Prenatally acquired vitamin A deficiency alters innate immune responses to human rotavirus in a gnotobiotic pig model

摘要

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.