Infection Genetics

Which role do genes play during the host defense against an infection? What is the contribution of environmental factors? Can we study this complex interaction of genes and environment in silico? We can now start to ask these questions because, in recent years, we have gained an enormous knowledge about the genes and their functions in the mouse and human organism. The researchers in the Department of Infection Genetics are seeking to answer such questions. They study how genes and their different variants can positively or negatively influence the host response to an infection with influenza A virus.

Leader

Our Research

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.

Lungs cells

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.

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Audio Podcast

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