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Dr. Regine Kleber and

María García

infoOad4∂heika-research de

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

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

Dr. Thomas Jänisch, Department of Infectious Diseases, University of Heidelberg

Dr. Felix Löffler, Institute of Microstructure Technology, KIT

Project Group:

Synthetic Biology

Startdate:

01.01.2016

Enddate:

31.12.2016

Summary

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.