Towards solving the puzzle of aging

Aging is still an enigma, which has challenged scientists and philosophers for centuries. For example, individuals within one species or population show a divers range of life spans (most humans die around 80 years of age, whereas some reach the age of 100 or even more). Which genes are responsible for this variance in lifespan and how exactly is aging caused? We try to help answer these questions by the means of transcriptomic data analysis, including the identification of genes and biological processes that are differentially regulated through time, in different species and tissues.

People involved: Emanuel BarthAkash Srivastava

Collaborations: Alessandro Cellerino, Otto Witte

Grants: RegenerAging — Analyzing the regulation of aging

Related publications:


Molecular serology for rapid determination of vaccination titers

The Permanent Vaccination Commission (STIKO) annually publishes a list of recommended vaccinations. A high vaccination rate in a population is the best requirement to prevent the spread of vaccine-preventable diseases. However, the present system is being challenged by massive migration of people from crisis areas. Therefore, we want to develop a novel diagnostic tool to determine, in a single test run, the antibody status against all vaccinations recommended by the STIKO. For this purpose, new bioinformatic tools for in silico identification of diagnostically relevant epitopes will be developed. This will render the diagnosis faster, less expensive and less time consuming and, at the same time, considerably more informative.

People involved: Konrad Sachse, Maximilian Collatz

Collaborations:

Grants: Zwanzig20 – InfectControl 2020: Molekulare Serologie zur schnellen Bestimmung der Impftiter gegen impf-präventable Infektionskrankheiten (STIKO-Liste) bei Migranten und anderen Patientengruppen; Subproject: STIKO-Serologie

Related publications:

  • [DOI] K. Sachse, K. S. Rahman, C. Schnee, E. Müller, M. Peisker, T. Schumacher, E. Schubert, A. Ruettger, B. Kaltenboeck, and R. Ehricht, “A novel synthetic peptide microarray assay detects chlamydia species-specific antibodies in animal and human sera,” Sci Rep, vol. 8, iss. 1, 2018.
    [Bibtex]
    @Article{Sachse:18,
    author = {Konrad Sachse and Kh. Shamsur Rahman and Christiane Schnee and Elke M\"{u}ller and Madlen Peisker and Thomas Schumacher and Evelyn Schubert and Anke Ruettger and Bernhard Kaltenboeck and Ralf Ehricht},
    title = {A novel synthetic peptide microarray assay detects Chlamydia species-specific antibodies in animal and human sera},
    journal = {{Sci Rep}},
    year = {2018},
    volume = {8},
    number = {1},
    doi = {10.1038/s41598-018-23118-7},
    publisher = {Springer Nature},
    }


Viruses in groundwater

The principle aim of the CRC AquaDiva is to increase our understanding of the links between surface and subsurface, especially how organisms inhabiting the subsurface critical zone reflect and influence their physical, ecological and geochemical environment. In project A06, we will determine the diversity of previously known viruses in groundwater by high-throughput sequencing of viral genomes. A challenge in virology is the identification of previously undetected viruses, which we will tackle with our new approach of virus assembly. We complement the approach by investigating the differences of metatranscriptomes of the different sampling sites. Finally, we will determine the broadly unknown virus decay in groundwater to gain insights in communication pauses with other organisms.

People involved: Martin Hölzer, Celia Diezel

Collaborations: Kirsten Küsel, Antonis Chatzinotas, René Kallies

Grants: CRC 1076 — AquaDiva: A6: Viral Diversity, Viral de novo Assembly, and Viral Decay in Groundwater

Related publications:

  • [DOI] R. Gerst and M. Hölzer, “PCAGO: an interactive web service to analyze RNA-seq data with principal component analysis,” bioRxiv, p. 433078, 2018.
    [Bibtex]
    @Article{Gerst:18,
    author = {Ruman Gerst and Martin H\"{o}lzer},
    title = {{PCAGO}: An interactive web service to analyze {RNA}-Seq data with principal component analysis},
    journal = {{bioRxiv}},
    year = {2018},
    pages = {433078},
    doi = {10.1101/433078},
    publisher = {Cold Spring Harbor Laboratory},
    }


