Research Programmes

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Molecular Immunology and Microbiology

MUDr. Tomáš Freiberger, Ph.D.
Research Group Leader

THEMATIC RESEARCH FOCUS

RESEARCH AREAS

• Characterisation of genetic factors of microbial pathogenicity, human susceptibility to infections and their interactions
• Molecular diagnostics of primary immunodeficiencies
• Functional analysis of mutations in genes involved in immune response
• New diagnostic approaches in pathogen identification based on molecular methods

MAIN OBJECTIVES

• Genomic characterisation of medically important emerging pathogens; identification and characterisation of bacterial and fungal features on a genome-wide scale. Identification of potential virulence factors, antigens, pathogenicity islands, mobile elements and plasmids using whole-genome sequencing, comparative genomic sequencing and transcriptome profiling. Detailed characterisation of microorganisms causing nosocomial infections including the genetic background of antibiotic resistance. Characterisation of human genetic factors determining susceptibility to infection. Analysis of microbial and human genetic factors interplay.
• The analysis of genes involved in disturbed immune response predominantly in patients with immunodeficiencies. Mapping human mutations and polymorphisms associated with altered immune response and their functional analysis. The analysis of genotype-phenotype relationship in patients with immune system disorders using high-throughput methods.
• Development of new diagnostic possibilities leading to improved early detection of etiological agents in patients with infectious complications using molecular methods.

CONTENT OF RESEARCH

Molecular immunology and microbiology

Human infectious diseases remain an important global health problem causing about 25 % of fatalities worldwide. A course of infection is determined by both microbial and human genetic factors, environment and their mutual interactions. Early diagnostics followed by targeted antimicrobial therapy and adequate immune response are crucial for a favourable outcome. Immunodeficiencies are important in human medicine for their very significant consequences including fatal infections, tumour development and autoimmune complications.

Genetic factors of microbial pathogenicity and human susceptibility to infections, as well as genetic background and immunoregulatory mechanisms leading to immunodeficiency will be studied. New molecular based pathogen identification approaches will be developed.

The introduction of several new genomic approaches in the last decade has allowed bacterial human pathogens to be studied on a genome-wide scale. The traditional approach to the study of human infectious diseases was mainly focused on microbial pathogens. However, understanding the mechanisms of the host response during the infectious process resulting in the elimination of the invading pathogen appears to be equally important. Medically important emerging and nosocomial bacterial and fungal pathogens will be studied from several different perspectives including the characterisation of virulence determinants of etiological agents, population and clonal aspects of microorganisms, resistance to antibiotics, microbial genetic and genomic structure etc. The comparative genomic approach and comparative genomic expression profiling will be used to define strain-specific genetic determinants causing different pathogenicity and invasiveness in different strains of the same species. Host-oriented research will be focused on the polymorphic regions of the human genome and their correlation with the predisposition and severity of the infection process. Detailed characterisation of the microorganisms causing nosocomial infections will be focused on the genetic background of antibiotic resistance and on mapping the transmission routes of nosocomial pathogens.

The precise identification of mutations in genes involved in immune response important in immunodeficiency development and an analysis of their functional significance will be performed. Genome- and transcriptome based functional tests such as: (a) dual-luciferase reporter assay system for investigating the influence of promoter and transcription factors mutations on gene transcription; (b) reverse transcription and quantitative PCR for exploring qualitative and quantitative gene expression changes; (c) splicing minigene construct assays for the analysis of mutations possibly affecting RNA splicing events; (d) electromobility shift assays for probing the binding efficiency of transcription factors to mutated DNA or splicing affecting proteins to mutated RNA; (e) supershift assays for detecting particular protein binding which is affected by the gene mutation; and (f ) immunoprecipitation for the analysis of protein interactions with mutated genes both at the DNA and RNA level, will be used. Improved diagnostics of immunodeficiencies and contribution to better understanding of mechanisms of immune response are expected.

Technologies used: cell cultures, high-throughput DNA sequencing, resequencing, quantitative PCR (qPCR), transcriptome analysis, microarrays, genetic profiling, genome fingerprinting, SNP mapping, human microbiome analysis, cultivation and characterisation of highly infectious organisms.

