Kliniken & Institute ... Institute Zentrum für... Sektion Klinische... Forschung Zika

Clinical and Molecular Investigation of Zika Virus Pathogenesis “ZIKAPath”

Förderinstitution:                      Europäische Kommission (EC HORIZON 2020)
Laufzeit:                                    2016-2019
WissenschaftlerInnen (Sektion
Klinische Tropenmedizin):
        T. Jänisch, K. Rosenberger, F. Tobian
Kooperationspartner:                Renommierte universitäre Partner in Europa, Lateinamerika,
                                                       Afrika und Asien
Internet:                                    https://zikalliance.tghn.org/

The aim of this project is to understand key factors of the ZIKV pathogenesis through a multidisciplinary approach (see figure below).

This includes clinical-epidemiological studies in Brazil raising data on the ZIKV infection burden (Tropical Medicine, Heidelberg University Hospital, UKH1) and identifying severe cases of ZIKV disease (Virology, University of Bonn Medical Centre, in collaboration with Brazilian partners, UKB). The in vivo interplay between DENV and ZIKV infection will be investigated by generating novel tools to investigate the flaviviral serostatus and by the genetic characterization of DENV circulating before the arrival of ZIKV in different Brazilian regions (Virology, University of Bonn Medical Centre, UKB). ADE mediated by sera from these Brazilian regions will be investigated experimentally using different in vitro and in vivo models for ZIKV and DENV, including cell culture- and organoid-based models (Molecular Virology, Heidelberg University Hospital, UKH2; Microbiology/Immunology, University of Cologne, UKK), IFNAR (UKH2) and immunocompetent pregnancy mouse models (Heinrich Pette Institute for Experimental Virology, Hamburg), as well as in non-human primates (University of Veterinary Medicine, Hannover, TiHo). Finally, a novel antiviral tool to combat ZIKV infection will be tested in vitro and in vivo in the pre-clinical models developed in this project (Helmholtz Centre for Infection Research, Braunschweig, HZI).

A proof-of-concept approach for high-throughput screening of protective vs. harmful antibody profiles in infectious diseases

Förderinstitution:                              HeiKa Heidelberg Karlsruhe Research Partnership
Laufzeit:                                             2016-2017
Wissenschaftler (Sektion
Klinische Tropenmedizin):
               T. Jänisch
Kooperationspartner:                        Karlsruher Institut für Technologie (KIT)

In this project, we have expanded our successful collaboration on malaria and flavivirus research on the basis of a new technological array platform. We analyzed interactions of human serum antibodies with linear peptides for their value in diagnostic applications and understanding disease mechanisms.
The goal of this project was to apply systematic partial and whole proteome approaches to characterize antibody profiles of infectious diseases where antibodies are implicated in protection or enhancing disease – but at the same time not well characterized. Therefore, we exploited our novel peptide array technologies to generate arrays containing the whole proteome of different pathogens (or large parts thereof) as overlapping linear peptides. Then, we analyzed our well-characterized patient serum collection with these arrays to obtain the antibody interaction profiles. With this information, we could find important pathogen-specific epitopes with diagnostic and immunogenic value. Furthermore, we compared and quantified the antibody response between different related pathogens (dengue virus and zika virus) to gain insight into possible immune mechanisms.
Three tropical infectious diseases, malaria, dengue fever, and zika served as examples, but the proof-of-principle results will be applicable for a wide range of diseases, where heterogeneous antibody populations are implicated in the clinical symptoms or severity. Furthermore, we could establish the single amino acid fingerprinting approach, to acquire in depth knowledge on binding epitopes and their specificity.
Dengue virus (DENV) infections are currently on the rise in many countries, causing a global pandemic, which could potentially also threaten parts of Europe in the context of climate change. The disease can take a severe course where the underlying pathophysiology is still poorly understood – yet, most researchers agree that immunological mechanisms, and especially enhancement by antibodies, seem to play an important role.
Zika virus (ZIKV) has recently emerged in the Americas causing an epidemic, which lead WHO to declare a ‘Public Health Emergency of International Concern’ for the clusters of microcephaly and neurological disease associated with Zika infections. An immunological interaction after previous exposure to Dengue is potentially associated with a higher risk of severe congenital complications after Zika virus infection. In adults, the auto-immune mediated ‘Guillain-Barré-Syndrome’ was the most important complication seen after Zika virus infections. The detailed pathomechanism is unknown, but antibodies need to be examined if they contribute to this complication.
In malaria, a decrease in the transmission is associated with a decrease of other infectious diseases, notably bacteremia and sepsis. These indirect beneficial effects of anti-malaria control interventions are potentially ascribed to an immune-modulatory effect of acute malaria, which is not well understood.
With these proof-of-principle results, we can expand our successful collaboration to investigate other pathogens and analyze the role of elicited antibodies in immunity and immune escape mechanisms.

A Global Alliance for Zika Virus Control and Prevention “ZIKAlliance”

Förderinstitution:                   Europäische Kommission (EC HORIZON 2020)
Laufzeit:                                 2016-2019
(Sektion Klinische Tropenmedizin):
      T. Jänisch, K. Rosenberger, F. Tobian
Kooperationspartner:             Renommierte universitäre Partner in Europa, Lateinamerika,
                                                     Afrika und Asien
Internet:                                  https://zikalliance.tghn.org/

The Zika virus (ZIKV) infection is an iconic example of re-emerging arboviral diseases. Observed as a human disease as early as in the 1950ies, it was identified as a major public health issue only in 2015, when imported into Latin America. Clusters of microcephaly and neurological manifestations urged WHO to declare a ‘Public Health Emergency of International Concern’ on 1st of February 2016 which lasted until November 2016.

Major tasks are ahead of the scientific and public health community and need urgent resolution, in particular:
the assessment of the scale of the problem - absolute and relative risk of fetal damage in relation to time of infection during pregnancy, and postnatally;
-   understanding the natural history of the infection at different scales - from cellular mechanisms to human infection and circulation of the virus in the environment.

These are essential prerequisites to the development of modes of prevention or treatment, to the assessment of the socioeconomic and disability burden of the disease, and to the implementation of informed public health decisions to reduce disease burden and the risk of further spread of the pandemic.

The three-year multidisciplinary ZIKAlliance project will link large observational multicentre cohort studies with basic scientific research to address the above questions,
(i) with longstanding shared work experience on arboviral diseases in basic, clinical and applied sciences;
(ii) with an established network of clinical cohorts currently studying Dengue Fever in Latin America & the Caribbean;
(iii) guided by the principles of One Health approach to respond to the challenges of vector-borne epidemics.

The consortium will focus on three key objectives, building on ongoing prospective cohort studies of ZIKAlliance partners in Latin America and the Caribbean.
1.   impact of Zika virus infection during pregnancy and short & medium term effects on newborns.
2.   natural history of Zika virus infection in humans and their environment in the context of other circulating arboviruses.
3.   building the overall capacity for preparedness research for future epidemic threats in Latin America and the Caribbean.