Innate immune responses to human rotavirus in the neonatal gnotobiotic piglet disease model

Intestinal and systemic dendritic cell (DC) frequencies, serum and small intestinal content cytokines and uptake/binding of human rotavirus (HRV) virus‐like particles (VLP) were studied in HRV acutely infected or mock‐inoculated neonatal gnotobiotic piglets. Intestinal, mesenteric lymph node (MLN) and splenic plasmacytoid DCs (pDCs), conventional DCs (cDCs) and macrophages/monocytes were assessed by flow cytometry. In infected pigs, serum and small intestinal content interferon‐α (IFN‐α) were highest, interleukin‐12 (IL‐12) was lower and IL‐10, tumour necrosis factor‐α and IL‐6 were minimal. Compared with mock‐inoculated piglets, frequencies of total intestinal DCs were higher; splenic and MLN DC frequencies were lower. Most intestinal pDCs, but few cDCs, were IFN‐α⁺ and intestinal macrophages/monocytes were negative for IFN‐α. Serum IFN‐α levels and IFN‐α⁺ intestinal pDCs were highly correlated, suggesting IFN‐α production in vivo by intestinal pDCs (r = 0·8; P < 0·01). The intestinal pDCs and cDCs, but not intestinal macrophages/monocytes, of HRV‐infected piglets showed significantly lower VLP uptake/binding compared with mock‐inoculated piglets, suggesting higher activation of pDCs and cDCs in infected piglets. Both intestinal pDCs and cDCs were activated (IFN‐α⁺ and lower VLP binding) after HRV infection, suggesting their role in induction of HRV‐specific immunity. Dose‐effects of HRV on serum IFN‐α and IFN‐α⁺ DCs were studied by infecting piglets with 100‐fold higher HRV dose. A high dose increased parameters associated with inflammation (diarrhoea, intestinal pathology) but serum IFN‐α and IFN‐α⁺ DCs were similar between both groups. The pDCs have both anti‐ and pro‐inflammatory functions. Stimulation of the anti‐inflammatory effects of pDCs after the high dose, without increasing their pro‐inflammatory impacts, may be critical to reduce further immunopathology during HRV infection.