Ecology and Species Barriers in Emerging Viral Diseases

Emerging viruses existing in animal reservoirs may cause epidemic or epizootic diseases if transmitted to humans or livestock. While we understand the pathogenicity and epidemiology of prototypic emerging viral diseases, we know little about mechanisms driving virus emergence from animal reservoirs. To move ahead, we need to generalise our view on emerging viruses, taking into consideration the ecology of viruses in their natural reservoirs. We hypothesise that small mammals, mainly bats and rodents, constitute most relevant virus reservoirs due to their large group sizes, population density, mixing and turnover, as well as their exposure to arthropod vectors.

People involved: Martin Hölzer, Nelly Fernanda Mostajo Berrospi

Collaborations: Christian Drosten, Friedemann Weber, Stephan Becker, Martin Beer, Georg Kochs

Grants: DFG SPP 1596: Ecology and Species Barriers in Emerging Viral Diseases

Related publications:

  • [DOI] J. Fuchs, M. Hölzer, M. Schilling, C. Patzina, A. Schoen, T. Hoenen, G. Zimmer, M. Marz, F. Weber, M. A. Müller, and G. Kochs, “Evolution and antiviral specificities of interferon-induced Mx proteins of bats against Ebola, Influenza, and other RNA viruses,” J Virol, vol. 91, 2017.
    [Bibtex]
    @Article{Fuchs:17,
    author = {Fuchs, Jonas and H\"{o}lzer, Martin and Schilling, Mirjam and Patzina, Corinna and Schoen, Andreas and Hoenen, Thomas and Zimmer, Gert and Marz, Manja and Weber, Friedemann and M\"{u}ller, Marcel A and Kochs, Georg},
    title = {Evolution and Antiviral Specificities of Interferon-Induced {Mx} Proteins of Bats against {E}bola, {I}nfluenza, and Other {RNA} Viruses},
    journal = {{J Virol}},
    year = {2017},
    volume = {91},
    abstract = {Bats serve as a reservoir for various, often zoonotic viruses, including significant human pathogens such as Ebola and influenza viruses. However, for unknown reasons, viral infections rarely cause clinical symptoms in bats. A tight control of viral replication by the host innate immune defense might contribute to this phenomenon. Transcriptomic studies revealed the presence of the interferon-induced antiviral myxovirus resistance (Mx) proteins in bats, but detailed functional aspects have not been assessed. To provide evidence that bat Mx proteins might act as key factors to control viral replication we cloned cDNAs from three bat families, Pteropodidae, Phyllostomidae, and Vespertilionidae. Phylogenetically these bat genes cluster closely with their human ortholog MxA. Using transfected cell cultures, minireplicon systems, virus-like particles, and virus infections, we determined the antiviral potential of the bat Mx1 proteins. Bat Mx1 significantly reduced the polymerase activity of viruses circulating in bats, including Ebola and influenza A-like viruses. The related Thogoto virus, however, which is not known to infect bats, was not inhibited by bat Mx1. Further, we provide evidence for positive selection in bat genes that might explain species-specific antiviral activities of these proteins. Together, our data suggest a role for Mx1 in controlling these viruses in their bat hosts. Bats are a natural reservoir for various viruses that rarely cause clinical symptoms in bats but are dangerous zoonotic pathogens, like Ebola or rabies virus. It has been hypothesized that the interferon system might play a key role in controlling viral replication in bats. We speculate that the interferon-induced Mx proteins might be key antiviral factors of bats and have coevolved with bat-borne viruses. This study evaluated for the first time a large set of bat Mx1 proteins spanning three major bat families for their antiviral potential, including activity against Ebola virus and bat influenza A-like virus, and we describe here their phylogenetic relationship, revealing patterns of positive selection that suggest a coevolution with viral pathogens. By understanding the molecular mechanisms of the innate resistance of bats against viral diseases, we might gain important insights into how to prevent and fight human zoonotic infections caused by bat-borne viruses.},
