Human parainfluenza virus type 1 regulates cholesterol biosynthesis and establishes quiescent infection in human airway cells.
Human parainfluenza virus type 1 regulates cholesterol biosynthesis and establishes quiescent infection in human airway cells.
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DOI：
10.1371/journal.ppat.1009908
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发表时间：
2021-09
期刊：
影响因子：
6.7
通讯作者：
Takimoto T
中科院分区：
文献类型：
--
作者：
Kurebayashi Y;Bajimaya S;Watanabe M;Lim N;Lutz M;Dunagan M;Takimoto T
人类副流感病毒1型（hPIV1）和3型（hPIV3）引起季节性流行，但对它们与人类气道细胞的相互作用知之甚少。在这项研究中，我们在体外长期感染中测定了人气道细胞的细胞病理学、复制和子代病毒粒子释放。这两种病毒很容易建立持续感染而不引起显著的细胞病变效应。然而，由于病毒核糖核衣壳（vRNP）运输和病毒组装受损，hPIV1的组装和释放迅速下降，与hPIV3形成鲜明对比。转录组学分析显示，这两种病毒诱导了相似水平的I型和III型ifn。然而，hPIV1诱导比hPIV3更强的特异性isg，如MX2，在感染细胞中与hPIV1 vRNPs结合。此外，hPIV1而非hPIV3抑制参与脂质生物发生的基因，hPIV1感染导致3-羟基-3-甲基戊二酰辅酶A还原酶的泛素化和降解，3-羟基-3-甲基戊二酰辅酶A是胆固醇生物合成的限速酶。因此，在感染hPIV1的细胞中，富含胆固醇的脂筏的形成受到损害。这些结果表明，hPIV1能够调节胆固醇的生物发生，这可能与isg一起有助于建立静止感染。副流感病毒引起的季节性流行给儿童造成了严重的疾病负担。这些病毒感染气道上皮细胞并引起急性呼吸道感染。人类是这些病毒已知的唯一宿主，但这些病毒如何在人群中维持尚不清楚。在这项研究中，我们分析了感染1型和3型副流感病毒的人气道细胞。这两种病毒都很容易建立持续感染而不引起主要的细胞病变效应。然而，与hPIV3形成鲜明对比的是，随着时间的推移，hPIV1的组装和释放迅速下降。感染HPIV1的细胞在较晚的时间点形成大的病毒核衣壳聚集体，表明核衣壳运输和病毒组装受损。感染细胞的转录组学分析显示，两种病毒在干扰素诱导方面没有显著差异，而与hPIV3相比，hPIV1诱导干扰素刺激基因（ISGs）水平升高。有趣的是，hPIV1感染特异性下调了参与胆固醇生物发生的基因。我们还发现，hPIV1感染诱导泛素化和3-羟基-3-甲基戊二酰辅酶A还原酶的降解，这是胆固醇生物合成中的限速酶。这些结果表明，hPIV1诱导ifn非依赖性isg和抑制胆固醇可能在人呼吸道上皮细胞中建立静止感染中发挥作用。
Human parainfluenza virus type 1 (hPIV1) and 3 (hPIV3) cause seasonal epidemics, but little is known about their interaction with human airway cells. In this study, we determined cytopathology, replication, and progeny virion release from human airway cells during long-term infection in vitro. Both viruses readily established persistent infection without causing significant cytopathic effects. However, assembly and release of hPIV1 rapidly declined in sharp contrast to hPIV3 due to impaired viral ribonucleocapsid (vRNP) trafficking and virus assembly. Transcriptomic analysis revealed that both viruses induced similar levels of type I and III IFNs. However, hPIV1 induced specific ISGs stronger than hPIV3, such as MX2, which bound to hPIV1 vRNPs in infected cells. In addition, hPIV1 but not hPIV3 suppressed genes involved in lipid biogenesis and hPIV1 infection resulted in ubiquitination and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate limiting enzyme in cholesterol biosynthesis. Consequently, formation of cholesterol-rich lipid rafts was impaired in hPIV1 infected cells. These results indicate that hPIV1 is capable of regulating cholesterol biogenesis, which likely together with ISGs contributes to establishment of a quiescent infection. Seasonal epidemics caused by parainfluenza viruses result in a significant burden of disease in children. These viruses infect airway epithelial cells and cause acute respiratory infection. Humans are the only known hosts for these viruses, but how these viruses are maintained within the population is not known. In this study, we analyzed human airway cells infected with type 1 and 3 parainfluenza viruses. Both viruses readily established persistent infection without causing major cytopathic effects. However, assembly and release of hPIV1 rapidly declined over time in sharp contrast to hPIV3. HPIV1 infected cells formed large aggregates of viral nucleocapsid at late time points, suggesting impaired nucleocapsid trafficking and virus assembly. Transcriptomic analysis of infected cells showed no major difference in IFN induction between the viruses, while hPIV1 induced elevated levels of interferon stimulated genes (ISGs) compared to hPIV3. Interestingly, hPIV1 infection specifically downregulated genes involved in cholesterol biogenesis. We also found that hPIV1 infection induced ubiquitination and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate limiting enzyme in cholesterol biosynthesis. These results suggest that induction of IFN-independent ISGs and suppression of cholesterol by hPIV1 likely play a role in establishing quiescent infection in human respiratory epithelial cells.
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