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The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär virologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär virologi. Linköpings universitet, Hälsouniversitetet.
University of Valencia.
Sahlgrenska University Hospital.
Vise andre og tillknytning
2009 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, nr 5, s. e5593-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

In November 2004, 116 individuals in an elderly nursing home in El Grao de Castellón, Spain were symptomatically infected with genogroup II.4 (GII.4) norovirus. The global attack rate was 54.2%. Genotyping of 34 symptomatic individuals regarding the FUT2 gene revealed that one patient was, surprisingly, a non-secretor, hence indicating secretor-independent infection. Lewis genotyping revealed that Lewis-positive and negative individuals were susceptible to symptomatic norovirus infection indicating that Lewis status did not predict susceptibility. Saliva based ELISA assays were used to determine binding of the outbreak virus to saliva samples. Saliva from a secretor-negative individual bound the authentic outbreak GII.4 Valencia/2004/Es virus, but did not in contrast to secretor-positive saliva bind VLP of other strains including the GII.4 Dijon strain. Amino acid comparison of antigenic A and B sites located on the external loops of the P2 domain revealed distinct differences between the Valencia/2004/Es and Dijon strains. All three aa in each antigenic site as well as 10/11 recently identified evolutionary hot spots, were unique in the Valencia/2004/Es strain compared to the Dijon strain. To the best of our knowledge, this is the first example of symptomatic GII.4 norovirus infection of a Le(a+b-) individual homozygous for the G428A nonsense mutation in FUT2. Taken together, our study provides new insights into the host genetic susceptibility to norovirus infections and evolution of the globally dominating GII.4 viruses.

sted, utgiver, år, opplag, sider
2009. Vol. 4, nr 5, s. e5593-
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-18974DOI: 10.1371/journal.pone.0005593PubMedID: 19440360OAI: oai:DiVA.org:liu-18974DiVA, id: diva2:222187
Merknad
Original Publication: Beatrice Carlsson, Elin Kindberg, Javier Buesa, Gustaf E Rydell, Marta Fos Lidón, Rebeca Montava, Reem Abu Mallouh, Ammi Grahn, Jesús Rodríguez-Díaz, Juan Bellido, Alberto Arnedo, Göran Larson and Lennart Svensson, The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection., 2009, PLoS ONE, (4), 5, e5593. http://dx.doi.org/10.1371/journal.pone.0005593 Licensed under Creative CommonsTilgjengelig fra: 2009-06-10 Laget: 2009-06-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert
Inngår i avhandling
1. Host genetic risk factors to viral diseases - a double-edged sword: Studies of norovirus and tick-borne encephalitis virus
Åpne denne publikasjonen i ny fane eller vindu >>Host genetic risk factors to viral diseases - a double-edged sword: Studies of norovirus and tick-borne encephalitis virus
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

It is today well known that the outcome of a certain infection depends on factors of both the host and the pathogen. Studies of host genetic susceptibility to infectious diseases aim to increase the understanding of why some individuals are more susceptible than others, to a certain infection. Knowledge of genetic susceptibility to a viral disease may be used in development of new therapeutic means, and also to recognize individuals who are at increased risk of severe symptoms if infected with a pathogen. It seems however that a risk factor for one disease may play a protective role in another situation; like a double-edged sword.

In this thesis I have studied genetic factors affecting susceptibility to norovirus (NoV) and factors affecting the risk of developing tick-borne encephalitis (TBE) after infection with TBE virus (TBEV). NoV is the cause of the “winter vomiting disease”, affecting millions of people every year, and causing up to 200,000 fatalities among children in developing countries, each year. It is today recognized that the secretor status of an individual, i.e. the ability to express ABO blood groups and related antigens, in secretions and on mucosa, affect the risk of being infected by NoV. By studying authentic NoV outbreaks in Denmark, Spain and Sweden and by comparing the secretor status of affected and unaffected individuals we were able to confirm that secretor status have indeed great impact on susceptibility to some NoV strains, but also that there are strains circulating, which infect individuals regardless of secretor status.

TBEV is endemic in many parts of Europe and Asia but studies have shown that 70-95% of all infections are asymptomatic or sub-clinical. Some individuals do however develop TBE, a severe disease including meningitis or encephalitis with or without myelitis. Also, many patients suffer from long-time sequelae and TBEV infections may in worst case be fatal. The reason for difference in disease outcome is not known and we have chosen to study if genetic factors affecting the immune response may play a role in disease outcome. To do this we used a prospectively collected Lithuanian material with samples from patients with TBE, AME (aseptic meningoencephalitis) and matched healthy controls. So far we have found that a deletion in chemokine receptor 5 (CCR5), a gene encoding a receptor involved in cell migration, is a risk factor for developing disease. We have also data showing that toll-like receptor 3 (TLR3), a receptor recognizing double stranded RNA (dsRNA), which is a product of TBEV replication, may instead of being protective increase the risk of TBE.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2010. s. 77
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1183
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-54923 (URN)978-91-7393-393-3 (ISBN)
Disputas
2010-05-28, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2010-04-27 Laget: 2010-04-22 Sist oppdatert: 2020-02-26bibliografisk kontrollert
2. Human Caliciviruses: a study of viral evolution, host genetics and disease susceptibility
Åpne denne publikasjonen i ny fane eller vindu >>Human Caliciviruses: a study of viral evolution, host genetics and disease susceptibility
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The viruses described in this thesis are the norovirus and sapoviruses, which belong to the family of human caliciviruses and are known to cause gastroenteritis in humans. Gastroenteritis has emerged as a global health problem and is based on the large number of infected considered as one of the most common diseases today. According to estimates of the World Health Organization (WHO), gastroenteritis causes over five times more pediatric deaths compared to pediatric deaths caused by HIV/AIDS worldwide. Norovirus, the cause of the famous “winter vomiting disease”, is alone responsible for more than 200 000 deaths each year in children less than 5 years of age.

The mechanism for emergence and evolution of new human calicivirus strains, as well as protective immunity in the human population is poorly understood. The main focus for this thesis was to elucidate the possible correlation between human calicivirus evolution, host genetics and disease susceptibility. One of the main findings presented in this thesis is the documentation of in vivo capsid gene evolution and quasispecies dynamics during chronic NoV GI.3 infection (Paper 1). In paper II, we reported that the G428A nonsense mutation in the FUT2 gene provides strong but not absolute protection against symptomatic GII.4 NoV infection. In my last two papers (Paper III and IV), we were the first to investigate host genetic susceptibility factors during authentic SaV infection.

To summarize, the results presented in this thesis show that the success of human calicivirus infection probably is determined by a delicate interplay between virus evolution and susceptibility of the host, both genetically and immunologically.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2012. s. 77
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1303
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-76036 (URN)978-91-7519-922-1 (ISBN)
Disputas
2012-04-12, Eken, Hälsouniversitetet, Campus US, Linköpings univeristet, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2012-03-23 Laget: 2012-03-23 Sist oppdatert: 2019-12-10bibliografisk kontrollert

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