Simvastatin Reduces Protection and Intestinal T Cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs
| dc.contributor.author | Kocher, Jacob | en |
| dc.contributor.author | Castellucci, Tammy Bui | en |
| dc.contributor.author | Wen, Ke | en |
| dc.contributor.author | Li, Guohua | en |
| dc.contributor.author | Yang, Xingdong | en |
| dc.contributor.author | Lei, Shaohua | en |
| dc.contributor.author | Jiang, Xi | en |
| dc.contributor.author | Yuan, Lijuan | en |
| dc.contributor.department | Center for Emerging, Zoonotic, and Arthropod-borne Pathogens | en |
| dc.contributor.department | Biomedical Sciences and Pathobiology | en |
| dc.date.accessioned | 2021-07-09T18:29:36Z | en |
| dc.date.available | 2021-07-09T18:29:36Z | en |
| dc.date.issued | 2021-07-01 | en |
| dc.date.updated | 2021-07-08T14:24:13Z | en |
| dc.description.abstract | Noroviruses (NoVs) are a leading cause of acute gastroenteritis worldwide. P particles are a potential vaccine candidate against NoV. Simvastatin is a cholesterol-reducing drug that is known to increase NoV infectivity. In this study, we examined simvastatin’s effects on P particle-induced protective efficacy and T-cell immunogenicity using the gnotobiotic pig model of human NoV infection and diarrhea. Pigs were intranasally inoculated with three doses (100 µg/dose) of GII.4/VA387-derived P particles together with monophosphoryl lipid A and chitosan adjuvants. Simvastatin-fed pigs received 8 mg/day orally for 11 days prior to challenge. A subset of pigs was orally challenged with 10 ID<sub>50</sub> of a NoV GII.4/2006b variant at post-inoculation day (PID) 28 and monitored for 7 days post-challenge. Intestinal and systemic T cell responses were determined pre- and postchallenge. Simvastatin abolished the P particle’s protection and significantly increased diarrhea severity after NoV infection. Simvastatin decreased proliferation of virus-specific and non-specific CD8 T cells in duodenum and virus-specific CD4 and CD8 T cells in spleen and significantly reduced numbers of intestinal mononuclear cells in vaccinated pigs. Furthermore, simvastatin significantly decreased numbers of duodenal CD4+IFN-γ+, CD8+IFN-γ+ and regulatory T cells and total duodenal activated CD4+ and CD8+ T cells in vaccinated pigs pre-challenge at PID 28. Following challenge, simvastatin prevented the IFN-γ+ T cell response in spleen of vaccinated pigs. These results indicate that simvastatin abolished P particle vaccine-induced partial protection through, at least in part, impairing T cell immunity. The findings have specific implications for the development of preventive and therapeutic strategies against NoV gastroenteritis, especially for the elderly population who takes statin-type drugs. | en |
| dc.description.version | Published version | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Kocher, J.; Castellucci, T.B.; Wen, K.; Li, G.; Yang, X.; Lei, S.; Jiang, X.; Yuan, L. Simvastatin Reduces Protection and Intestinal T Cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs. Pathogens 2021, 10, 829. | en |
| dc.identifier.doi | https://doi.org/10.3390/pathogens10070829 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/104137 | en |
| dc.language.iso | en | en |
| dc.publisher | MDPI | en |
| dc.rights | Creative Commons Attribution 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
| dc.subject | simvastatin | en |
| dc.subject | human norovirus | en |
| dc.subject | P particle vaccine | en |
| dc.subject | gnotobiotic pig | en |
| dc.subject | T cells | en |
| dc.subject | protective efficacy | en |
| dc.title | Simvastatin Reduces Protection and Intestinal T Cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs | en |
| dc.title.serial | Pathogens | en |
| dc.type | Article - Refereed | en |
| dc.type.dcmitype | Text | en |
| dc.type.dcmitype | StillImage | en |