Infektionsgenetik

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.

Genetic control of susceptibility towards influenza infections

Lungenzellen

The role of genetic determinants has been well documented for viral, bacterial, and parasite pathogens in humans. In the case of influenza, the value of the mouse model has been demonstrated for recent and historical (1918) influenza A/H1N1 subtypes, as well as the highly pathogenic bird subtype A/H5N1. In our research group, we are characterizing genetic factors that influence the susceptibility of the host to influenza A infections. For these studies, we use different mouse families (genetic reference populations), mutants (knock-out lines) and various influenza subtypes (H1N1, 2009 H1N1, H7N7). After infection, we study the survival, weight loss, viral load, immune cell infiltrates, histopathology, chemokine / cytokine profiles and changes in gene expression.

So far, our studies revealed a strong influence of the genetic background for the host susceptibility to influenza infections. One resistant and one susceptible mouse strain were studied in detail. The high susceptibility in the DBA/2J mouse strain is caused by high viral loads in infected lungs and a hyper-inflammatory response. The mapping of the susceptible trait in BXD recombinant inbred strains revealed five Quantitative Trait Loci (QTLs) that are currently investigated in more detail.

We also showed that Rag2, Irf7 and Socs3 knock-out mice were more susceptible to influenza A infection than wild type mice.

In addition, we initiated a large scale systems biology study in which we profiled the changes in gene expression patterns in the lungs of C57BL/6J mice after influenza A infection over a period of 60 days post infection. This data set will provide an essential basis for future modeling of the host-pathogen-interactions during influenza infections.

Furthermore, we performed whole genome expression studies for 30 – 50 BXD strains and several inbred mouse strains in non-infected lungs, regulatory T cells and T helper cells. We identified many cis- and trans-expression QTLs as well as specific gene-regulatory circuits.

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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