Project descriptions

1. Comparative analysis of canine distemper virus cell tropism, replication and translation in canine 2D and 3D neuronal ex vivo culture systems as well as detection of new viruses

Title of PhD project: Comparative analysis of canine distemper virus cell tropism, replication and translation in canine 2D and 3D neuronal ex vivo culture systems as well as detection of new viruses

PI: Wolfgang Baumgärtner

Aim and objectives:

The general aim of the project is to establish innovative in vitro 3D canine CNS culture systems and to study CDV-host cell interactions with special emphasis on the role of the hemagglutinin protein derived from various CDV strains causing polio- or leukoencephalomyelitis in dogs after naturally occurring infection.

Specific objectives:

  • Characterization of modified CDV-strains blinded for the SLAM, the nectin-4 or both receptors and exchanged strainspecific H proteins
  • Establisment of canine neurospheres and neuronal organoids
  • Investigation of CDV CNS cell tropism

2. Investigation of potential viral etiology and associated pathogenesis in disease syndromes of unknown cause in wildlife and marine mammals

Title of PhD project: Investigation of potential viral etiology and associated pathogenesis in disease syndromes of unknown cause in wildlife and marine mammals

PIs: Andreas Beineke & Ursula Siebert

Hypothesis:

It is hypothesized that the combined application of various molecular tools for virus discovery and their correlation with pathological changes will allow the detection of so far unrecognized pathogens in wildlife and marine animals and will provide further insights in their pathogenesis including virus tissue/organ and cell tropism

Aim and objectives:

  • Application of “a cocktail of detection tools” in well-known diseases of wildlife and marine mammals to substantiate the formulated hypothesis.
  • Screening of archival tissues displaying lesions (retrospective analysis) reminiscent of a viral cause by “cocktail of detection tools”.
  • Cases of suspected virus etiology of so far unknown origin (prospective analysis) will be investigated.

3. Automated unsupervised clustering of viral meta-genomes derived from sequence read archives

Title of PhD project: Automated unsupervised clustering of viral meta-genomes derived from sequence read archives

PI: Klaus Jung

Hypothesis:

  • Methods for normalization of and batch effect removal in high-dimensional read count data can be employed to optimize unsupervised clustering results.
  • Viromes estimated from NGS data of the SRA build clusters that can be related to sample annotations.

Aim and objectives:

The general aim of the project is to: improve preprocessing of virome data sets and subsequent unsupervised clustering algorithms, and to apply these new methods to build cluster maps from data of the SRA.

Specific objectives:

  • To evaluate normalization and batch removal methods for their application to virome data in the form of high-dimensional read count data.
  • To sample data from the SRA and use unsupervised clustering methods to build annotated virome maps.

 

4. Virus discovery and characterization platform

Title of PhD project: Virus discovery and characterization platform

PIs: Albert Osterhaus & Ursula Siebert

Hypothesis:

It is hypothesized that wildlife and domestic animal reservoirs host viruses that may cause major disease outbreaks among domestic animals and humans. Their discovery as well as identification of their potential host range and transmissibility in domestic and wildlife animal reservoirs are key elements of future epidemic and pandemic preparedness. 

Aim and objectives:

The general aim of the project is to:

Build on the established VIPER-1 wildlife and domestic animal disease and etiology monitoring in Germany and abroad.

Specific objectives:

  • Continue and extend ongoing VIPER-1 wildlife and domestic animal sampling activities.
  • Exploit and streamline TiHo’s molecular and biological virus discovery and characterization platforms.
  • Evaluate the threat to animal and human health posed by a selection of dozens of viruses identified within VIPER.

5. Long-term consequences of SARS-CoV-2 infection in the lung and the CNS in the golden Syrian hamster model

Title of PhD project: Long-term consequences of SARS-CoV-2 infection in the lung and the CNS in the golden Syrian hamster model

PI: Wolfgang Baumgärtner

Hypothesis:

It is hypothesized that despite virus clearance, SARS-CoV-2-infected hamsters show incomplete regeneration characterized by morphological non-functional regeneration and/or lung fibrosis, which will be associated with reduced exercise tolerance in vivo and potential alterations in non-respiratory tract tissues.

Aim and objectives:

The general aim of the project is to characterize SARS-CoV-2-induced alterations in the lower respiratory tract (LRT). The first part of the project targets SARS-CoV-2 induced effects on the LRT during active virus infection and replication, with special emphasis on the investigation of bronchial epithelium and pneumocytes type 1 and 2. The second part focuses on alterations in the LRT after virus clearance.

