functional activity, and different alleles of full-length recombinant VAR2CSA ectodomain [9] should be assessed as reagents to measure complement-fixing antibody.

Future studies will also benefit by enrolling women earlier in gestation, as Opi et al. suggest, since C1q-binding serum antibody did not predict protection in women without infection at enrollment, a majority of the study population. Capturing the many parasitemia events that appear early in second trimester might strengthen the associations beyond those seen in this study. Finally, larger studies or meta-analyses will be needed to discriminate the independent contributions made by anti-adhesion antibodies, complement-dependent anti-adhesion activity, opsonizing antibodies, and other immune measures, to protection from PM.

Opi and colleagues describe a role for complement to enhance protective anti-adhesion antibody activity during PM. Thus, VAR2CSA vaccine activity may similarly be enhanced by inducing antibodies that fix complement. The human response to the VAR2CSA vaccine PRIMVAC was dominated by IgG1 and IgG3, but nevertheless, serum anti-adhesion activity measured in vitro was modest against different parasite variants [10]. Given the findings of Opi et al., antisera from past and future trials should henceforth be examined with careful attention to complement in the assays. Vaccine design and formulation should also consider the potential contribution of complement-fixing antibodies to protective efficacy, alongside the contributions of opsonizing/phagocytosing and anti-adhesion antibodies. Ultimately, vaccine trials might provide the clearest evidence for the individual and combined benefits of these different immune mechanisms for preventing PM.

Not applicable

1.
Opi H, Boyle M, McLean A, Reiling L, Chan J, Stanisic D, et al. Reduced risk of placental parasitaemia associated with complement fixation on Plasmodium falciparum by antibodies among pregnant women. BMC Med. 2021; Article in press.
2.
McGready R, Nosten F, Barnes KI, Mokuolu O, White NJ. Why is WHO failing women with falciparum malaria in the first trimester of pregnancy? Lancet. 2020;395(10226):779. https://doi.org/10.1016/S0140-6736(20)30161-6.
Article PubMed Google Scholar
3.
Fried M, Nosten F, Brockman A, Brabin BJ, Duffy PE. Maternal antibodies block malaria. Nature. 1998;395(6705):851–2. https://doi.org/10.1038/27570.
CAS Article PubMed Google Scholar
4.
Keen J, Serghides L, Ayi K, Patel SN, Ayisi J, van Eijk A, et al. HIV impairs opsonic phagocytic clearance of pregnancy-associated malaria parasites. PLoS Med. 2007;4(5):e181. https://doi.org/10.1371/journal.pmed.0040181.
CAS Article PubMed PubMed Central Google Scholar
5.
Cutts JC, Agius PA, Zaw L, Powell R, Moore K, Draper B, et al. Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: a systematic review. BMC Med. 2020;18(1):14. https://doi.org/10.1186/s12916-019-1467-6.
Article PubMed PubMed Central Google Scholar
6.
Stanley HA, Mayes JT, Cooper NR, Reese RT. Complement activation by the surface of Plasmodium falciparum infected erythrocytes. Mol Immunol. 1984;21(2):145–50. https://doi.org/10.1016/0161-5890(84)90129-9.
CAS Article PubMed Google Scholar
7.
Wiesner J, Jomaa H, Wilhelm M, Tony HP, Kremsner PG, Horrocks P, et al. Host cell factor CD59 restricts complement lysis of Plasmodium falciparum-infected erythrocytes. Eur J Immunol. 1997;27(10):2708–13. https://doi.org/10.1002/eji.1830271034.
CAS Article PubMed Google Scholar
8.
Larsen MD, Quintana MDP, Ditlev SB, Bayarri-Olmos R, Ofori MF, Hviid L, et al. Evasion of classical complement pathway activation on Plasmodium falciparum-infected erythrocytes opsonized by PfEMP1-specific IgG. Front Immunol. 2018;9:3088.
CAS Article Google Scholar
9.
Renn JP, Doritchamou JYA, Duffy PE. Expression of large full-length PfEMP1 proteins in HEK293 cells. Methods Mol Biol. 2021; Article in press.
10.
Sirima SB, Richert L, Chene A, Konate AT, Campion C, Dechavanne S, et al. PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: a first-in-human, randomised, double-blind, placebo-controlled study. Lancet Infect Dis. 2020;20(5):585–97. https://doi.org/10.1016/S1473-3099(19)30739-X.
CAS Article PubMed Google Scholar

Download references

We thank J. Patrick Gorres for editing the manuscript.

