Simvastatin Reduces Protection and Intestinal T Cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs.

Jacob Kocher,Shaohua Lei,Xingdong Yang,Guohua Li,Xi Jiang,Lijuan Yuan,Tammy Bui Castellucci,Ke Wen

doi:10.3390/pathogens10070829

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 ID50 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.

Highlights

IntroductionNoroviruses (NoVs) are a member of the Caliciviridae family and a leading cause of acute, non-bacterial gastroenteritis [1]
We identified simvastatin’s effects on NoV vaccine-induced protection and T cell immune responses
Particle vaccine-induced protection against NoV shedding and abolished the protection against NoV diarrhea when compared to non-simvastatin treated Gn pigs in our previous study [16]

Summary

Introduction

Noroviruses (NoVs) are a member of the Caliciviridae family and a leading cause of acute, non-bacterial gastroenteritis [1]. NoVs account for approximately 20% of all cases of gastroenteritis worldwide with GII. causing 60–90% of all outbreaks, but new GII variants are increasingly become predominate [2,3,4]. NoVs cause an estimated 20 million illnesses and $10.6 billion in clinical and economic losses in the United States each year [5]. NoVs are transmitted in semi-closed communities, such as senior care homes and cruise ships [6,7,8]. NoV infections are known to cause more severe disease in the elderly population [9]. In the United States, NoV is the second only to Clostridium difficile as a cause

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