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A Missense Mutation in the Toll‐like Receptor 3 Gene (TLR3) is Associated with Decreased Risk of Tick‐borne Encephalitis
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
Swedish Institute for Infectious Disease Control and Karolinska Institutet, Stockholm, Sweden.
Clinic of Infectious Diseases, Kaunas University of Medicine, Kaunas, Lithuania.
Swedish Institute for Infectious Disease Control and Karolinska Institutet, Stockholm, Sweden.
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(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
URN: urn:nbn:se:liu:diva-55017OAI: diva2:314071
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2010-04-27
In thesis
1. Host genetic risk factors to viral diseases - a double-edged sword: Studies of norovirus and tick-borne encephalitis virus
Open this publication in new window or tab >>Host genetic risk factors to viral diseases - a double-edged sword: Studies of norovirus and tick-borne encephalitis virus
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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1183
National Category
Microbiology in the medical area
urn:nbn:se:liu:diva-54923 (URN)978-91-7393-393-3 (ISBN)
Public defence
2010-05-28, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2010-04-27 Created: 2010-04-22 Last updated: 2010-04-27Bibliographically approved

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