Overview

Our laboratory is focused on the study of viral hemorrhagic fevers (VHFs), in particular those caused by filoviruses such as Ebola and Marburg virus. Using animal models as well as clinical studies in Africa we aim to understand the physiology of host immune responses to these viruses. In most VHFs the host immune response plays a dual role. It is essential for viral clearance and recovery, but it is also an important driver of the multiorganic disease that, in many cases, unfortunately leads to death. Therefore, our primary research question is: what factors control the balance between immunity and immunopathology in VHFs? The findings from this basic research are used to identify correlates of disease outcome as well as targets for post-exposure immunotherapy.

RESEARCH PROJECTS

Role of dendritic cells on filovirus immunity and dissemination

Dendritic cells (DC) are at the forefront of pathogen recognition in mucosae and skin, and provide a bridge between innate an adaptive immunity. We have engineered chimeric and humanized mice where we can manipulate and track specific DC subsets in vivo. Through the use of this technology we study the susceptibility of DC to filovirus infection and their role in virus dissemination from the sites of infection. We also utilize antibody-targeting technology to deliver filovirus-derived antigens to DC.

T cell immunity in recovery and immunopathology of Ebola virus disease and Lassa fever

T cells are critical for clearance of virus-infected cells and play additional roles in adaptive immune responses such as coordination of humoral immunity, immune regulation and cytokine production. We have previously observed that dysregulation of T cell responses is correlated with severity of Ebola virus disease and, at least in animal models, with disruption of the endothelial barrier during Lassa fever. We are using multiparametric flow cytometry, T cell receptor sequencing and transplantation technology to assess the role of T cells during Lassa and Ebola virus infection paying special attention to the kinetics over the course of the disease. Additionally, we plan to evaluate whether antibody-based targeting of T cell immune checkpoints can influence disease outcome. In collaboration with the Department of Virology at BNITM we are studying T cell immune responses in Lassa fever patients in Nigeria.

Comparative pathology of filoviruses

Severely immunodeficient mice such as NOD-scid-IL-2gR-/- (NSG) tolerate xenotransplantation of hematopoietic progenitor cells from other species, thereby providing an in vivo platform to study hematopoietic-driven immune responses from different virus hosts. We are using this strategy to model and compare the pathophysiology of different filoviruses (i. e. Reston, Ebola, Bundibugyo virus) in mice harboring immune components of different host species (i. e. humans, bats). The goal of this project is to identify species-specific correlates of filovirus susceptibility.

Vaccine development

In the context of different laboratory consortia, we participate in the development of several vaccine platforms against VHFs. We provide modeling tools to assess vaccine immunity and safety as well as effectiveness (challenge studies).

Immune memory to VHFs in human survivors

Survivors of VHFs such as Ebola virus disease may provide important cues for correlates of immune protection. We are using immunogenomics, flow cytometry and bioinformatics to compile multiparametric data and to identify signatures related with protection. These studies are done in collaboration with multiple partners including NIH, NCU, Public Health England as well as the ministries of health of Guinea and Liberia.

Publication Highlights

Ebola virus infection kinetics in chimeric mice reveal a key role of T cells as barriers for virus dissemination.
Lüdtke A, Ruibal P, Wozniak DM, Pallasch E, Wurr S, Bockholt S, Gómez-Medina S, Qiu X, Kobinger GP, Rodríguez E, Günther S, Krasemann S, Idoyaga J, Oestereich L, Muñoz-Fontela C.
Sci Rep. 2017 Mar 3;7:43776. doi: 10.1038/srep43776.

Ebola virus disease is characterized by poor activation and reduced levels of circulating CD16 (+) monocytes.
Lüdtke A, Ruibal P, Becker-Ziaja B, Rottstegge M, Wozniak DM, Cabeza-Cabrerizo M, Thorenz A, Weller R, Kerber R, Idoyaga J, Magassouba NF, Gabriel M, Günther S, Oestereich L, Muñoz-Fontela C.
J Infect Dis. 2016 Oct 15;214(suppl 3):S275-S280. Epub 2016 Aug 11.

Chimeric mice with competent hematopoietic immunity reproduce key features of severe Lassa fever.
Oestereich L, Lüdtke A, Ruibal P, Pallasch E, Kerber R, Rieger T, Wurr S, Bockholt S, Pérez-Girón JV, Krasemann S, Günther S, Muñoz-Fontela, C.
PLoS Pathog. 2016 May 18;12(5):e1005656. doi: 10.1371/journal.ppat.1005656. eCollection 2016 May.

Unique human immune signature of Ebola virus disease in Guinea.
Ruibal P, Oestereich L, Lüdtke A, Becker-Ziaja B, […], Magassouba N, Carroll MW, Guenther S, Muñoz-Fontela, C.
Nature. 2016 May 5;533(7601):100-4. doi: 10.1038/nature17949.

Ebola virus disease in mice with transplanted human hematopoietic stem cells.
Lüdtke, A., Oestereich, L., Ruibal, P., Wurr, S., Pallasch, E., Bockholt, S., Ip, W.H., Rieger, T., Gomez-Medina, S., Stocking, C., Rodriguez, E., Günther, S., Muñoz-Fontela, C.
J Virol. 2015 Apr;89(8):4700-4. doi: 10.1128/JVI.03546-14. Epub 2015 Feb 11.

Laboratory Alumni

Dr. Paula Ruibal :

Dr. Jose V. Pérez-Girón :

Dr. Jazmina Gonzalez-Cruz :

Dr. Anja Lüdtke :

Contact

César Muñoz-Fontela PhD

Phone: +49 (0) 40 42818-541
Fax: +49 (0) 40 42818-512
E-Mail: munoz-fontela@bnitm.de


Students

Julia R. Port (-473)
Monika Rottstegge (-473)
András Bencsik (-473)
Catherine Olal (-473)

Technical Staff

Sergio Gómez-Medina (-471)
Jürgen Müller-Guhl (-471)

Links

@CesarMFontela on Twitter


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