liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Host genetic risk factors to viral diseases - a double-edged sword: Studies of norovirus and tick-borne encephalitis virus
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 77 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1183
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-54923ISBN: 978-91-7393-393-3 (print)OAI: oai:DiVA.org:liu-54923DiVA: diva2:311585
Public defence
2010-05-28, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2010-04-27 Created: 2010-04-22 Last updated: 2010-04-27Bibliographically approved
List of papers
1. Host genetic resistance to symptomatic norovirus (GGII.4) infections in Denmark
Open this publication in new window or tab >>Host genetic resistance to symptomatic norovirus (GGII.4) infections in Denmark
Show others...
2007 (English)In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 45, no 8, 2720-2722 p.Article in journal (Refereed) Published
Abstract [en]

A total of 61 individuals involved in five norovirus outbreaks in Denmark were genotyped at nucleotides 428 and 571 of the FUT2 gene, determining secretor status, i.e., the presence of ABH antigens in secretions and on mucosa. A strong correlation (P = 0.003) was found between the secretor phenotype and symptomatic disease, extending previous knowledge and confirming that nonsense mutations in the FUT2 gene provide protection against symptomatic norovirus (GGII.4) infections. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40699 (URN)10.1128/JCM.00162-07 (DOI)53918 (Local ID)53918 (Archive number)53918 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2010-04-27
2. The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection.
Open this publication in new window or tab >>The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection.
Show others...
2009 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 5, e5593- p.Article in journal (Refereed) 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18974 (URN)10.1371/journal.pone.0005593 (DOI)19440360 (PubMedID)
Note
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 CommonsAvailable from: 2009-06-10 Created: 2009-06-07 Last updated: 2012-03-23Bibliographically approved
3. Norovirus Gastroenteritis Outbreak with a Secretor-independent Susceptibility Pattern, Sweden
Open this publication in new window or tab >>Norovirus Gastroenteritis Outbreak with a Secretor-independent Susceptibility Pattern, Sweden
2010 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 16, no 1, 81-87 p.Article in journal (Refereed) Published
Abstract [en]

Norovirus (NoV) is recognized as the commonest cause of acute gastroenteritis among adults. Susceptibility to disease has been associated with histo-blood group antigens and secretor status; nonsecretors are almost completely resistant to disease. We report a foodborne outbreak of GI.3 NoV gastroenteritis that affected 33/83 (40%) persons. Symptomatic disease was as likely to develop in nonsecretors as in secretors (odds ratio [OR] 1.41, 95% confidence interval [CI] 0.46-4.36 vs. OR 0.71, 95% Cl 0.23-2.18, p = 0.57). Moreover, no statistical difference in susceptibility was found between persons of different Lewis or ABO phenotypes. The capsid gene of the outbreak strain shares high amino acid homology with the Kashiwa645 GI.3 strain, previously shown to recognize nonsecretor saliva, as well as synthetic Lewis a. This norovirus outbreak affected persons regardless of secretor status or Lewis or ABO phenotypes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53443 (URN)10.3201/eid1601.090633 (DOI)
Note
Original Publication: Johan Nordgren, Per-Eric Lindgren, Andreas Matussek and Lennart Svensson, Norovirus Gastroenteritis Outbreak with a Secretor-independent Susceptibility Pattern, Sweden, 2010, EMERGING INFECTIOUS DISEASES, (16), 1, 81-87. http://dx.doi.org/10.3201/eid1601.090633 Licensee: National Center for Infectious Diseases http://www.cdc.gov/ncidod/eid/index.htm Available from: 2010-01-22 Created: 2010-01-22 Last updated: 2010-04-27
4. A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis
Open this publication in new window or tab >>A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis
Show others...
2008 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, Vol. 197, no 2, 266-269 p.Article in journal (Refereed) Published
Abstract [en]