Authors JYAD and PED are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Affiliations

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA
Justin Y. A. Doritchamou & Patrick E. Duffy

Authors

Justin Y. A. DoritchamouView author publications
You can also search for this author in PubMed Google Scholar
Patrick E. DuffyView author publications
You can also search for this author in PubMed Google Scholar

Contributions

All authors read and approved the final manuscript

Corresponding author

Correspondence to Patrick E. Duffy.

Ethics approval and consent to participate

Not applicable

Competing interests

The authors declare no conflicts of interest are associated with this manuscript.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

Cite this article

Doritchamou, J.Y.A., Duffy, P.E. Can complement fix placental malaria?. BMC Med 19, 231 (2021). https://doi.org/10.1186/s12916-021-02083-5

Download citation

Received: 02 August 2021
Accepted: 02 August 2021
Published: 10 September 2021
DOI: https://doi.org/10.1186/s12916-021-02083-5

Keywords

Placental malaria
Plasmodium falciparum
Antibody
Complement
C1q
VAR2CSA
Vaccines

中文翻译：

补体能修复胎盘疟疾吗？

胎盘疟疾 (PM) 是由人类寄生虫恶性疟原虫引起的致命公共卫生问题，随着现有控制措施失去效力，这种祸害将变得更糟。我们对 PM 发病机制的理解表明疫苗是可行的，但第一代候选疫苗在早期试验中仅产生适度的变异特异性活性。在本期BMC Medicine 中，Opi 及其同事提供了一种迄今为止未被认识的保护性免疫机制的证据，即通过固定补体成分 C1q 来增强抗体对 PM 寄生虫的中和活性 [1]。

最近的估计 [2] 认为，非洲每年有多达 50,000 名孕产妇死亡和 200,000 名死产，以及与早产和低出生体重分娩相关的婴儿期额外死亡率。尽管公共卫生取得了进步，包括使用间歇性磺胺多辛-乙胺嘧啶 (SP) 治疗进行化学预防，以及使用杀虫剂处理过的蚊帐，但对母亲及其后代的可怕伤害仍在继续。随着寄生虫对 SP 的抵抗力增强和传播，死亡人数将增加。

PM 的根本原因已明确：感染恶性疟原虫的红细胞 (IE) 粘附于受体，主要是硫酸软骨素 A (CSA)，并隔离在胎盘的绒毛间隙（母血）中，引发与母婴结局不佳。CSA 的寄生虫配体 VAR2CSA 是恶性疟原虫红细胞膜蛋白 1 (PfEMP1) 家族变异表面抗原的成员。其大尺寸和广泛的序列变异使 VAR2CSA 成为疫苗开发人员的一个具有挑战性的目标，需要深入了解保护性抗体和表位以专注于免疫原设计。

Nature 提出了 PM 问题的解决方案。在连续怀孕期间，流行地区的孕妇会产生耐药性并同时获得针对胎盘 IE 的抗体，包括阻断 IE 与 CSA 结合的抗体 [3] 或介导 IE 调理作用/吞噬作用 [4]。这些功能性抗体被认为靶向 VAR2CSA，并且 VAR2CSA 抗体在连续怀孕期间增加，但 VAR2CSA 抗体与改善临床结果的关联一直不一致 [5]。

在他们的研究中，Opi 及其同事研究了可能有助于 PM 免疫的其他抗体机制。免疫球蛋白 IgG1 和 IgG3 支配着对胎盘 IE 和 VAR2CSA 的自然获得性反应，这两个亚类都固定补体，这促使作者检查抗体的补体依赖性功能活性 [1]。使用来自巴布亚新几内亚孕妇纵向队列的样本，作者首先证明了血清抗体将补体固定在 CSA 结合寄生虫的 IE 表面上。抗体介导的补体结合水平随着妊娠而增加，并且还预测在入组时感染的女性亚群中分娩时 PM 的风险较低。这种血清流行病学表明补体结合可能在保护性免疫中发挥作用。

