Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children.
Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children.
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DOI：
10.1128/iai.01120-15
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发表时间：
2016-04
影响因子：
3.1
通讯作者：
Osier FHA
中科院分区：
文献类型：
--
作者：
Murungi LM;Sondén K;Llewellyn D;Rono J;Guleid F;Williams AR;Ogada E;Thairu A;Färnert A;Marsh K;Draper SJ;Osier FHA
严重疟疾（SM）是恶性疟原虫感染的一种危及生命的并发症。流行病学观察长期以来表明，针对 SM 的免疫力获得相对较快，但调查其免疫学基础的前瞻性研究在逻辑上具有挑战性，并且很少进行。我们研究了与肯尼亚 0 至 2 岁儿童感染 SM 相关的裂殖子靶标和抗体介导机制。我们设计了一项独特的前瞻性匹配病例对照研究，对儿童纵向出生队列（n = 5,949）中明确表征的 SM 临床表型进行研究，并在生命的前 2 年进行监测。我们对 SM 事件前收集的病例及其单独匹配的对照血清中的免疫学参数进行了量化，以评估在生命的头 2 年内发生 SM 的预期几率。在调整对所有其他测试的裂殖子抗原的反应后，抗 AMA1 抗体与发展 SM 的几率显着降低相关（比值比 [OR] = 0.37；95% 置信区间 [CI] = 0.15 至 0.90；P = 0.029），而针对 MSP-2、MSP-3、恶性疟原虫 Rh2 [PfRh2]、 MSP-119 和受感染的红细胞表面抗原则不然。总 IgG 抑制寄生虫生长和介导中性粒细胞释放活性氧的综合能力与发生 SM 的几率显着降低相关（OR = 0.07；95% CI = 0.006 至 0.82；P = 0.03）。这两种功能机制的检测相关性较差（Spearman 等级相关系数 [rs] = 0.12；P = 0.07）。我们的数据提供了流行病学证据，表明多种抗体依赖性机制通过不同的靶点有助于保护性免疫，这些靶点的识别可以加速预防 SM 的疫苗的开发。
Severe malaria (SM) is a life-threatening complication of infection with Plasmodium falciparum. Epidemiological observations have long indicated that immunity against SM is acquired relatively rapidly, but prospective studies to investigate its immunological basis are logistically challenging and have rarely been undertaken. We investigated the merozoite targets and antibody-mediated mechanisms associated with protection against SM in Kenyan children aged 0 to 2 years. We designed a unique prospective matched case-control study of well-characterized SM clinical phenotypes nested within a longitudinal birth cohort of children (n = 5,949) monitored over the first 2 years of life. We quantified immunological parameters in sera collected before the SM event in cases and their individually matched controls to evaluate the prospective odds of developing SM in the first 2 years of life. Anti-AMA1 antibodies were associated with a significant reduction in the odds of developing SM (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.15 to 0.90; P = 0.029) after adjustment for responses to all other merozoite antigens tested, while those against MSP-2, MSP-3, Plasmodium falciparum Rh2 [PfRh2], MSP-119, and the infected red blood cell surface antigens were not. The combined ability of total IgG to inhibit parasite growth and mediate the release of reactive oxygen species from neutrophils was associated with a marked reduction in the odds of developing SM (OR = 0.07; 95% CI = 0.006 to 0.82; P = 0.03). Assays of these two functional mechanisms were poorly correlated (Spearman rank correlation coefficient [rs] = 0.12; P = 0.07). Our data provide epidemiological evidence that multiple antibody-dependent mechanisms contribute to protective immunity via distinct targets whose identification could accelerate the development of vaccines to protect against SM.