Tickborne encephalitis (TBE) virus infections can be asymptomatic or cause moderate to severe injuries of the central nervous system. Why some individuals develop severe disease is unknown, but a role for host genetic factors has been suggested. To investigate whether chemokine receptor CCR5 is associated with TBE, CCR5Δ32 genotyping was performed among Lithuanian patients with TBE (n = 129) or with aseptic meningoencephalitis (n = 76) as well as among control subjects (n = 134). We found individuals homozygous for CCR5Δ32 (P = .026) only among patients with TBE and a higher allele prevalence among patients with TBE compared with the other groups studied. CCR5Δ32 allele prevalence also increased with the clinical severity of disease. © 2007 by the Infectious Diseases Society of America. All rights reserved.

Keyword
Alleles Encephalitis, Tick-Borne/epidemiology/*genetics/physiopathology *Gene Deletion Gene Frequency *Genetic Predisposition to Disease Homozygote Humans Lithuania/epidemiology Meningoencephalitis/genetics Receptors, CCR5/*genetics Severity of Illness In
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43369 (URN)10.1086/524709 (DOI)73655 (Local ID)73655 (Archive number)73655 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2010-04-27Bibliographically approved
5. A Missense Mutation in the Toll‐like Receptor 3 Gene (TLR3) is Associated with Decreased Risk of Tick‐borne Encephalitis
Open this publication in new window or tab >>A Missense Mutation in the Toll‐like Receptor 3 Gene (TLR3) is Associated with Decreased Risk of Tick‐borne Encephalitis
Show others...
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

Infections with tick‐borne encephalitis virus (TBEV) may be asymptomatic or cause severe symptoms from the central nervous system, such as meningitis or encephalitis. A mutation in the chemokine receptor 5 (CCR5) gene has been associated with increased risk of TBE but can only explain a limited number of cases and investigations of further risk factors are clearly needed. To investigate the importance of the innate immune response, 128 Lithuanian TBE patients with meningitis or encephalitis, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls were analyzed for three mutations: two in the toll‐like receptor 3 (TLR3) gene and one in the 2´‐5´ oligoadenylate synthetase 1 (OAS1) gene. While no association was found between the mutation in OAS1 and TBE, the genotype distribution of one of the mutations in TLR3, rs3775291, differed significantly between the TBE patients and the controls. 61%, 32% and 7% of the TBE patients (n=127) were carriers of the wild‐type/wild‐type, heterozygous and mutant/mutant genotype of TLR3 rs3775291 genotype respectively. The corresponding percentages for healthy controls (n=126) were 52%, 29% and 19% (P=0.02) and for AME patients (n=75) 47%, 32% and 21% (P=0.009). The wild‐type rs3775291 allele was more common among TBE patients than healthy controls (allele frequency 0.768 vs. 0.663, P=0.01), suggesting that functional TLR3 is a risk factor for severe TBEV infection.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-55017 (URN)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2010-04-27

Open Access in DiVA

Host genetic risk factors to viral diseases - a double-edged sword : Studies of norovirus and tick-borne encephalitis virus(1196 kB)857 downloads
File information
File name FULLTEXT01.pdfFile size 1196 kBChecksum SHA-512
6993cb07994aed98829bf00a5283214b1fde878dbddaac0dee97e2ecd4cf1444e65f51bbbcf8f0eeb760f87caa5a19ee8c9ba4d62bf7e3da7531d013ab60f9e0
Type fulltextMimetype application/pdf
Cover(2248 kB)99 downloads
File information
File name COVER01.pdfFile size 2248 kBChecksum SHA-512
0efe7770f44697bc65b13df156fe143250c0460ffcd29978667d888108916f95a98af09e4604a30623ee03447cb3682d69b8a56b8d010e5597fe0aa15a0c0f94
Type coverMimetype application/pdf

Authority records BETA

Kindberg, Elin

Search in DiVA

By author/editor
Kindberg, Elin
By organisation
Molecular Virology Faculty of Health Sciences
Microbiology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
Total: 857 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1242 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf