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.
González
Ana M
AM
Department of Veterinary Preventive Medicine, Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA.
Azevedo
Marli S P
MS
Jung
Kwonil
K
Vlasova
Anastasia
A
Zhang
Wei
W
Saif
Linda J
LJ
D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D003967:Diarrhea / Q000175:diagnosis / Q000209:etiology; D004195:Disease Models, Animal; D005243:Feces / Q000821:virology; D005856:Germ-Free Life / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016898:Interferon-alpha / Q000097:blood / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000276:immunology / Q000473:pathology; D007583:Jejunum / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012401:Rotavirus / Q000235:genetics / Q000276:immunology; D012400:Rotavirus Infections / Q000097:blood / Q000150:complications / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D034421:Sus scrofa; D058425:Vaccines, Virus-Like Particle / Q000235:genetics / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D017201:Virus Shedding
D016207:Cytokines; D016898:Interferon-alpha; C082740:NSP3 protein, Rotavirus; D058425:Vaccines, Virus-Like Particle; D017361:Viral Nonstructural Proteins