Alterations in Cellular and Extracellular Immunity triggered by CCHFV Infection

• Applicants: Professor Dr. Janis-Alexander Müller; Professorin Dr. Chrysanthi Skevaki
• Subject Area: Immunology ; Clinical Immunology and Allergology ; Clinical Infectiology and Tropical Medicine ; Virology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562152472

Crimean-Congo Hemorrhagic Fever (CCHF) is an emerging infectious disease with a high mortality rate of approximately 30% for which no treatment or vaccine currently exists. The causative pathogen, CCHF virus (CCHFV), is transmitted by Hyalomma ticks, whose geographic range is expanding. The World Health Organization (WHO) classifies CCHF a top-priority emerging disease requiring urgent attention to mitigate the risk of potential epidemics. The pathogenesis of CCHFV is complex and not fully understood. CCHFV infections impact both the innate and adaptive immune responses, leading to delayed antibody responses that correlate with disease severity. While potential T cell epitopes have been predicted through immunoinformatics, T cell responses in patients remain largely uncharacterized, leaving the contribution of cellular immunity to disease progression and long-term immunity against CCHFV unclear. Additionally, viruses are known to manipulate the release and composition of extracellular vesicles (EVs), which can promote a pro-inflammatory state and dysregulate immune responses. Alterations in EV profiles can activate T cell responses or hinder virus neutralization as seen for Ebola. However, the role of EVs in CCHFV infection is still largely unexplored. Understanding how host immune and EV-mediated responses contribute to CCHFV pathogenesis and disease severity is therefore essential for advancing diagnostic and therapeutic approaches. This project aims to elucidate the immune profiles associated with CCHFV infection and recovery, with a particular focus on identifying immune dysregulation linked to disease severity. Characterizing these dynamics may uncover novel prognostic markers and therapeutic targets for CCHF treatment. This prospective study will enroll 60 CCHF patients with severe, moderate and mild disease during two peak CCHF seasons in Turkey and include age- and sex-matched controls. Clinical data will be recorded and blood and saliva samples collected during acute infection, early convalescence, and 1, 3, and 6 months after the onset of symptoms. The viral load will be quantified and genomes sequenced. In all acute and convalescent samples, IgM, IgG and IgA serology and inflammatory cytokine signature will be studied, while cellular immunity and autoantibody responses will be also assessed. Furthermore, EVs will be profiled for immune markers and antiviral activity. Finally, ex vivo studies will explore how EVs regulate CCHF-specific immune cell responses. The proposed project will characterize the cellular and extracellular responses in mild versus severe CCHFV patients and identify correlates for severe disease. This will reveal unknown immunopathogenic processes, which has the potential for prognostic or therapeutic applications.

• DFG Programme: Research Grants
• International Connection: Turkey
• Cooperation Partners: Professorin Dr. Füsun Can; Professor Önder Ergönül