Viruses in the pathogenesis of coeliac disease

• Název práce v češtině: Viry v patogenezi celiakie
• Název v anglickém jazyce: Viruses in the pathogenesis of coeliac disease
• Klíčová slova: enterovirus, adenovirus, longirudinal, nested case-control, coeliac disease
• Akademický rok vypsání: 2016/2017
• Typ práce: bakalářská práce
• Jazyk práce: angličtina
• Ústav: Katedra genetiky a mikrobiologie (31-140)
• Vedoucí / školitel: prof. MUDr. Ondřej Cinek, Ph.D.
• Řešitel: skrytý - zadáno vedoucím/školitelem, čeká na schválení garantem
• Datum přihlášení: 05.10.2016
• Datum zadání: 14.12.2016
• Datum odevzdání elektronické podoby: 14.05.2017
• Datum proběhlé obhajoby: 06.06.2017
• Oponenti: Mgr. Vojtěch Šroller, Ph.D.

Předběžná náplň práce

Coeliac disease (CD) is a polygenic multifactorial disorder. Its genetic component has been long known - patients with the condition have an increased frequency of certain alleles of the HLA class II DQ molecule (namely DQ2.5, and/or DQ8) as compared to the general population. However, genetics alone cannot explain the pathogenesis - there are many-fold more subjects carrying the alleles without celiac disease than with the condition, and inclusion of more genetic factors improves the overall predictive value only marginally. Clearly, environment plays a very important role in the initiation and development of the disease.
Since gut mucosal immunity has been shown to be primarily involved in the pathogenesis, the logical candidates for environmental triggers or accelerators of CD are nutrition, and infections. The proposed project will study the latter, namely virus infections as candidates for triggering the process. At least two different ways of infection involvement in the disease pathogenesis are at hand - it may be a direct tissue injury followed by an increased autoantigen presentation to immune cells, but the effect may also be mediated through a modification of the gut bacteriome following a severe virus infection. This bachelor's course thesis will include: a critical literature review on viruses and bacteria in coeliac disease pathogenesis, and evaluation of the published evidence, comparison of the state-of-the-art methods testing similar associations in type 1 diabetes and other polygenic diseases, the creation of a priority list of candidate viruses - including their frequency and the ability to inflict a gut mucosal injury, or to incite a change in the microbiome composition.

Předběžná náplň práce v anglickém jazyce

Coeliac disease (CD) is a polygenic multifactorial disorder. Its genetic component has been long known - patients with the condition have an increased frequency of certain alleles of the HLA class II DQ molecule (namely DQ2.5, and/or DQ8) as compared to the general population. However, genetics alone cannot explain the pathogenesis - there are many-fold more subjects carrying the alleles without celiac disease than with the condition, and inclusion of more genetic factors improves the overall predictive value only marginally. Clearly, environment plays a very important role in the initiation and development of the disease.
Since gut mucosal immunity has been shown to be primarily involved in the pathogenesis, the logical candidates for environmental triggers or accelerators of CD are nutrition, and infections. The proposed project will study the latter, namely virus infections as candidates for triggering the process. At least two different ways of infection involvement in the disease pathogenesis are at hand - it may be a direct tissue injury followed by an increased autoantigen presentation to immune cells, but the effect may also be mediated through a modification of the gut bacteriome following a severe virus infection.
The studies of diseases with a long preclinical period are generally hampered by the lack of proper retrospective samples, unless a longitudinal design is employed. The present work utilizes a large biobank of the MIDIA study, a Norwegian cohort of children carrying the highest risk genotype for type 1 diabetes, a genotype that also dramatically increases the risk of CD. A nested case-control dataset has been created, with cases being children developing positivity for anti-transglutaminase antibodies, markers of CD, and controls being anti-transglutaminase negative children tightly matched by place and time of birth. Stool samples covering the period before and after the first antibody appearance have been retrieved from the biobank, and will be utilized in an association study.
The studied infections exposures will be the most common gut viruses of childhood - enteroviruses and adenoviruses. Other agents may be added later in the study course, upon an evaluation of their frequency in the whole virome - our previous work on this MIDIA sample set has yielded a complex picture of multiple prevalent phages that may indeed be an interesting topic for epidemiological research.
The association between the exposure and the development of serological markers for celiac disease will be tested by means of generalized estimating equations taking into account the temporal structure of the dataset.
This bachelor's course thesis will include:
· a critical literature review on viruses and bacteria in coeliac disease pathogenesis, and evaluation of the published evidence,
· comparison of the state-of-the-art methods testing similar associations in type 1 diabetes and other polygenic diseases,
· the creation of a priority list of candidate viruses - including their frequency and the ability to inflict a gut mucosal injury, or to incite a change in the microbiome composition.