Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria
Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria
复制标题
以核酸感应 Toll 样受体为治疗靶点可预防实验性脑疟疾
DOI：
10.1073/pnas.1015406108
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发表时间：
2011-03-01
影响因子：
11.1
通讯作者：
Gazzinelli, Ricardo T.
中科院分区：
文献类型：
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作者：
Franklin, Bernardo S.;Ishizaka, Sally T.;Gazzinelli, Ricardo T.
先天免疫细胞过度释放促炎细胞因子是疟疾致病基础的重要组成部分。促炎细胞因子是微生物感染过程中Toll样受体(TLR)激活的直接产物。因此，干预TLR的功能可能会通过阻止其异常激活和炎性介质的过度释放而产生更好的临床结果。在此，我们描述了合成的核酸敏感TLRs拮抗剂E6446对伯氏疟原虫诱导的实验性脑疟疾的保护作用及其作用机制。我们发现，在体外，低剂量的E6446特异性地抑制人和小鼠TLR9的激活。这种化合物的浓度增加了10倍，也抑制了人类TLR8对单链RNA的反应。在体内，E6446的治疗减少了TLR9的激活，并防止了在急性疟原虫感染期间观察到的加剧的细胞因子反应。此外，严重的ECM症状，如肢体瘫痪、脑血管渗漏和死亡，都可以通过口服E6446预防。因此，我们提供的证据支持核酸感应TLRs参与疟疾的发病机制，并且干扰这些受体的激活是防止有害的炎症反应的一个有前景的策略，这些炎症反应介导了疟疾的发病和严重程度。
Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.