    doi = {10.1128/JVI.00361-17},
    issue = {15},
    keywords = {Animals; Antiviral Agents, metabolism; Chiroptera, immunology, virology; Cloning, Molecular; Evolution, Molecular; Myxovirus Resistance Proteins, genetics, metabolism; RNA Viruses, immunology; Selection, Genetic; Ebola virus; Mx protein; bat; bunyavirus; influenza; interferons; orthomyxovirus; vesicular stomatitis virus},
    pmid = {28490593},
    }
  • [DOI] M. Hölzer, V. Krähling, F. Amman, E. Barth, S. H. Bernhart, V. A. O. Carmelo, M. Collatz, G. Doose, F. Eggenhofer, J. Ewald, J. Fallmann, L. M. Feldhahn, M. Fricke, J. Gebauer, A. J. Gruber, F. Hufsky, H. Indrischek, S. Kanton, J. Linde, N. Mostajo, R. Ochsenreiter, K. Riege, L. Rivarola-Duarte, A. H. Sahyoun, S. J. Saunders, S. E. Seemann, A. Tanzer, B. Vogel, S. Wehner, M. T. Wolfinger, R. Backofen, J. Gorodkin, I. Grosse, I. Hofacker, S. Hoffmann, C. Kaleta, P. F. Stadler, S. Becker, and M. Marz, “Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells,” Sci Rep, vol. 6, p. 34589, 2016.
    [Bibtex]
    @Article{Hoelzer:16,
    author = {H\"{o}lzer, Martin and Kr\"{a}hling, Verena and Amman, Fabian and Barth, Emanuel and Bernhart, Stephan H and Carmelo, Victor A O and Collatz, Maximilian and Doose, Gero and Eggenhofer, Florian and Ewald, Jan and Fallmann, J\"{o}rg and Feldhahn, Lasse M and Fricke, Markus and Gebauer, Juliane and Gruber, Andreas J and Hufsky, Franziska and Indrischek, Henrike and Kanton, Sabina and Linde, J\"{o}rg and Mostajo, Nelly and Ochsenreiter, Roman and Riege, Konstantin and Rivarola-Duarte, Lorena and Sahyoun, Abdullah H and Saunders, Sita J and Seemann, Stefan E and Tanzer, Andrea and Vogel, Bertram and Wehner, Stefanie and Wolfinger, Michael T and Backofen, Rolf and Gorodkin, Jan and Grosse, Ivo and Hofacker, Ivo and Hoffmann, Steve and Kaleta, Christoph and Stadler, Peter F and Becker, Stephan and Marz, Manja},
    title = {Differential transcriptional responses to {E}bola and {M}arburg virus infection in bat and human cells},
    journal = {{Sci Rep}},
    year = {2016},
    volume = {6},
    pages = {34589},
    abstract = {The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms. The molecular basis of this striking difference in the response to filovirus infections is not well understood. We report a systematic overview of differentially expressed genes, activity motifs and pathways in human and bat cells infected with the Ebola and Marburg viruses, and we demonstrate that the replication of filoviruses is more rapid in human cells than in bat cells. We also found that the most strongly regulated genes upon filovirus infection are chemokine ligands and transcription factors. We observed a strong induction of the JAK/STAT pathway, of several genes encoding inhibitors of MAP kinases (DUSP genes) and of PPP1R15A, which is involved in ER stress-induced cell death. We used comparative transcriptomics to provide a data resource that can be used to identify cellular responses that might allow bats to survive filovirus infections.},
    doi = {10.1038/srep34589},
    keywords = {Animals; Cell Line, Tumor; Chiroptera; Ebolavirus, metabolism; Gene Expression Regulation; Hemorrhagic Fever, Ebola, metabolism; Humans; Marburg Virus Disease, metabolism; Marburgvirus, metabolism; Signal Transduction; Transcription, Genetic},
    pmid = {27713552},
    }


