Immune responses to human norovirus and human norovirus virus-like particles in gnotobiotic pigs and calves
Human noroviruses (HuNoV) are the leading cause of food- and water-borne non-bacterial gastroenteritis worldwide. In this study we delineated the local and systemic immune responses to a GII. HuNoV (HS66 strain) in gnotobiotic pigs and calves and evaluated the immune responses to HuNoV-HS66 virus-like particles vaccines adjuvanted with either ISCOM or mLT and also protection against the homologous virus in Gn pigs. In our study, low antibody titers and antibody-secreting cell (ASC) numbers were elicited in the HuNoV-HS66-inculated pigs, but 65% of the pigs seroconverted. A higher Th1 (high IL-12 but low and transient IFN-gamma), but also low Th2 (IL-4 and IL-10), low transient pro-inflammatory (IL-6) cytokine and delayed innate (IFN-alpha) responses were induced by the HuNoV-HS66 in the serum of the Gn pigs. Intestinal IFN-alpha and IL-12 (late) were also significantly elevated after infection. Higher numbers of Th1 (IL-12 and IFN-gamma) cytokine-secreting cells (CSC) were elicited when compared to Th2 (IL-4) and pro-inflammatory (IL-6) cytokines. The HuNoV-HS66 caused diarrhea and intestinal lesions, mainly in the proximal part of the intestine of one of the calves euthanized at PID 3. Viral shedding was detected from post-inoculation day 1-6 and 67% of the animals seroconverted with HuNoV-HS66-specific IgA and IgG antibodies. Both Th1 (IL-12 and IFN-gamma) and Th2/T-reg (IL-10) cytokines, but also pro-inflammatory (TNF-alpha) were induced in the serum and fecal samples of the HuNoV-HS66-inoculated calves. One-hundred percent seroconversion rate was observed in the vaccinated pigs, regardless of the vaccine regimen, and 100% of coproconversion was detected in the VLP+ISCOM pigs compared to 75% of the VLP+mLT group. However, only 57% of the control pigs shed virus post-challenge. The VLP+mLT vaccine induced a balanced Th1/Th2 response, whereas the VLP+ISCOM induced a more Th2 biased response, but both vaccine regimens induced high levels of protection against virus shedding and diarrhea.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:calicivirus human norovirus vaccines gnotobiotic pigs and calves
Date of Publication:01/01/2007