Human Norovirus Evolution in a Chronically Infected Host
Authors: Stefan Jennewein
Martin Chan
Christian Schwerk
Stefan Weichert
Ruediger Adam
Sylvie Y Doerflinger
Horst Schroten
Grant S Hansman
Anna Koromyslova
Journal: mSphere (2017)
Discipline: MICROBIOLOGY
Keywords: chronic infection; evolution; norovirus.
Affiliations: Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany; Schaller Research Group at the University of Heidelberg and the DKFZ, Heidelberg, Germany., Pediatric Infectious Diseases Unit, University Children's Hospital Mannheim, University of Heidelberg, Mannheim, Germany., Department of Microbiology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China., Jennewein Biotechnology, Rheinbreitbach, Germany.

Abstract:  Typically, human noroviruses cause symptoms of acute gastroenteritis for 2 to 4 days. Often, the virions are shed in stool for several days after the symptoms recede, which in turn can lead to further contamination and transmission. Moreover, a number of reports have considered that chronic norovirus infections, i.e., lasting months and years, might even function as reservoirs for the generation of novel strains that can escape the herd immunity or have modified binding interactions with histo-blood group antigens (HBGAs). In this study, we analyzed noroviruses isolated from a patient who has presented a chronic infection for more than 6 years. We found that the isolated capsid sequences clustered into two main genetic types (termed A and B), despite a plethora of capsid quasi-sequences. Furthermore, the two genetic types corresponded well with distinct antigenicities. On the other hand, we showed that numerous amino acid substitutions on the capsid surface of genetic types A and B did not alter the HBGA binding profiles. However, divergent binding profiles for types A and B were observed with human milk oligosaccharides (HMOs), which structurally mimic HBGAs and may act as natural antivirals. Importantly, the isolated capsid sequences only had approximately 90% amino acid identity with other known sequences, which suggested that transmission of these chronic noroviruses could be limited. IMPORTANCE The norovirus genogroup II genotype 4 (GII.4) variants have approximately 5% divergence in capsid amino acid identity and have dominated over the past decade. The precise reason(s) for the GII.4 emergence and persistence in the human population is still unknown, but some studies have suggested that chronically infected patients might generate novel variants that can cause new epidemics. We examined GII.4 noroviruses isolated from an immunocompromised patient with a long-term infection. Numerous norovirus capsid quasi-species were isolated during the 13-month study. The capsid quasi-species clustered into two genetic and antigenic types. However, the HBGA binding profiles were similar between the two antigenic clusters, indicating that the amino acid substitutions did not alter the HBGA binding interactions. The isolated sequences represented two new GII.4 variants, but similar sequences were not found in the database. These results indicated that chronically infected patients might not generate novel noroviruses that cause outbreaks. 

Retracted: No

PubPeer comments:
 Concern about Figure 5D. * Red boxes: two panels representing different experiments appear to overlap  , 
 Thank you for your remind.We had noticed this problem. The figures was combined by the students. Before the publication, we did not check the figures carefully. We will contact the publisher and correct them. , 
 Figure 4A from this paper appears to show two panels featured in an older, now-retracted paper by the same authors, where they represent different experiments. That older paper is: Chuan Zhang, Kun Ma Wuyin Li, Drug Design, Development and Therapy 2019 (RETRACTED), DOI: 10.2147 DDDT.S224312 - https: pubpeer.com publications 24D4E2E7ED00D69031002B9CD73ADE Shown with yellow and blue boxes.  , 
 The similarities of the spheroid panels in this paper also extend to the original figures in a third paper, i.e. Kun Ma, Chuan Zhang, Wuyin Li, Chemico-Biological Interactions (2020), doi: 10.1016 j.cbi.2020.109275 - https: pubpeer.com publications 0CA0E7E42734E226C86B5537F575E9 Here is a screenshot from ImageTwin, trying to capture similarities across panels. Each paper appears to show different experiments.  , 
 Figure 6C also appears to have a problem. One of the panels (si-TGFb Ki67) appears to match two panels in Kun Ma, Chuan Zhang, Wuyin Li, Chemico-Biological Interactions (2020), doi: 10.1016 j.cbi.2020.109275 - https: pubpeer.com publications 0CA0E7E42734E226C86B5537F575E9 Shown with purple and cyan boxes. The panels display very different experiments in the other paper.  , 
 Ad comment #2. Instead of blaming students, as authors can you please take responsibility for mentoring and file management? There appear to be many problems with the figures here, in particular reuse of figures in other papers, and I have only checked three papers from your group so far. , 
 Retracted [18 March 2022] . ---------------------------- We, the Editors and Publisher of the journal *Cell Cycle*, have retracted the following article: Kun Ma, Chuan Zhang, and Wuyin Li. TGF-u03b2 is associated with poor prognosis and promotes osteosarcoma progression via PI3K Akt pathway activation. Cell Cycle. 2020;19(18):2327-2339. doi: 10.1080 15384101.2020.1805552. Since publication, concerns have been raised about the integrity of the data in the article. When approached for an explanation, the authors have been unable to address all the concerns raised and have not been able to provide all their original data, or sufficient supporting information. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u2018Retractedu2019. ,