Specific objectives:

  • Investigation of morphologic alterations of bronchial epithelium and pneumocytes 1 and 2 and the interstitial tissue at the light and ultrastructural level in the LRT and other organs in the golden Syrian hamster model
  • Investigation of morphologic alterations to bronchial epithelium and pneumocytes 1 and 2 and the interstitial tissue at the light and ultrastructural level in the LRT in the golden Syrian hamster model after virus clearance

6. Morphologic Examination of Ciliated Epithelia in Upper Respiratory Airways with special consideration of olfactory epithelium after SARS-CoV-2-infection

Title of PhD project: Morphologic Examination of Ciliated Epithelia in Upper Respiratory Airways with special consideration of olfactory epithelium after SARS-CoV-2-infection

PI: Wolfgang Baumgärtner

Hypothesis:

The first hypothesis is that SARS-CoV-2 induces ciliary damage and loss in the RE and that the degree of cilia damage correlates with spread of infection to the lung in susceptible animal species. The second hypothesis refers to the infection of olfactory sensory neurons and postulated subsequent spread to the CNS by the olfactory route in hACE2-mice, but not ferrets and hamsters.

Aim and objectives:

The general aim of the project is to illuminate SARS-CoV-2-induced alterations in the epithelium of the URT. The first part of the project targets SARS-CoV-2 induced effects on the integrity of RE, with special emphasis on the investigation of ciliary damage. The second part focuses on alterations in the OE and connected brain structures.

Specific objectives:

  • Investigation of morphologic alterations to ciliated epithelia in the URT after SARS-CoV-2 infection in golden Syrian hamsters, ferrets and hACE2-mice
  • Investigation of underlying pathomechanisms of ciliary loss after SARS-CoV-2-infection in golden Syrian hamsters, ferrets and hACE2-mice
  • Investigation of morphologic alterations and virus distribution in the OE in the nose and in the olfactory bulb in the brain after SARS-CoV-2-infection in golden Syrian hamsters, ferrets and hACE2-mice

7. Investigation of pathogenesis, virulence and immunoreaction following infection with a genetically modified OVA-Theilervirus in a murine model of multiple sclerosis

Title of PhD project: Investigation of pathogenesis, virulence and immunoreaction following infection with a genetically modified OVA-Theilervirus in a murine model of multiple sclerosis

PI: Wolfgang Baumgärtner

Hypotheses:

SJL- and CD28KO-mice can be persistently infected with XhoI-OVA8 after intracerebral infection. C57BL/6-, OT-2 mice show persistence only after intraspinal infection. OT-1 mice are able to eliminate the virus, irrespective of the infection route.

Aim and objectives:

The general aim of the project is to elucidate the possible beneficial and adverse effects of virus specific CD4+ and CD8+ T cell responses in a murine model for epilepsy and multiple sclerosis.

Specific objectives:

  • Determination of the virulence of XhoI-OVA8 in different mouse strains after intracerebral and intraspinal infection

8. Characterization of recently identified novel viruses from wild boar and other wild animal species

Title of PhD project: Characterization of recently identified novel viruses from wild boar and other wild animal species

PI: Paul Becher

Hypothesis:

Several recently identified viruses from wild animals (e.g. bunyavirus, astrovirus, birnavirus, circoviruses) cannot be propagated in permanent cell lines. Therefore, we will explore the hypothesis that at least some of these viruses can be isolated and propagated in established polarized epithelial cells or organoid cultures and use these tissue cultures for characterization of viral replication and virus-host interactions of selected viruses.

Aim and objectives:

The general aim of the project is to isolate and characterize selected viruses from wild boar and other wild animals to enhance our knowledge on evolution, host range, and biological properties including virus-host interactions of these viruses.

Specific objectives:

  • to isolate recently identified viruses from wild boar and other wild animals
  • to characterize selected viruses (viral growth kinetics, viral genome replication)
  • to determine the host range of selected viruses
  • to study cellular interferon type 1 (IFN-type 1) mediated immune responses and viral factors counteracting innate host defenses

9. Overcoming the airway epithelium barrier in the early phase of bovine viral diarrhea virus (BVDV) infection

Title of PhD project: Overcoming the airway epithelium barrier in the early phase of bovine viral diarrhea virus (BVDV) infection

PI: Paul Becher

Hypothesis:

BVDV and other pestiviruses have a strong tropism for immune cells. Therefore, we will explore the hypothesis that immune cells are significantly involved in crossing the airway epithelium and study the pathway by which BVDV crosses the barrier of the respiratory epithelium and spreads from there to immune cells.

