Infektionsgenetik

Welche Rolle spielen die Gene bei Infektionskrankheiten? Welche Rolle spielt die Umwelt? Lässt sich dieses komplexe Zusammenspiel aus Genen und Umwelteinflüssen am Computer simulieren? Fragen, die erst aufgekommen sind, weil die Wissenschaft inzwischen einen recht guten Überblick über Gene in Mensch, Tier und anderen Organismen hat. Antworten auf diese Fragen suchen unsere Forscher in der Infektionsgenetik. Sie untersuchen, welchen Einfluss die Gene des Wirts und verschiedene Varianten dieser Gene auf die Abwehr gegenüber einer Infektion mit dem Influenza A Virus haben.

Leitung

Unsere Forschung

The main objective of our research is to study host-pathogen interactions during influenza A virus (IAV) infections in mouse models and human patients with the ultimate goal to find novel biomarkers as well as new strategies for prevention and treatment of severe IAV infections.

Lungenzellen

The host response to influenza A infections – cross species studies in mice and humans

Influenza disease: Infections caused by Influenza A virus (IAV) is one of the most important health problems world-wide. In Germany, between 8,000 and 20,000 people die from influenza infections each season. The yearly economic loss is estimated at about 1 billion Euros. Only two anti-viral IAV drugs are presently in use. However, several virus variants exist that have already developed resistance. Thus, additional therapeutic targets are urgently needed. The clinical symptoms of IAV infections are moderate in most cases. However in some cases severe and often fatal disease outcome may develop. Presently, the severe course of disease cannot be predicted because biomarkers are not available to classify severe course of disease in the early symptomatic phase.

Objectives of our research studies: The main objective of our research is to study host-pathogen interactions during influenza A virus (IAV) infections in mouse models and human patients with the ultimate goal to find novel biomarkers and new strategies for prevention and treatment of severe IAV infections. For this, we have established mouse model systems (genetic reference populations and knock-out mutants) to investigate host resistance and susceptibility to IAV infections, evaluate novel anti-virals and aim to discover novel intervention targets. In addition, we have collected a large number of IAV-infected patient samples and established a bioinformatics pipeline for the discovery of novel biomarkers for respiratory viral infections and severe IAV disease. Our cross-species approach allows us to translate findings from controlled animal experimental systems to human patients and vice versa.

Human cohort studies: We collected blood samples from 159 human IAV patients and controls and performed whole genome expression arrays. We identified biomarkers of IAV infection and for severe IAV disease. Also, we discovered that neutrophil activation is strongly increased in patients with severe infections. Dampening an overshooting neutrophil activation may be a novel avenue for therapeutic intervention. We will enlarge our sample collections in the coming 3-4 years. In addition to transcriptome studies, we will analyze genotypes, proteomes and metabolomes to find more biomarkers and to identify genetic variants that predispose to severe disease. 

Testing novel anti-viral drug candidates: We are testing novel anti-viral drug candidates and drug targets in mouse model systems. We identified host proteases in mouse knockout (KO) mutants as potential novel drug targets. We observed that Tmprss2 KO mice are completely resistant to H1N1 influenza A infections. Thus, our studies validated host proteases as potential targets for influenza A virus intervention and therapy. In addition, we generated knock-out mice for two additional protease genes, Tmprss4 and Tmprss11d. We demonstrated that Tmprss4 alone does not block H3N2 virus spreading in infected lungs whereas the double-knock-out Tmprss2/4 strongly inhibits viral replication. These studies demonstrate that inhibitors targeted to TMPRSS proteases should be suitable targets for development of new anti-virals. In addition, we are evaluating specialized pro-resolving mediators (SPM) and defective interfering particles (DIP) in the mouse model as novel approaches to prevent or treat severe IAV infections.

A genetically highly diverse mouse population: We established a novel genetically highly diverse mouse population at the HZI which is equivalent to the genetic diversity observed in the human population. This Collaborative Cross population represents an important model system for personalized human medicine. We are determining pathological, molecular and genetic factors that correlate with disease severity to find novel risk factors and/or biomarkers that will then be validated in our human cohorts.

Functional analysis in mouse knock-out mutants: Mouse knock-out mutants allow testing of the functional role of a given gene in the context of a defined genetic background. Our laboratory is part of a world-wide consortium (International Mouse Phenotyping Consortium, IMPC) of geneticists who aim to perform a systematic functional analysis of all mouse genes using knock-out mutants. In this context, we have studied several mouse mutants with deletions in Irf7, Irf3, Ifi27l2a, Rag2, Ifit2, Reg3g, Tmprss2, Mx1, Tmprss4, Lst1 genes and demonstrated the functional importance for several genes in the host defense against IAV infections.

