Post-exposure antiviral treatment of norovirus infections effectively protects against diarrhea and reduces virus shedding in the stool in a mortality mouse model

Abstract

Noroviruses are a leading cause of gastroenteritis across the world in all age groups and are linked to increased hospitalization and mortality in children, the elderly and immunocompromised. The development of specific antiviral treatment for norovirus gastroenteritis is urgently needed. We explored in a mouse model whether an inhibitor of norovirus replication could be used therapeutically post murine norovirus (MNV)-infection of mice. Using the MNV, we previously discovered that the viral polymerase inhibitor 2’-C-methylcytidine (2CMC) is able to protect against diarrhea and mortality in mice when used prophylactically and to block the transmission of MNV between mice. Here, we investigated whether 2CMC could be used therapeutically, starting treatment between 12 h and 3 days post-infection with 2CMC. Post-exposure treatment of MNV-infected mice with 2CMC was efficient up to 2 days after infection, preventing norovirus-induced diarrhea, delaying and reducing MNV shedding in stool of treated mice. Rehydration of 2CMC-treated animals did not result in a further improvement of the disease evolution compared to antiviral treatment only. The presence of MNV antigens and inflammation in the small intestine of infected mice inversely correlated with the effectiveness of delayed antiviral treatment. Anti-MNV IgGs were detected in re-challenged mice 10 weeks after the first contact, these protected the mice from re-infection. We here demonstrate the benefit of antiviral treatment in ongoing norovirus infections.

Inhibitory Effects of Laminaria japonica Fucoidans Against Noroviruses

“…The 2CMC treatment of AG129 mice resulted in a 2 log reduction of viral RNA copies shedding in stool at 3 dpi. In the present mouse examination, the mice in the control group showed symptoms of NoV illness such as weight loss, hunched posture and ruffled fur at 3 dpi, which was consistent with the results of the AG129 mice [ 47 ]. The illness progressed rapidly and all the mice of the control group were euthanized at 4 dpi.…”

“…A significant proportion of infected animals ultimately succumbed to the disease. It was also reported that the treatment with 2′-C-methylcytidine (2CMC) 1 h before infection exhibited protection from MNoV-induced diarrhea and mortality in AG129 mice (129/Sv mice deficient in IFN-α, β and γ receptors) [ 47 ]. The 2CMC treatment of AG129 mice resulted in a 2 log reduction of viral RNA copies shedding in stool at 3 dpi.…”

The Superoxide Dismutase Mimetic M40403, Improves 5-Fluorouracil-induced Small Intestinal Mucositis in a Mouse Model

“…Many previous studies have employed different diarrheascoring methods to assess the severity of diarrhea in mouse models (29)(30)(31)(32)(33)(34). A frequently used one is the four-step diarrhea-scoring method as follows: 0 (normal stool), 1 (slightly wet and soft stool), 2 (wet and unformed stool with moderate perianal staining of the fur coat), and 3 (watery stool with severe perianal staining of the fur coat) (35).…”

Current and Future Antiviral Strategies to Tackle Gastrointestinal Viral Infections

“…The most studied compound has been 2′ -C- methylcytidine (2CMC), a cytidine analogue that was initially developed for HCV [ 134 ]. Since it has been tested in every available model, it has been regarded as a benchmark compound for NoV [ 49 , 56 , 80 , 135 , 136 , 137 , 138 ]. Jin et al showed that 2CMC triphosphate (2CMC-TP) inhibited the viral polymerases by competing directly with natural CTP during primer elongation, therefore acting as a classic chain terminator [ 139 ].…”