Aim and objectives:

The general aim of the project is to elucidate how BVDV can cross the barrier of the airway epithelium.

Specific objectives:

  • to characterize apical and basolateral infection of differentiated Air-liquid-interface (ALI) cells by BVDV including monitoring of viral release
  • to study BVDV infection of precision cut lung slices
  • to analyze the role of bovine CD46 for cell tropism 
  • to investigate the role of macrophages for overcoming the epithelial barrier by BVDV

10. The role of Card-9 regulated pathways in orthobunyavirus infections

Title of PhD project: The role of Card-9 regulated pathways in orthobunyavirus infections

PI: Stefanie Becker

Hypothesis:

Reassortant viruses differ from parental strains in respect of infection efficiency and pathogenicity in mammalian and insect hosts.

This difference can be linked to C-type lectin receptors either by viral recognition or differential immune activation

Aim and objectives:

The general aim of the project is to continue the analysis of factors responsible for the differential pathogenicity of reassortant orthobunyviruses in mammalian and insect hosts. Thus far we were able to prove, that reassortant between Batai and Bunyamwera orthobunyaviruses, specifically the reassortant Batunya orthobunyavirus show increased replication in mammalian and decreased replication in insect cells. Furthermore, we were able to identify differential expression of C-type lectins in mouse dendritic cells infected with Batai orthobunyavirus.

Specific objectives:

  • characterize the interaction of parental and reassortant viruses with C-type lectin receptors
  • characterize the C-type lectin dependent immune response in cell infected with parental or reassortant viruses

11. The role of Anti-RVFV immunity in germline infection and behavior modulation in insects

Title of PhD project: The role of Anti-RVFV immunity in germline infection and behavior modulation in insects

PI: Stefanie Becker

Hypothesis:

Several small RNA pathways interlink to enable transovarial transmission of viral pathogens in insects.

Aim and objectives:

The overall aim of this project is to better understand how different innate immune pathways interlink to control infection in reproductive tissue. Therefore we propose, based on the knowledge gained through our studies of antiviral RNAi using RVFV, to:1) Analyse the induction of antiviral mechanisms in infected germline cells of Drosophila, as well as Culex and Aedes mosquitoes (siRNA, piRNA, inducible immune response) concerning their role in control of viral replication and 2) Test the hypothesis that RVFV infection of Drosophila and mosquitoes affects olfactory sensitivity and behavioural response to odours and to study the role of antiviral pathways in in these processes.

12. Identification of intracellular host range restriction factors of canine distemper virus

Title of PhD project: Identification of intracellular host range restriction factors of canine distemper virus

PIs: Andreas Beineke & Martin Ludlow

Hypothesis:

In this project, we will test the hypothesis that CDV strains originating from different wildlife species display phenotypic differences following infection of immune cells including the ability to inhibit T-cell stimulation and antagonize the innate immune system.

Aim and objectives:

The general aim of the project is to identify species differences in the ability of CDV to infect and disrupt the normal functioning of immune cells.

Specific objectives:

  • Characterize the host response in lymphoid organs of CDV-infected animals
  • Investigate functional consequences of morbillivirus infection on different immune cell types
  • Elucidate the mechanisms underlying the ability of CDV to antagonize the innate immune response

13. Investigations upon the role of C-type lectin receptors in the pathogenesis of Theiler’s murine encephalomyelitis virus-induced hippocampal damage

Title of PhD project:  Investigations upon the role of C-type lectin receptors in the pathogenesis of Theiler’s murine encephalomyelitis virus-induced hippocampal damage

PIs: Andreas Beineke & Martin Ludlow

Hypothesis:

In this project, we will test the hypothesis an activation of APCs in the brain causes excessive neuroinflammation and hippocampal damage.

Aim and objectives:

The planned project aims to analyze the effect of activating CLR signaling in the neuropathogenesis of TMEV infection in detail.

Specific objectives:

  • Investigation of APC effector functions mediated by CLR/TMEV interaction in vitro.
  • Mechanistic studies to characterize the effects of Dectin-1, Dectin-2, and Mincle activation upon virus-mediated neuropathology in knockout mice.

