W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
Viruses. 2023 Jan 17;15(2):260. doi: 10.3390/v15020260.
In humans and non-human primates, wild type (WT) measles virus (MeV) replicates extensively in lymphoid tissue and induces an innate response characteristic of NF-κB and inflammasome activation without type I interferon. In contrast, the live attenuated MeV vaccine (LAMV) replicates poorly in lymphoid tissue with little detectable in vivo cytokine production. To characterize the innate responses of macrophages to WT MeV and LAMV infection, we analyzed primary human monocyte-derived macrophages and phorbol myristic acid-matured monocytic THP-1 cells (M0) polarized to inflammatory (M1) and anti-inflammatory (M2) phenotypes 24 h after MeV infection. LAMV infected macrophages more efficiently than WT MeV but produced less virus than WT MeV-infected macrophages. Both strains induced production of NF-κB-responsive cytokines IL-6 and TNFα and inflammasome products IL-1β and IL-18 without evidence of pyroptosis. Analysis of THP-1 cells deficient in inflammasome sensors NOD-like receptor pyrin (NLRP)3, IFN-γ-inducible protein 16 (IFI16) or absent in melanoma (AIM)2; adaptor apoptosis-associated speck-like protein containing a CARD (ASC) or effector caspase 1 showed that IL-18 production was dependent on NLRP3, ASC, and caspase 1. However, M1 cells produced IL-1β in the absence of ASC or caspase 1 indicating alternate pathways for MeV-induced pro-IL-1β processing. Therefore, the innate response to in vitro infection of macrophages with both LAMV and WT MeV includes production of IL-6 and TNFα and activation of the NLRP3 inflammasome to release IL-1β and IL-18. LAMV attenuation impairs production of infectious virus but does not reduce ability to infect macrophages or innate responses to infection.
在人类和非人类灵长类动物中，野生型（WT）麻疹病毒（MeV）在淋巴组织中广泛复制，并诱导固有反应，其特征是 NF-κB 和炎性小体的激活，而不依赖 I 型干扰素。相比之下，活减毒 MeV 疫苗（LAMV）在淋巴组织中复制能力较差，体内细胞因子产生量可检测到很少。为了研究巨噬细胞对 WT MeV 和 LAMV 感染的固有反应，我们分析了原代人单核细胞衍生的巨噬细胞和佛波醇肉豆蔻酸酯（PMA）成熟的单核细胞 THP-1 细胞（M0），在 MeV 感染后 24 小时向炎症（M1）和抗炎（M2）表型极化。与 WT MeV 相比，LAMV 感染的巨噬细胞效率更高，但产生的病毒量少于 WT MeV 感染的巨噬细胞。两种毒株均诱导产生 NF-κB 反应性细胞因子 IL-6 和 TNFα，以及炎性小体产物 IL-1β 和 IL-18，而没有细胞焦亡的证据。分析缺乏炎性小体传感器 NOD 样受体 pyrin（NLRP）3、IFN-γ诱导蛋白 16（IFI16）或黑色素瘤缺失（AIM）2 的 THP-1 细胞；衔接凋亡相关斑点样蛋白含有 CARD（ASC）或效应半胱氨酸蛋白酶 1 表明，IL-18 的产生依赖于 NLRP3、ASC 和半胱氨酸蛋白酶 1。然而，M1 细胞在缺乏 ASC 或半胱氨酸蛋白酶 1 的情况下产生 IL-1β，表明 MeV 诱导的 pro-IL-1β 加工存在替代途径。因此，LAMV 和 WT MeV 体外感染巨噬细胞的固有反应包括产生 IL-6 和 TNFα，以及激活 NLRP3 炎性小体释放 IL-1β 和 IL-18。LAMV 减毒作用会损害感染性病毒的产生，但不会降低感染巨噬细胞的能力或对感染的固有反应。
