Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality.
Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality.
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DOI：
10.1016/j.chom.2016.05.008
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发表时间：
2016-06-08
影响因子：
30.3
通讯作者：
Iwasaki A
中科院分区：
文献类型：
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作者：
Khoury-Hanold W;Yordy B;Kong P;Kong Y;Ge W;Szigeti-Buck K;Ralevski A;Horvath TL;Iwasaki A
单纯疱疹病毒1型（HSV-1）是生殖器疱疹的主要原因，在感染外周感觉神经系统之前先感染口腔或生殖器粘膜上皮细胞。HSV-1在感觉神经系统以外的传播以及由此产生的更广泛的疾病谱尚不清楚。使用生殖器疱疹的小鼠模型，我们发现HSV-1感染相关的致死性与严重的粪便和尿潴留相关。脑部无明显炎症或感染。相反，HSV-1通过背根神经节传播到结肠中肠神经系统（ENS）的自主神经节。ENS感染导致病毒基因转录、病理性炎症反应和嗜中性粒细胞介导的肠神经元破坏，最终导致永久性结肠炎和毒性巨结肠的发展。泻药治疗挽救了生殖器HSV-1感染后的小鼠死亡。这些结果揭示了与ENS感染相关的HSV的意想不到的发病机制。
Herpes simplex virus 1 (HSV-1), a leading cause of genital herpes, infects oral or genital mucosal epithelial cells before infecting the peripheral sensory nervous system. The spread of HSV-1 beyond the sensory nervous system and the resulting broader spectrum of disease are not well understood. Using a mouse model of genital herpes, we found that HSV-1-infection-associated lethality correlated with severe fecal and urinary retention. No inflammation or infection of the brain was evident. Instead, HSV-1 spread via the dorsal root ganglia to the autonomic ganglia of the enteric nervous system (ENS) in the colon. ENS infection led to robust viral gene transcription, pathological inflammatory responses, and neutrophil-mediated destruction of enteric neurons, ultimately resulting in permanent loss of peristalsis and the development of toxic megacolon. Laxative treatment rescued mice from lethality following genital HSV-1 infection. These results reveal an unexpected pathogenesis of HSV associated with ENS infection.