KEY RESEARCH EQUIPMENT

PLANNED RESEARCH INFRASTRUCTURE

Core Facility

The research group will be one of the principal users of the equipment available within CEITEC Genomics Core Facility.

Technology Units

Molecular oncology

CURRENT RESEARCH INFRASTRUCTURE

Equipment particularly for nucleic acids analyses and tissue cultures, including cyclers for PCR, real-time PCR, HRM analysis (RotorGene6000, ABI7500Fast), DNA sequencer (ABI3100 Avant), electrophoresis (incl. DGGE and SSCP), western blotting, gel documentation (incl. chemiluminiscence imaging), CO2 box, fluorescent microscope, class II biohazard laminar boxes etc.

MAIN PROJECTS

• Genetic determination of clinical manifestation in patients with hereditary angioedema (NR7921), Ministry of Health, 2004-2006, Tomáš Freiberger, Centre of Cardiovascular and Transplant Surgery, Jirí Litzman, St. Anne´s University Hospital Brno.
• Screening of mutations and polymorphisms in neonatal Fc receptor gene in patients with primary disorders of antibody production (NR9192), Ministry of Health, 2007-2009, Tomáš Freiberger, Centre of Cardiovascular and Transplant Surgery, Jirí Litzman, St. Anne´s University Hospital Brno, Barbora Kurecová, University Hospital Brno.
• Development of diagnostics and treatment of serious heart and vascular diseases using genomic and proteomic approaches (2B08060), Ministry of Education, Youth and Sports, 2008-2011, Lenka Fajkusová, University Hospital Brno, Tomáš Freiberger, Centre of Cardiovascular and Transplant Surgery, Zbynek Zdráhal, Masaryk University.
• The role of the gene coding for TACI and abnormalities in lymphocyte subpopulations in the pathogenesis of IgA deficiency (NR10662), Ministry of Health, 2009-2011, Jirí Litzman, St. Anne´s University Hospital Brno.
• Complement in the pathogenesis of autoimmune thyreopaties (NR10662), Ministry of Health, 2009-2011, E. Potkuková.

SELECTED PUBLICATIONS

• GULACSY, V., FREIBERGER, T., SHCHERBINA, A., PAC, M., CHERNYSHOVA, L., AVCIN, T., KONDRATENKO, I., KOSTYUCHENKO, L., PROKOFJEVA, T., PASIC, S., BERNATOWSKA, E., KUTUKCULER, N., RASCON, J., IAGARU, N., MAZZA, C., TOTH, B., ERDOS, M., VAN DER BURG, M., MARODI, L. Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome. Mol Immunol. 2011, 48(5), p. 788-792.
• FREIBERGER, T., GRODECKA, L., RAVCUKOVA, B., KURECOVA, B., POSTRANECKA, V., VLCEK, J., JARKOVSKY, J., THON, V., LITZMAN, J. Association of FcRn expression with lung abnormalities and IVIG catabolism in patients with common variable immunodeficiency. Clin Immunol. 2010, 136(3), p. 419-425.
• FREIBERGER, T., RAVCUKOVA, B., GRODECKA, L., KURECOVA, B., JARKOVSKY, J., BARTONKOVA, D., THON, V., LITZMAN, J. No association of FCRN promoter VNTR polymorphism with the rate of maternal-fetal IgG transfer. J Reprod Immunol. 2010, 85(2), p.193-197.
• DANNAOUI, E., SCHWARZ, P., SLANY, M., LOEFFLER, J., JORDE, A., T., CUENCA-ESTRELLA, M., HAUSER, P., M., SHRIEF, R., HUERRE, M., FREIBERGER, T., ET AL. Molecular detection and identifi cation of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation. J Clin Microbiol. 2010, 48(6), p. 2043-2046.
• SKALNIKOVA, H., FREIBERGER, T., CHUMCHALOVA, J., GROMBIRIKOVA, H., SEDIVA, A. Cost-effective genotyping of human MBL2 gene mutations using multiplex PCR. Journal of Immunological Methods. 2004, 295(1-2), p. 139-147.