14. The role of tetraspanins in cross-species transmission of re-emerging alphaviruses

Title of PhD project:  The role of tetraspanins in cross-species transmission of re-emerging alphaviruses

PI: Gisa Gerold

Hypothesis:

We hypothesize that tetraspanins are alphavirus host factors not only in humans, but also in vertebrate reservoir and dead end host species as well as in mosquito vectors. Moreover, we will challenge the hypothesis that tetraspanins directly or indirectly, through protein interactions, determine the host range of alphaviruses.

Aim and objectives:

The proposed project aims at characterizing in detail, which of the 33 human tetraspanins in addition to CD81 are host factors for alphaviruses and whether tetraspanins from reservoir species, dead end host species and transmitting mosquito vectors serve as host factors of alphaviruses. Thereby the work will contribute to the understanding of the molecular composition and function of alphavirus replication complexes and determine the role of tetraspanins in species range, transmission and consequently emergence of alphaviruses.

Specific objectives:

  • Characterization of the role of human tetraspanins in alphavirus infection.

  • Elucidation of the impact of tetraspanins on vertebrate host range of alphaviruses.

  • Analysis of the role of mosquito tetraspanins in alphavirus transmission.

15. Host factor interactions during early steps of hepatitis C virus cell entry and their interindividual modulation by genetic and pharmacological perturbations

Title of PhD project:  Host factor interactions during early steps of hepatitis C virus (HCV) cell entry and their interindividual modulation by genetic and pharmacological perturbations

PI: Gisa Gerold

Hypothesis:

We hypothesize that lipid receptors and lipid modifying pharmacological agents interplay to regulate HCV infection.

Aim and objectives:

The overall purpose of this project is to attain a more comprehensive understanding of the interactions between incoming HCV and the key host factors SR-BI, LDLr and CD81 during the initial phase of HCV cell entry and to evaluate how this interplay is modulated by host genetic variation.

16. Prediction of miRNAs involved during viral infections using gene-set tests on expression data of mRNA targets

Title of PhD project: Prediction of miRNAs involved during viral infections using gene-set tests on expression data of mRNA targets

PI: Klaus Jung

Hypothesis:

  • For some miRNAs, the result of a global test on mRNA target expression profiles is correlated with the single test result of related miRNA.
  • There are subsets of common miRNAs involved in closely related infectious diseases.

Aim and objectives:

The general aim of the project is to 1) evaluate and 2) apply computational approaches via global tests on mRNA expression profiles to predict indirectly changes in miRNA expression profiles during viral infections.

Specific objectives:

  • Development and evaluation of new computational method to predict miRNA expression changes from mRNA expression profiles.
  • Application of new approach to identify miRNAs commonly altered in closely related infectious diseases.

17. Tick-borne encephalitis neuro-pathogenesis

Title of PhD project: Tick-borne encephalitis neuro-pathogenesis

PI: Albert Osterhaus

Hypothesis:

TBEV that escapes peripheral immune responses, enter the CNS, infect neurons and glial cells and induce neuroinflammation which may play a crucial role in controlling viral pathogenesis. Additionally, neuroinflammation may contribute to recruitment of peripheral immune cells into the CNS and resulting neural damage may have long lasting consequences on the functioning of the CNS.

Aim and objectives:

  • To study the role of local innate immune response against TBEV; beneficial or detrimental?
    • Global gene expression profiling of brain of experimental mice challenged with pathogenic and attenuated strains of TBEV/MVA
    • Comparative analysis of neuroinflammatory response to attenuated and pathogenic TBEV
  • To study the role of microglia, astrocytes and neurons in this process
  • To study the contribution of TBEV induced neuroinflammation in the recruitment of immune cells into the CNS
  • Virus control mechanisms within the CNS

18. In vitro systems to study antibody escape and antiviral resistance mechanisms during RSV and SARS-CoV-2 infections

Title of PhD project: In vitro systems to study antibody escape and antiviral resistance mechanisms during RSV and SARS-CoV-2 infections

PIs: Albert Osterhaus & Martin Ludlow

Aim and objectives:

The aim of this project is to complement the increasing sophistication of molecular virological techniques with respect to rapid assembly and manipulation of recombinant viruses with in vitro models that better recapitulate key features of the respiratory tract. This will provide robust data sets that can offer alternatives to animal experimentation for characterizing the ability of respiratory viral infections to escape from therapeutic intervention strategies.

