Abstract:
Measles virus (MeV), the causative agent of measles, is an enveloped RNA virus of the family Paramyxoviridae, which remains an important cause of childhood morbidity and mortality. MeV has two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. During viral entry or virus-mediated fusion between infected cells and neighboring susceptible cells, the head domain of the H protein initially binds to its receptors, signaling lymphocytic activation molecule family member 1 (SLAM) and nectin-4, and then the stalk region of the H protein transmits the fusion-triggering signal to the F protein. MeV may persist in the human brain and cause a fatal neurodegenerative disease, subacute sclerosing panencephalitis (SSPE). Recently, we showed, using in vitro cell culture, that cell adhesion molecule (CADM) 1 and CADM2 are host factors that trigger hyperfusogenic mutant F proteins, causing cell-to-cell fusion and the transfer of the MeV genome between neurons. Unlike conventional receptors, CADM1 and CADM2 interact in cis (on the same membrane) with the H protein and then trigger membrane fusion. Here, we show that alanine substitutions in part of the stalk region (positions 171-175) abolish the ability of the H protein to mediate membrane fusion triggered by CADM1 and CADM2, but not by SLAM. The recombinant hyperfusogenic MeV carrying this mutant H protein loses its ability to spread in primary mouse neurons as well as its neurovirulence in experimentally infected suckling hamsters. These results indicate that CADM1 and CADM2 are key molecules for MeV propagation in the brain and its neurovirulence in vivo. IMPORTANCE Measles is an acute febrile illness with skin rash. Despite the availability of highly effective vaccines, measles is still an important cause of childhood morbidity and mortality in many countries. The World Health Organization estimates that more than 120,000 people died from measles worldwide in 2021. Measles virus (MeV), the causative agent of measles, can also cause a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. There is currently no effective treatment for this disease. In this study, using recombinant MeVs with altered receptor usage patterns, we show that cell adhesion molecule (CADM) 1 and CADM2 are host factors critical for MeV spread in neurons and its neurovirulence. These findings further our understanding of the molecular mechanism of MeV neuropathogenicity.
摘要:
麻疹病毒(MeV),麻疹的病原体,是副粘病毒科的包膜RNA病毒,这仍然是儿童发病和死亡的重要原因。MeV有两种包膜糖蛋白,血凝素(H)和融合(F)蛋白。在感染细胞和邻近易感细胞之间的病毒进入或病毒介导的融合过程中,H蛋白的头域最初与其受体结合,信号淋巴细胞激活分子家族成员1(SLAM)和nectin-4,然后H蛋白的茎区将融合触发信号传递给F蛋白。MeV可能在人脑中持续存在并导致致命的神经退行性疾病,亚急性硬化性全脑炎(SSPE)。最近,我们展示了,使用体外细胞培养,细胞粘附分子(CADM)1和CADM2是引发致衰突变型F蛋白的宿主因子,导致细胞与细胞融合和MeV基因组在神经元之间的转移。与传统受体不同,CADM1和CADM2以顺式(在相同的膜上)与H蛋白相互作用,然后引发膜融合。这里,我们表明,部分茎区(位置171-175)中的丙氨酸取代消除了H蛋白介导由CADM1和CADM2而不是SLAM触发的膜融合的能力。携带该突变H蛋白的重组高致敏MeV失去了在原代小鼠神经元中传播的能力以及在实验感染的乳鼠仓鼠中的神经毒力。这些结果表明,CADM1和CADM2是MeV在脑中传播及其体内神经毒力的关键分子。重要性麻疹是一种伴有皮疹的急性发热性疾病。尽管有高效的疫苗,在许多国家,麻疹仍然是儿童发病和死亡的重要原因。世界卫生组织估计,2021年全球有超过12万人死于麻疹。麻疹病毒(MeV),麻疹的病原体,也会导致致命的进行性神经系统疾病,亚急性硬化性全脑炎(SSPE),急性感染后几年。目前尚无有效的治疗方法。在这项研究中,使用受体使用模式改变的重组MeV,我们发现细胞粘附分子(CADM)1和CADM2是MeV在神经元中传播及其神经毒力的关键宿主因子。这些发现进一步了解了MeV神经致病性的分子机制。