该团队研究了补体中和寄生虫的可能机制。他们发现结合重组 VAR2CSA 结构域的血清抗体可以固定补体成分 C1q 和 C3。然而，使用在其 IE 表面保持 VAR2CSA 的 CSA 结合实验室分离物 CS2，该小组没有观察到补体固定导致形成膜攻击复合物或抑制体外生长的证据。这些发现与早期对非妊娠个体 IE 的研究相呼应，其中补体活性的缺失归因于红细胞表面的补体调节蛋白 [6, 7]。相反，令人惊讶的是，C1q 的固定增强了针对 CSA 结合 IE 的血清抗粘附活性。

CS2 被设计成阻断 PfEMP-1 表面表达后，IE 上的补体水平降低，进一步暗示 VAR2CSA 作为目标。总之，数据支持 VAR2CSA 抗体固定补体的想法，这增强了它们对 CSA 结合 IE 的抗粘附活性，从而可能防止胎盘隔离。值得注意的是，在没有表面 PfEMP1 的 IE 上仍然检测到中等水平的补体，因此，其他表面抗原也可能是补体固定抗体的目标。

与这些新发现相反，最近对加纳孕妇的一项研究 [8] 观察到血清抗体对重组 VAR2CSA 的补体固定，但在结合 CSA 的 IT4/FCR3 寄生虫（与此处研究的 CS2 寄生虫同基因）的 IE 表面上没有观察到补体固定. Opi 及其同事证实了 C3 固定在来自巴布亚新几内亚的另一个母体分离物的 IE 表面上，还表明血清抗体与来自不同等位基因的重组 VAR2CSA 片段结合，固定了 C1q 或 C3。然而，有必要在不同的地理区域使用不同的寄生虫进行研究，以了解宿主或寄生虫的异质性如何影响补体依赖性功能活性，并且应评估全长重组 VAR2CSA 胞外域的不同等位基因 [9] 作为测量补体固定抗体的试剂.

正如 Opi 等人所说，未来的研究也将通过在妊娠早期招募女性而受益。表明，由于 C1q 结合血清抗体不能预测入组时未感染女性的保护作用，因此大多数研究人群。捕捉在孕中期早期出现的许多寄生虫血症事件可能会加强本研究中所见之外的关联。最后，需要更大规模的研究或荟萃分析来区分抗粘连抗体、补体依赖性抗粘连活性、调理抗体和其他免疫措施对预防 PM 的独立贡献。

Opi 及其同事描述了补体在 PM 期间增强保护性抗粘连抗体活性的作用。因此，VAR2CSA 疫苗活性可以通过诱导固定补体的抗体类似地增强。人类对 VAR2CSA 疫苗 PRIMVAC 的反应主要是 IgG1 和 IgG3，但尽管如此，体外测量的血清抗粘连活性对不同的寄生虫变体是适度的 [10]。鉴于 Opi 等人的发现，今后应仔细检查来自过去和未来试验的抗血清，并仔细注意检测中的补体。疫苗设计和配方还应考虑补体固定抗体对保护功效的潜在贡献，以及调理/吞噬和抗粘连抗体的贡献。最终，