Specific objectives:

  • Characterization of the impact of antibody escape mutations on RSV fitness
  • Assessment of the fitness of SARS-CoV-2 following evolution of escape mutations to specific antibodies targeting the spike protein
  • Investigation of the capacity of RSV and SARS-CoV-2 to infect epithelial cells under hypoxic conditions.

19. Investigations of virulence factors and host-pathogen-interaction of newly emerging avian Influenza viruses in chickens

Title of PhD project: Investigations of virulence factors and host-pathogen-interaction of newly emerging avian Influenza viruses in chickens

PI: Silke Rautenschlein

Hypothesis:

We speculate that virulence associated variations in the viral genome associate with differences with virus-host-interaction.

Aim and objectives:

Our aim is to understand the determinants of increased virulence of LPAIV and their impact on host cell tropism.

Specific objectives:

  • To determine difference in the induction of the innate host immune response by comparing wild-type (WT) and mutated LPAIV
  • To determine the impact of host receptor distribution on the virus-host-interaction by comparing WT and mutant LPAIV
  • To establish in vitro systems which can be used for risk assessment of newly emerging LPAIV

20. Modulation of cellular stress responses in RNA virus infections

Title of PhD project: Modulation of cellular stress responses in RNA virus infections

PI: Imke Steffen

Hypothesis:

The ability to modulate cellular stress responses is a major hallmark of virus replication and correlates with tissue-specific pathogenesis. Few changes in the viral genome have a strong impact on tissue tropism, cell fate and outcome of infection.

Aim and objectives:

The general aim of the project is to identify virus and strain specific properties that modulate cellular stress responses in relevant target cells. Besides different tick-borne encephalitis virus (TBEV) strains, low and highly pathogenic flaviviruses and coronaviruses will be investigated for their ability to modulate cellular stress responses. Understanding tissue-specific pathogenic mechanisms will lead to strategies for therapeutic interference.

Specific objectives:

  • Comparative analysis of cell stress in low or highly pathogenic flavivirus and coronavirus infections
  • Identification of viral factors associated with high pathogenicity and specific modulation of cell stress
  • Pharmacological interference with cell stress signals to limit viral replication and change cell fate

21. C-type lectin receptor interactions of SARS-CoV-2

Title of PhD project: C-type lectin receptor interactions of SARS-CoV-2

PI: Imke Steffen

Hypothesis:

Immune recognition of SARS-CoV-2 by CLRs plays a role in myeloid cell inactivation. CLR binding of SARS-CoV-2 or immune complexes initiates signaling pathways that contribute to inflammatory immune signatures observed in SARS-CoV-2 infection.

Aim and objectives:

The general aim of the project is to identify CLRs that interact with SARS-CoV-2 directly or in complex with specific antibodies and initiate immune signaling pathways that may influence disease outcomes and can be modulated by genetic or pharmacologic intervention techniques.

Specific objectives:

  • CLR interactions with SARS-CoV-2 spike protein and immune complexes
  • CLR expression profiling and activation of myeloid cell subsets
  • Immune modulation of SARS-CoV-2 induced CLR signaling in myeloid cells

22. Host restriction factors in zoonotic hepatitis E virus infection

Title of PhD project: Host restriction factors in zoonotic hepatitis E virus infection

PIs: Eike Steinmann & Paul Becher

Hypothesis:

HEV infection can be cleared in an immune-competent host. Therefore, we hypothesize that constitutive expressed proteins as well as HEV-triggered host proteins can restrict the HEV replication cycle.

Aim and objectives:

The general aim of the project is to identify and characterize constitutive and viral-induced host expressed proteins in a species-specific manner that can restrict the HEV replication cycle.

Specific objectives:

  • Identification of potential HEV restriction factors using an antibody-based microarray of host signaling proteins, RNA sequencing and proteomics of HEV-infected cells
  • Validation of identified hits by ectopic expression and knock-out of candidate restriction factors
  • Determination of species-specific restriction using swine orthologous

23. Innate immune response to equine hepatotropic viruses

Title of PhD project: Innate immune response to equine hepatotropic viruses

PIs: Eike Steinmann & Paul Becher

Hypothesis:

Equine liver tropic viruses from diverse virus families (Parvoviridae, Flaviviridae, Hepadnaviridae) have been recently identified with limited knowledge about host innate immune recognition. Therefore, we aim to perform a comparative analysis of innate immune response in naturally and experimentally infected equids using RNA sequencing (RNAseq).

