Non-anticoagulant Heparin as a Pre-exposure Prophylaxis Prevents Lyme Disease Infection
Non-anticoagulant Heparin as a Pre-exposure Prophylaxis Prevents Lyme Disease Infection
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DOI：
10.1021/acsinfecdis.9b00425
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发表时间：
2020-03-13
影响因子：
5.3
通讯作者：
Linhardt, Robert J.
中科院分区：
文献类型：
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作者：
Lin, Yi-Pin;Yu, Yanlei;Linhardt, Robert J.
莱姆病（LD）是由螺旋体伯氏疏螺旋体（Bbsl）引起的。通过蜱传播给人类后，Bbsl扩散到多个器官，导致关节炎、心脏炎和神经疏螺旋体病。目前还没有有效的预防措施来预防人类在接触蜱虫之前发生LD。因此，需要对LD进行暴露前预防（PrEP）。LD细菌在不同位点的建立部分取决于Bbsl与组织中的蛋白聚糖（PG）和糖胺聚糖（GAG）的结合。药物肝素在结构上类似于这些GAG，并抑制Bbsl与PG、GAG、细胞和组织的附着，表明其预防LD的潜力。然而，肝素的抗凝活性经常导致出血，阻碍了这种化合物作为LD PrEP的发展。我们以前合成了一种非抗凝版本的肝素（NACH），在小鼠和人类中验证了其安全性。在这里，我们表明NACH阻断Bbsl与PG、GAG和哺乳动物细胞的附着。我们还发现，在暴露携带Bbsl的蜱之前用NACH处理小鼠，随后连续施用该化合物防止了Bbsl的组织定殖。此外，NACH处理的小鼠在感染的早期阶段产生更高水平的针对Bbsl的IgG和IgM，表明抗体免疫应答的上调可能是NACH介导的LD预防的机制之一。这是第一个研究检查肝素基化合物在蜱暴露前预防LD的能力。所提供的信息也可以扩展到预防其他传染病病原体。
Lyme disease (LD) is caused by the spirochete Borrelia burgdorferi sensu lato (Bbsl). After transmission to humans by ticks, Bbsl spreads to multiple organs, leading to arthritis, carditis, and neuroborreliosis. No effective prophylaxis against human LD prior to tick exposure is currently available. Thus, a pre-exposure prophylaxis (PrEP) against LD is needed. The establishment of LD bacteria at diverse sites is dictated partly by the binding of Bbsl to proteoglycans (PGs) and glycosaminoglycans (GAGs) in tissues. The drug heparin is structurally similar to these GAGs and inhibits Bbsl attachment to PGs, GAGs, cells, and tissues, suggesting its potential to prevent LD. However, the anticoagulant activity of heparin often results in hemorrhage, hampering the development of this compound as LD PrEP. We have previously synthesized a non-anticoagulant version of heparin (NACH), which was verified for safety in mice and humans. Here, we showed that NACH blocks Bbsl attachment to PGs, GAGs, and mammalian cells. We also found that treating mice with NACH prior to the exposure of ticks carrying Bbsl followed by continuous administration of this compound prevents tissue colonization by Bbsl. Furthermore, NACH-treated mice develop greater levels of IgG and IgM against Bbsl at early stages of infection, suggesting that the upregulation of antibody immune responses may be one of the mechanisms for NACH-mediated LD prevention. This is one of the first studies examining the ability of a heparin-based compound to prevent LD prior to tick exposure. The information presented might also be extended to prevent other infectious diseases agents.