Prenatally Acquired Vitamin A Deficiency Alters Innate Immune Responses to Human Rotavirus in a Gnotobiotic Pig Model

Abstract

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.

Influence of nutrient-derived metabolites on lymphocyte immunity

“…Booster vaccinations in later life do not seem to result in restoration of the impairment observed in early life 38,39 . This is in line with a study in pigs in which induced vitamin A deficiency in sows impaired vaccination in the offspring that could not be rescued by dietary supplementation 50 . Furthermore, nasal washes of infants from malnourished mothers have low levels of immunoglobulin A, an antibody isotype produced at mucosal sites in structures such as the Peyer's patches 51 .…”

Tissue-specific mRNA expression profiles of porcine Toll-like receptors at different ages in germ-free and conventional pigs

“…As described previously, 10 5 cells were stained with mouse anti-porcine CD3e-FITC (SouthernBiotec, Birmingham, Alabama, USA), mouse anti-porcine CD21-FITC (SouthernBiotec, Birmingham, Alabama, USA), mouse anti-porcine SWC1-FITC (AbD Serotec, Raleigh, NC, USA) and mouse anti-porcine SWC9-FITC (AbD Serotec, Raleigh, NC, USA) monoclonal antibodies (mAb) to characterize the frequencies of T cell, B cell, granulocyte/monocyte and macrophage and to determine the purity of isolated DCs by flow cytometry (Vlasova et al, 2013). Acquisition of 50,000 events was conducted using MACSQuant ® Analyzer flow cytometer (Miltenyi Biotec, San Diego, CA, USA).…”

Strategies for Design and Application of Enteric Viral Vaccines

“…These studies have shown a general role of vit A in regulating gut mucosal immune responses. To determine the effect of VAD and supplementation on oral RV vaccines, prepartum VAD was established by manipulating sow dietary vit A levels, and the derived Gn piglets were used as a VAD model (118). The VAD piglets were characterized by significantly lower hepatic vit A levels compared with vit A-sufficient (VAS) pigs from vit A-supplemented sows (118).…”

“…To determine the effect of VAD and supplementation on oral RV vaccines, prepartum VAD was established by manipulating sow dietary vit A levels, and the derived Gn piglets were used as a VAD model (118). The VAD piglets were characterized by significantly lower hepatic vit A levels compared with vit A-sufficient (VAS) pigs from vit A-supplemented sows (118). Vaccinated (33 attenuated RV) VAD pigs had higher diarrhea severity scores compared with vaccinated VAS pigs, which coincided with lower serum IgA RV antibody titers and significantly lower intestinal IgA ASC post challenge in the former groups, suggesting lower anamnestic IgA antibody responses owing to VAD (119).…”