Aim and objectives:

The objective of the project is to decipher the innate immune responses of recently discovered liver-tropic equine viruses and to identify correlates of liver pathogenesis.

Specific objectives:

  • Establishment of a EqHBV-specific quantitative PCR
  • Surveillance of EqHV, EqHBV and EqPV-H in an isolated horse cohort
  • Longitudinal RNA sequencing of infected liver biopsies 
  • Bioinformatic analysis of innate immune signatures

24. Coronavirus infections of the reproductive tract in mammals and birds: interplay of hormones and innate immunity

Title of PhD project: Coronavirus infections of the reproductive tract in mammals and birds: interplay of hormones and innate immunity

PIs: Gülsah Gabriel & Silke Rautenschlein

Hypothesis:

We speculate that host-pathogen-interactions may be modified by the sexual maturation stage of the host and therefore an age effect on SARS-CoV-2 as well as on IBV pathogenesis may be observed.

Aim and objectives:

Our aim is to understand the impact of sex hormones on viral replication, host immune responses and tissue damage after inoculation of SARS-CoV-2 in comparison to IBV.

Specific objectives:

  • To determine differences in coronavirus-host-interaction in reproductive tissues of chickens and guinea pigs as a model for SARS-CoV-2 infections in humans
  • To determine the impact of sex hormones on virus infection and host innate immune responses in ex vivo models
  • To determine hormone-associated changes in target cell distribution and receptor expression pattern

25. Treatment of pulmonary virus infection with genetically modified myeloid cells

Title of PhD project: Treatment of pulmonary virus infection with genetically modified myeloid cells

PI: Ulrich Kalinke

Hypothesis:

Pulmonary adoptive transfer of primary myeloid cells transduced to express virus-neutralizing single-chain IgG will help to resolve virus airway infection.

Aim and objectives:

The general aim of the project is to transduce murine myeloid cells to obtain expression of SARS-CoV-2 neutralizing scIgG. Transduced cells will be studied whether they can be used for prevention or therapy of SARS-CoV-2 infection.

Specific objectives:

  • Transduce murine and human myeloid cells with lentiviral vectors and determine expression of virus-neutralizing IgG.
  • Determine IgG levels in mice after adoptive transfer of transduced cells via the intranasal or the intravenous route.
  • Test in K18-hACE2 transgenic mice the efficacy of preventive and therapeutic settings against SARS-CoV-2 infection.

26. Assessment of antibody-dependent enhancement (ADE) by SARS-CoV-2 specific monoclonal antibodies

Title of PhD project: Assessment of antibody-dependent enhancement (ADE) by SARS-CoV-2 specific monoclonal antibodies

PI: Ulrich Kalinke

Hypothesis:

In vitro and in vivo assays assessing antibody-dependent enhancement (ADE) can be developed for SARS-CoV-2 specific monoclonal antibodies.

Aim and objectives:

The aim of the project is to develop in vitro and in vivo assays for the assessment of the risk of ADE induction by SARS-CoV-2 specific mAbs.

Specific objectives:

  • Assessment of the capacity of in vitro differentiated and ex vivo isolated human myeloid cell subsets to support productive SARS-CoV-2 infection.
  • Assessment of these cell subsets for their capacity to support productive virus infection upon incubation with complexes consisting of SARS-CoV-2 specific mAbs and replication competent SARS-CoV-2.
  • Analysis of cytokine as well as chemokine production of cells in a) and b).
  • Monitoring of disease course and severity in SARS-CoV-2 susceptible K18-hACE mice upon treatment with SARS-CoV-2 or complexes consisting of SARS-CoV-2 specific mAbs and the replication competent virus.
  • In case of ADE induction, analysis of “silenced” mAbs in vitro and in vivo assays.

27. Exploitation of the TiHo SARS-CoV-2-hamster model under BSL-3 conditions for testing of novel intervention strategies for COVID-19

Title of PhD project: Exploitation of the TiHo SARS-CoV-2-hamster model under BSL-3 conditions for testing of novel intervention strategies for COVID-19

PI: Albert Osterhaus

Hypothesis:

The hypothesis is that the hamster model established at TiHo offers a unique opportunity to preclinically test the potential of novel human monoclonal antibodies, antiviral strategies, and vaccination concepts, to overcome the major limitations of the currently used pharmaceutical intervention strategies for COVID-19.