Limiting viral outbreaks with Machine Learning

Zoonosis, the natural transmission of infections from animal to human, is a far-reaching global problem, occurring more often due to globalization. In case of a virus outbreak, it is helpful to know which host organism was the original carrier of the virus, so people can be separated from this hosts. The sooner this happens, the greater the chances of limiting an outbreak.
As a fast method of predicting the original host, we are working on the ability to predict the host of a virus based on the viral genome sequence. Due to the lack of knowledge about virus adaptation, it is difficult to find practical features for machine learning methods. With this in mind, we apply deep learning methods because they do not require predefined features and are one of todays most powerful machine learning methods.

People involved: Florian Mock, Adrian Viehweger


The role of non-coding RNAs in human placental development

Inside the placenta, the fetal syncytiotrophoblast forms the interface between fetus and mother, from which exosomes and microvesicles are permanently released into the maternal circulation. These particles contain fetal proteins and ncRNAs for communication with neighboring and distant maternal cells. The number, size and content of these particles may reflect or predict placental disorders. Several severe pregnancy pathologies, including preeclampsia, are human-specific and their pathomechanisms are not yet understood.
To date, most examples of ncRNAs which have been identified to be specific for fetal tissues, such as placenta, are members of the group of microRNAs (miRNAs). Long ncRNAs have only been marginally investigated. We need to expand the knowledge about ncRNAs in the placenta and ncRNAs released from it to revolutionize the understanding of regulation processes inside the placenta and of fetal-maternal communication.

People involved: Sebastian KrautwurstDiana Maria Morales Prieto, Celia Diezel

Collaborations: Udo Markert

Grants: DFG MA 5082/9-1: Embryonale nicht-kodierende RNAs in der menschlichen Plazenta und dem mütterlichen Blutkreislauf

Related publications: 

  • W. Chaiwangyen, R. N. Gutiérrez-Samudio, U. R. Markert, M. Marz, D. M. Morales-Prieto, and S. Ospina-Prieto, “KL 5 Trophoblast-immune cell communication via microRNA transported in extracellular vesicles,” Pregnancy Hypertens, vol. 9, p. 5, 2017.
    [Bibtex]
    @Article{Chaiwangyen:17,
    author = {Chaiwangyen, Wittaya and Guti{\'e}rrez-Samudio, Ruby N and Markert, Udo R and Marz, Manja and Morales-Prieto, Diana M and Ospina-Prieto, Stephanie},
    title = {{KL} 5 {T}rophoblast-immune cell communication via micro{RNA} transported in extracellular vesicles},
    journal = {{Pregnancy Hypertens}},
    year = {2017},
    volume = {9},
    pages = {5},
    publisher = {Elsevier},
    }
  • [DOI] D. M. Morales-Prieto, E. Barth, R. N. Gutièrrez-Samudio, W. Chaiwangyen, S. Ospina-Prieto, B. Gruhn, E. Schleußner, M. Marz, and U. R. Markert, “Identification of miRNAs and associated pathways regulated by Leukemia Inhibitory Factor in trophoblastic cell lines,” bioRxiv, p. 410381, 2018.
    [Bibtex]
    @Article{Morales-Prieto:18,
    author = {Diana M. Morales-Prieto and Emanuel Barth and Ruby N. Guti{\`{e}}rrez-Samudio and Wittaya Chaiwangyen and Stephanie Ospina-Prieto and Bernd Gruhn and Ekkehard Schleu{\ss}ner and Manja Marz and Udo R. Markert},
    title = {Identification of {miRNAs} and associated pathways regulated by {L}eukemia {I}nhibitory {F}actor in trophoblastic cell lines},
    journal = {{bioRxiv}},
    year = {2018},
    pages = {410381},
    doi = {10.1101/410381},
    publisher = {Cold Spring Harbor Laboratory},
    }


