Programs of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
PLoS One. 2013;8(4):e60838. doi: 10.1371/journal.pone.0060838. Epub 2013 Apr 2.
Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.
甘露聚糖结合凝集素 (MBL) 是先天免疫系统的关键可溶性效应因子，可识别病原体表面特定的糖基。令人惊讶的是，可能使儿童和免疫功能低下者易患传染病的低产 MBL 遗传变异在人类群体中比预期更为常见。由于某些免疫防御分子，如免疫球蛋白，可以被入侵病原体利用，因此我们假设 MBL 在某些情况下也可能增强感染。因此，人类群体中常见的低和中等 MBL 水平可能是平衡选择的结果。使用带有假型和天然糖基化病毒的模型感染系统，我们证明 MBL 确实在低补体条件下增强了埃博拉、亨德拉、尼帕和西尼罗河病毒的感染。用埃博拉病毒 (EBOV) 糖蛋白假型慢病毒进行的机制研究证实，MBL 通过 MBL 碳水化合物识别结构域以特定方式与病毒表面的 N 连接糖基化表位结合，这对于增强感染是必需的。MBL 通过似乎需要较少肌动蛋白或早期内体处理的途径介导 EBOV 的脂质筏依赖性巨胞饮作用，与丝状病毒经典内吞途径相比。使用经过验证的 RNA 干扰筛选，我们鉴定了 C1QBP（gC1qR）作为一种候选表面受体，它介导 MBL 依赖性增强 EBOV 感染。我们还鉴定了 dectin-2（CLEC6A）作为 EBOV 的潜在新型候选附着因子。我们的研究结果支持先天免疫单倍型的概念，该单倍型代表了 MBL 和补体成分 C4 基因之间的关键相互作用，并且可能修饰了对某些糖基化病原体的易感性或抗性。因此，在相对低补体血症的情况下，内源性或外源性 MBL 水平升高可能有害，这种情况可以是遗传的，也可以是由于在活动性感染期间免疫耗竭引起的。我们的研究结果证实了我们的假设，即传染病的压力可能部分促成了 MBL 突变单倍型的进化选择。