Aim and objectives:

The general aim of the project is to explore novel intervention strategies for COVID-19 in a preclinical model.

Specific objectives:

  • Testing of new generation human monoclonal antibodies with broad reactivity against recently emerged VOCs
  • Testing of novel antiviral strategies, like one-for-all CRISPR/Cas13-based ATMP in collaboration with UMG, towards a universal anti-coronavirus drug.
  • Testing of a RBD-based COVID19 vaccine C1 based vaccines as a tool to hugely increase production capacity, reduce cost of goods and avoid cold-chain problems

28. Immunity to CNS infection caused by Rift Valley Fever Virus (RVFV)

Title of PhD project: Immunity to CNS infection caused by Rift Valley Fever Virus (RVFV)

PI: Guus F. Rimmelzwaan

Hypothesis:

We hypothesize that CMI-specific RVFV is an important correlate of protection against RVFV CNS infection. This hypothesis will be tested using: 1. A vaccine (RVFV-4s) known to induce CMI, 2. Synthetic peptides and oligomers for detection of virus-specific T cells, and 3. A mouse model for RVFV CNS infection.

Aim and objectives:

The general aim of the project is to: Obtain a better understanding of (vaccine) induced immunity to RVFV infections. 

Specific objectives:

  • Define RVFV T cell epitopes recognized by Balb/c mice. 
  • Using this information to produce MHC class I peptide oligomers for the detection of virus specific T cells in spleen, lymph nodes and brains by flow cytometry/immunohistochemistry
  • Establish a mouse model for RVFV induced encephalitis based on the wildtype strain 35/74, using various infectious doses and challenge routes
  • Define the role of the respective arms of the immune system in the pathogenesis of RVFV infections

29. Towards a better understanding of cell-mediated immunity to Respiratory Syncytial Virus (RSV)

Title of PhD project: Towards a better understanding of cell-mediated immunity to Respiratory Syncytial Virus (RSV)

PI: Guus F. Rimmelzwaan

Hypothesis:

We hypothesize that RSV-host interactions define the outcome of RSV-specific T cell responses. This hypothesis will be tested by analyzing the human RSV-specific T cell response in vitro using PBMC, RSV-specific T cell clones, synthetic peptides, molecularly cloned RSV, +/-  mutations in CX3CR1-binding domain, various antigen-presenting cells and flowcytometry.

Aim and objectives:

The general aim of the project is to: Obtain a better understanding of cell-mediated immunity to RSV infections. 

Specific objectives:

  • Generate human RSV-specific T cell clones. 
  • Use these T cell clones to study functional profiles after stimulation by APC incubated with peptides or recombinant viruses with and without mutations in the chemokine receptor CX3CR1-binding domain of the RSV G-protein, by flow cytometry/luminex.
  • Investigate the role of CX3CR1-binding in the tropism of RSV for lymphocyte subpopulations.

30. Biodistribution and reactogenicity of SARS-CoV-2 antigens delivered by MVA candidate vector vaccines against COVID-19

Title of PhD project: Biodistribution and reactogenicity of SARS-CoV-2 antigens delivered by MVA candidate vector vaccines against COVID-19

PIs:  Gerd Sutter & Wolfgang Baumgärtner

Hypothesis:

The evaluation of MVA-SARS-2-S distribution, antigen persistence, local reactogenicity and potential systemic toxicity will contribute to the further development of recombinant MVA as general vector technology platform for rapid investigation of vaccine candidates in clinical trials. The so called ‘biodistribution’ of a test vaccine is important to estimate risks potentially associated with an in vivo application of a candidate vector. The analysis of vaccine-associated lesions will provide information on in vivo distribution of MVA DNA/antigen and recombinant antigens such as SARS-CoV-2 S protein.

Aim and objectives:

The aim of our investigation is to provide a detailed characterization of local and systemic impact of MVA-SARS-2-S administration in the Syrian hamster model.

Specific objectives:

  • Evaluation of distribution and antigen persistence of MVA-SARS-2-S administration.
  • Detection of vaccine-associated lesions and local reactogenicity such as inflammatory after the application of MVA-SARS-S.
  • Evaluation of systemic toxicity after the application of MVA-SARS-S.
  • Evaluation of MVA/SARS-CoV-2 specific antibodies