Antibiotic resistance in the Ganges river valley

Antibiotics increasingly fail to treat a growing number of medical conditions due to antimicrobial resistance. This trend is especially acute in developing countries such as India, where broad resistances are known to have emerged. It is known that densely populated cities can drive the emergence and spread of antimicrobial resistance through for example industrial production sites, wastewater management practices and other cultural characteristics. Proximity to waterways or associated water collections seems especially relevant.
To identify controllable drivers of resistance emergence and spread we investigate two cities on the river Ganges in India – Allahabad and Kanpur. We also investigate the effect of human interference by analyzing samples before and after Kumbh Mela, which is by far the largest religious gathering in Prayagraj. This will allow us to discern naturally occurring resistance from resistance created by humans.

People involved: Akash Srivastava, Adrian Viehweger

Collaborations: Ziauddin Ahammad Shaikh

Grants: BMBF – DBT Cooperative Science Program: Development of metagenomics assisted surveillance tools for tracking antibiotic resistance in river bodies — A study in the Ganges river valley (NANOLOG)

 


Statistical modeling of genomic and transcriptomic data

In the last two decades in the biotechnological area, one revolutionary advancement was chased by another, leading the life sciences into the big data era. However, besides the availability of vast amounts of different biological data, we still lack sufficient statistical models and methods to accurately process and evaluate these data. We aim to develop specialised statistical tools in the context of genomics (e.g., fuzzy k-meres) and transcriptomics (e.g., accurate modeling of read count distributions). We work on different aspects of statistical analysis, starting from the theoretical problem formulation, to the implementation of statistical models and the appropriated visualisation of results.

People involved: Emanuel Barth


Finding mitogenomes in fungi using short-read NGS data

Mitochondria are essential energy producing cell organelles in eukaryotes. Their genomes are common objects for phylogenetic studies. For fungi, mitochondria play also a key role for pathogenicity and drug resistance. The structure and evolution of the mitogenomes differs between plants, animals and fungi, whereby fungal mitogenomes have been less studied than in plants or animals. The loss of tRNAs and ribosomal proteins has been reported in fungal mitogenome, as well as recombination and variable gene distribution. Hence de novo tools for reconstructing the mitogenome in silico should work with as few information from related species as possible. We will develop a pipeline to find and annotate mitogenomes of fungal short-read NGS data automatically.

People involved: Marie Lataretu

Collaborations: Matthias Bernt


 RNA structures and functions in viruses

Non coding RNAs (ncRNA) are known regulatory elements in organisms from all kingdoms. The secondary structure of RNA is often linked to its function. When looking at a viral genome (especially an RNA genome) it only makes sense that viruses make strong use of ncRNAs to bypass the host’s immune response, to regulate their own genes or to stop the gene expression of the host genes. We are concerned with the analysis of conserved RNA structures in well described virus families and the de novo prediction of potentially functional structural elements in less known families. We use combinations of machine learning, clustering and homology based methods. The identification of functional structural elements could help to develop new antiviral therapies in the future, as important replication mechanisms of the virus can be disturbed.

People involved: Kevin Lamkiewicz


Multiplex-sequencing for different kingdoms 

The concept of the German Centre for Integrative Biodiversity Research (iDiv) encompasses the detection of biodiversity, understanding its emergence, exploring its consequences for ecosystem functions and services, and developing strategies to safeguard biodiversity under global change.
To record biological diversity is fundamental but faces many challenges. To analyse genomes and transcriptomes from all organisms e.g. in soil or gut of insects, we usually use different (wet-lab) extraction protocols for bacteria, fungi and viruses. Sometimes also a common host needs to be sequenced. Instead of sequencing about 10 times the same sample from different extraction protocols to obtain the complete biodiversity, we aim to develop a method to multiplex organisms from different kingdoms into one sequencing approach.

People involved: Franziska Hufsky

Grants: DFG iDiv: All-in-one Multiplex-Sequencing