不适用

1.
Opi H、Boyle M、McLean A、Reiling L、Chan J、Stanisic D 等。降低与孕妇抗体对恶性疟原虫的补体结合相关的胎盘寄生虫血症的风险。BMC 医学。2021；新闻中的文章。
2.
McGready R、Nosten F、Barnes KI、Mokuolu O、White NJ。为什么世卫组织对怀孕头三个月感染恶性疟的妇女不合格？柳叶刀。2020;395(10226):779。https://doi.org/10.1016/S0140-6736(20)30161-6。
文章 PubMed Google Scholar
3.
Fried M、Nosten F、Brockman A、Brabin BJ、Duffy PE。母体抗体可阻断疟疾。自然。1998;395(6705):851-2。https://doi.org/10.1038/27570。
CAS 文章 PubMed Google Scholar
4.
Keen J、Serghides L、Ayi K、Patel SN、Ayisi J、van Eijk A 等。HIV 损害与妊娠相关的疟疾寄生虫的调理吞噬清除。公共科学图书馆医学。2007;4(5):e181。https://doi.org/10.1371/journal.pmed.0040181。
CAS 文章 PubMed PubMed Central Google Scholar
5.
Cutts JC、Agius PA、Zaw L、Powell R、Moore K、Draper B 等。妊娠特异性疟疾免疫和妊娠期疟疾风险和不良分娩结果：系统评价。BMC 医学。2020；18(1):14。https://doi.org/10.1186/s12916-019-1467-6。
文章 PubMed PubMed Central Google Scholar
6.
Stanley HA、Mayes JT、Cooper NR、Reese RT。通过恶性疟原虫感染的红细胞表面进行补体激活。摩尔免疫学。1984;21(2):145-50。https://doi.org/10.1016/0161-5890(84)90129-9。
CAS 文章 PubMed Google Scholar
7.
Wiesner J、Jomaa H、Wilhelm M、Tony HP、Kremsner PG、Horrocks P 等。宿主细胞因子 CD59 限制了恶性疟原虫感染的红细胞的补体裂解。欧洲免疫学杂志。1997;27(10):2708-13。https://doi.org/10.1002/eji.1830271034。
CAS 文章 PubMed Google Scholar
8.
Larsen MD、Quintana MDP、Ditlev SB、Bayarri-Olmos R、Ofori MF、Hviid L 等。在 PfEMP1 特异性 IgG 调理的恶性疟原虫感染红细胞上逃避经典补体途径激活。前免疫学。2018 年；9:3088。
CAS 文章 Google Scholar
9.
Renn JP、Doritchamou JYA、Duffy PE。大的全长 PfEMP1 蛋白在 HEK293 细胞中的表达。方法分子生物学。2021；新闻中的文章。
10.
Sirima SB、Richert L、Chene A、Konate AT、Campion C、Dechavanne S 等。PRIMVAC 疫苗以 Alhydrogel 或 GLA-SE 为佐剂以预防胎盘疟疾：一项首次人体随机、双盲、安慰剂对照研究。柳叶刀感染 Dis。2020;20(5):585–97。https://doi.org/10.1016/S1473-3099(19)30739-X。
CAS 文章 PubMed Google Scholar

下载参考

我们感谢 J. Patrick Gorres 编辑手稿。

JYAD 和 PED 的作者得到了美国国立卫生研究院国家过敏和传染病研究所的校内研究计划的支持。

隶属关系

疟疾免疫学和疫苗学实验室，国家过敏和传染病研究所，美国国立卫生研究院，贝塞斯达，美国
Justin YA Doritchamou & Patrick E. Duffy

作者

Justin YA Doritchamou查看作者出版物
您也可以在PubMed Google Scholar中搜索此作者
Patrick E. Duffy查看作者出版物
您也可以在PubMed Google Scholar中搜索此作者

贡献

所有作者阅读并认可的终稿

通讯作者

与 Patrick E. Duffy 的通信。

伦理批准和同意参与

不适用

利益争夺

作者声明与本手稿没有利益冲突。

出版商说明

Springer Nature 对已发布地图和机构附属机构中的管辖权主张保持中立。

开放获取本文根据知识共享署名 4.0 国际许可协议获得许可，该许可允许以任何媒体或格式使用、共享、改编、分发和复制，只要您适当注明原作者和来源，提供链接到知识共享许可，并指出是否进行了更改。本文中的图像或其他第三方材料包含在文章的知识共享许可中，除非在材料的信用额度中另有说明。如果文章的知识共享许可中未包含材料，并且您的预期用途未得到法律法规的允许或超出允许的用途，则您需要直接从版权所有者处获得许可。要查看此许可证的副本，请访问 http://creativecommons.org/licenses/by/4.0/。

重印和许可