J Med Virol. 2015 Nov;87(11):1872-80. doi: 10.1002/jmv.24242.

Long-Term Viral Shedding and Viral Genome Mutation in Norovirus Infection


Tatsuya Miyoshi,1,2 Kiyoko Uchino,1 Hisayoshi Yoshida,1 Kazushi Motomura,2 Naokazu Takeda,2 Yoshiharu Matsuura,2 and Tomoyuki Tanaka1

1 Sakai City Institute of Public Health, Sakai, Osaka, Japan

2 Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan



The duration of viral shedding in the patients from two outbreaks and four sporadic cases of norovirus (NoV) infections was investigated. The longest period of viral shedding into feces was for 173 days in an inpatient from one case of outbreak. The VP1 sequence from two long-term viral shedding cases in the outbreak revealed four synonymous and one non-synonymous mutations in one inpatient at 26 days from the onset of illness, and nine synonymous and two non-synonymous mutations and a deletion, 10 synonymous mutations and a deletion in other inpatient at 29 days and 54 days from the onset of illness, respectively. Ten of the 11 amino acid positions detected in these two inpatients were in the outermost P2 domain of the viral capsid protein, and mutations at positions 295, 297, and 394 were shared in the inpatients. Mutations in the P2 domain were in epitopes A and D or near epitopes A, C, and E, suggesting that the long-term carrier state of norovirus infection contributes to the generation of escape mutants by host immunoselection.

KEYWORDS: Norovirus; genome mutation; infectious gastroenteritis; long-term shedding

PMID: 25991049



Norovirus (NoV), the major causative virus of infectious gastroenteritis, plays an important role in food poisoning and outbreaks of infectious gastroenteritis in facilities. Handlers of NoV-infected foods spread contamination and cause outbreaks of food poisoning and human-to-human infections in nursing care facilities, kindergartens, educational institutions (e.g., elementary schools), and hospitals. Thus, appropriate measures should be taken on identifying NoV-infected individuals to prevent secondary infections.

NoV-infected individuals frequently suffer from vomiting and diarrhea, but recover within a few days with a good prognosis (1). However, NoV may cause secondary infections even after the disappearance of symptoms, such as vomiting and diarrhea, because it is excreted in feces over a long period of time.

Thus, we raised the following two questions: “How long is NoV excreted in feces of infected individuals?” and “Is it mutated during prolonged excretion?”

This article presents two findings. One is that NoV is excreted in feces for more than three weeks. In a patient with the longest period of excretion, viral genes were detected even at 173 days after onset. The other is that 11 amino acid mutations were identified by gene analysis in two patients with long-term viral excretion in feces. Of these mutations, 10 were derived from the P2 domain, the outermost region of the virus particle. These mutations were located in or around epitopes A-E (2-5), which have been suggested to be involved in binding to histo-blood group antigens (HBGAs).

NoV mutations have been assessed by genetic analyses of epidemic viruses and in vitro analyses of virus-like particles (VLPs) produced by a baculovirus expression system (2-6). We demonstrated that important mutations, identified in vitro, were also detected in vivo. These results provide important data to analyze the developmental mechanisms of NoV mutations and reveal the relationship between NoV and hosts.



1) Green KY. 2007. Caliciviridae: The Noroviruses. In: Knipe DM, Howley PM, editors. Fields Virology, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams and Wilkins. p 949-979.

2) Cao S, Lou Z, Tan M, Chen Y, Liu Y, Zhang Z, Zhang XC, Jiang X, Li X, Rao Z. 2007. Structural basis for the recognition of blood group trisaccharides by norovirus. J Virol. 81:5949–5957.

3) Shanker S, Choi J-M, Sankaran B, Atmar RL, Estes MK, Prasad BVV. 2011. Structural Analysis of Histo-Blood Group Antigen Binding Specificity in a Norovirus GII.4 Epidemic Variant: Implications for Epochal Evolution. J Virol. 85:8635–8645.

4) Debbink K, Donaldson EF, Lindesmith LC, Baric RS. 2011. Genetic Mapping of a Highly Variable Norovirus GII.4 Blockade Epitope: Potential Role in Contribution in Escape from Human Herd Immunity. J Virol. 86:1214–1226.

5) Lindesmith LC, Beltramello M, Donaldson EF, Corti D, Swanstrom J, Debbink K, Lanzavecchia A, Baric RS. 2012. Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation. PLoS Pathog. 8:e1002705.

6) Zakikhany K, Allen DJ, Brown D, Iturriza-Gomara M. 2012. Molecular Evolution of GII-4 Norovirus Strains. PLoS One. 7:e41625.


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