FluResearchNet

This project is funded by the German Ministry of Education and Research (BMBF).

Co-Coordinator: Prof. Dr. Klaus Schughart

FluResearchNet is a German network studying the zoonotic potential and virulence influenza virus. In our laboratory, we determine the genetic factors in mammalian species that influence host susceptibility to influenza A infections. The LD50, general patho-physiology, lung pathology, virus dissemination, and various aspects of the host immune response is being investigated in mice after infection with two mouse-adapted influenza A/H1N1 subtypes. Different inbred mouse strains as well as recombinant inbred strains of mice will be used to identify Mendelian and quantitative genetic traits of host susceptibility. These studies will provide new targets for prevention and therapy of influenza infections in humans and life stock.

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SYSGENET

SYSGENET is funded through the COST framework (http://www.cost.eu/about_cost).

Coordinator: Prof. Dr. Klaus Schughart

SYSGENET, a network of scientists, will contribute to the discovery of gene networks that are involved in the development of complex genetic diseases in human. Mouse genetic reference populations (GRPs) are being used as model systems to investigate the biological mechanisms and gene regulatory networks involved in infectious diseases, behavioural abnormalities, metabolic diseases, regeneration, and others.

The network is in the process to establish an infrastructure to provide the EU research community with access to existing and future GRP resources. In this way, SYSGENET will create a basis for the European research community to make major scientific contributions in the field of complex genetics, systems biology and development of sophisticated experimental model systems for the better understanding and treatment of human diseases. SYSGENET will also reach out to similar activities in the United States and Australia.

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Infrafrontier – preparatory phase

This project is funded by of the 7th Framework Programme of the European Commission.

Work Package 5 - Draft Engineering Specifications coordinator: Prof. Dr. Klaus Schughart

Infrafrontier is an Integrated Project of the 7th Framework Programme of the European Commission.

The major bottlenecks identified by the user community will be proper characterization (Mouse Clinics), archiving and dissemination of mouse disease models to the research laboratories. The current capacities, governance structures and funding strategies of existing infrastructures will not be able to serve the upcoming urgent needs. Thus it is imperative to organize and establish now an efficient distributed infrastructure for the phenotyping, archiving and dissemination of mouse models on a well-concerted, large-scale and pan-European level. The objectives of our work package are to develop detailed specifications for designing and building or upgrading of mouse holding and breeding facilities, archiving and distribution facilities and mouse phenotyping facilities.

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Infrafrontier – Infection challenge - Secondary phenotyping of mouse mutant lines

This project is funded by the German Ministry of Education and Research (BMBF).

Coordinator: Prof. Dr. Klaus Schughart

This project is performed in the context of Infrafrontier, a large European infrastructure, to perform systematic functional studies of genes using mouse knock-out models. In collaboration with the German Mouse Clinic at the HMGU in Munich, we will investigate a larger number of mouse knock-out mutants for their susceptibility to infections. Both bacterial and viral pathogens will be used. Close interactions will be maintained with international consortia for large scale phenotyping, especially the IMPC (International Mouse Phenotyping Consortium). In our laboratory about 5 – 10 mouse lines will be studied per year.

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HRJRG – Host genetic susceptibility to Mycobacterium tuberculosis

This project is funded by the Presidential Fund of the Helmholtz-Association.

Coordinator: Prof. Dr. Klaus Schughart

In the context of the Helmholtz-Russian Joint Research Group (HRJRG), we work together with the laboratory of Alexander Apt at the Tuberculosis Centre in Moscow on the genetic susceptibility to Mycobacterium tuberculosis infections in the mouse model. The gene expression changes in susceptible and resistant mouse strains after infection with M. tuberculosis in the lung will be studied in our laboratory, the genetics of inbred and congenic resistant and susceptible mouse strains will be analyzed by the laboratory in Moscow.

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German-Egyptian Research Project

Mutation detection and molecular genetic diagnosis of the Egyptian H1N1 and H5N1 viral strains

This project is funded by the German Ministry of Education and Research (BMBF).

Coordinator: Prof. Dr. Klaus Schughart

In this joint German-Egyptian research project, influenza isolates of various subtypes and sources from Egypt will be characterized molecularly and phenoytpically. The determination of viral sequences and the analysis of their virulence in cell culture systems will be studied by the Egyptian partner. The investigations on the virulence in established mouse infection models will be performed by the German partner.

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