Prenatally acquired vitamin A deficiency alters innate immune responses to human rotavirus in a gnotobiotic pig model.
Prenatally acquired vitamin A deficiency alters innate immune responses to human rotavirus in a gnotobiotic pig model.
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DOI：
10.4049/jimmunol.1203575
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Saif LJ
中科院分区：
文献类型：
--
作者：
Vlasova AN;Chattha KS;Kandasamy S;Siegismund CS;Saif LJ
我们研究了产前获得性维生素A缺乏症（VAD）如何调节先天性免疫反应和人轮状病毒（HRV）疫苗在猪HRV腹泻模型中的有效性。对VAD和维生素A充足（VAS）的Gn猪接种减毒HRV (AttHRV)，同时口服或不同时补充维生素A (100,000IU)，并攻毒HRV （VirHRV）。无论疫苗接种状态如何，VAD仔猪的常规树突状细胞和浆细胞样树突状细胞（cdc和pDCs）数量在攻毒前较高，但与VAS猪相比，攻毒后显著下降。我们观察到在攻毒后，VAS与VAD仔猪中CD103（整合素αEβ7）表达dc的频率显著高于VAD仔猪，这表明VAD可能干扰归巢（包括肠道）表型获得。在未接种VAD疫苗的仔猪中，VirHRV攻击后，我们观察到更长时间和更明显的腹泻和更高的VirHRV粪便滴度。与更高的VirHRV脱落滴度一致，攻毒后第2天（PCD），对照VAD仔猪与VAS仔猪血清中IFNα水平升高。从VAD猪的脾脏和血液中分离的体外hrv刺激的单核细胞（MNCs）也产生更多的IFNα。相比之下，在PCD10时，我们观察到VAD猪的IFNα水平降低，与TLR3+ MNC频率降低相一致。VAD猪在攻毒前脾脏（与其他VAD动物的脾肿大一致）和攻毒后肠道组织（与较高的VirHRV诱导的肠道损伤一致）中坏死的MNCs数量较高。因此，产前VAD导致先天免疫反应失衡，加剧了VirHRV感染，而维生素A的补充不能弥补这些VAD的影响。
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 (100,000IU) 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 pre-challenge, but decreased substantially post-challenge as compared to VAS pigs. We observed significantly higher frequency of CD103 (integrin αEβ7) expressing DCs in VAS vs. VAD piglets post-challenge, 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 non-vaccinated VAD piglets. Consistent with higher VirHRV shedding titers, higher IFNα levels were induced in control VAD vs. VAS piglet sera at post-challenge day (PCD)2. Ex vivo HRV-stimulated mononuclear cells (MNCs) isolated from spleen and blood of VAD pigs pre-challenge also produced more IFNα. In contrast at PCD10, we observed reduced IFNα 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) pre-challenge and intestinal tissues (coincident with higher VirHRV induced intestinal damage) post-challenge. 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.
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