Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Veterinary Preventive Medicine Department, The Ohio State University, Wooster, OH 44691, USA.
J Immunol. 2013 May 1;190(9):4742-53. doi: 10.4049/jimmunol.1203575. Epub 2013 Mar 27.
We examined how prenatally acquired vitamin A deficiency (VAD) modulates innate immune responses and human rotavirus (HRV) vaccine efficacy in a gnotobiotic (Gn) piglet model of HRV diarrhea. The VAD and vitamin A-sufficient (VAS) Gn pigs were vaccinated with attenuated HRV (AttHRV) with or without concurrent oral vitamin A supplementation (100,000 IU) and challenged with virulent HRV (VirHRV). Regardless of vaccination status, the numbers of conventional and plasmacytoid dendritic cells (cDCs and pDCs) were higher in VAD piglets prechallenge, but decreased substantially postchallenge as compared with VAS pigs. We observed significantly higher frequency of CD103 (integrin αEβ7) expressing DCs in VAS versus VAD piglets postchallenge, indicating that VAD may interfere with homing (including intestinal) phenotype acquisition. Post-VirHRV challenge, we observed longer and more pronounced diarrhea and higher VirHRV fecal titers in nonvaccinated VAD piglets. Consistent with higher VirHRV shedding titers, higher IFN-α levels were induced in control VAD versus VAS piglet sera at postchallenge day 2. Ex vivo HRV-stimulated mononuclear cells (MNCs) isolated from spleen and blood of VAD pigs prechallenge also produced more IFN-α. In contrast, at postchallenge day 10, we observed reduced IFN-α levels in VAD pigs that coincided with decreased TLR3(+) MNC frequencies. Numbers of necrotic MNCs were higher in VAD pigs in spleen (coincident with splenomegaly in other VAD animals) prechallenge and intestinal tissues (coincident with higher VirHRV induced intestinal damage) postchallenge. Thus, prenatal VAD caused an imbalance in innate immune responses and exacerbated VirHRV infection, whereas vitamin A supplementation failed to compensate for these VAD effects.
我们研究了产前维生素 A 缺乏（VAD）如何调节先天免疫反应和人轮状病毒（HRV）疫苗在 HRV 腹泻的无菌（Gn）仔猪模型中的功效。VAD 和维生素 A 充足（VAS）Gn 仔猪用减毒 HRV（AttHRV）接种疫苗，无论是否同时口服维生素 A 补充剂（10 万 IU），并用毒力 HRV（VirHRV）进行攻击。无论接种状态如何，VAD 仔猪在预挑战前常规和浆细胞样树突状细胞（cDC 和 pDC）的数量较高，但与 VAS 仔猪相比，接种后数量显著下降。我们观察到，与 VAD 仔猪相比，VAS 仔猪在接种后 CD103（整合素 αEβ7）表达的 DC 频率显著更高，表明 VAD 可能干扰归巢（包括肠道）表型获得。接种 VirHRV 后，我们观察到未接种 VAD 仔猪的腹泻时间更长、更严重，粪便中的 VirHRV 滴度更高。与更高的 VirHRV 脱落滴度一致，在接种后第 2 天，对照 VAD 仔猪血清中的 IFN-α水平升高。在接种前，从 VAD 仔猪的脾脏和血液中分离出的 HRV 刺激的单核细胞（MNC）也产生了更多的 IFN-α。相比之下，在接种后第 10 天，我们观察到 VAD 仔猪的 IFN-α水平降低，同时 TLR3（+）MNC 频率降低。在接种前，VAD 仔猪的脾脏（与其他 VAD 动物的脾肿大一致）和肠道组织（与更高的 VirHRV 诱导的肠道损伤一致）中的坏死 MNC 数量更高。因此，产前 VAD 导致先天免疫反应失衡，加重了 VirHRV 感染，而维生素 A 补充未能弥补这些 VAD 效应。
