Roles of innate and memory NK cell responses in viral clearance and severe dengue pathogenesis in children.

• Applicant: Dr. Lennart Hermanussen
• Subject Area: Clinical Infectiology and Tropical Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557106817

Dengue virus (DENV) is a major cause of morbidity and mortality infecting 400 million people annually, and the global incidence of dengue has grown dramatically in recent decades. Most infected individuals are asymptomatic or experience mild symptoms, but 5% progress to severe dengue (SD) which is potentially lethal. SD is a leading cause of serious illness and death in some Asian and Latin American countries, particularly in children, who progress more often to SD than adults and have higher hospitalization and mortality rates. Prior exposure to one of the four DENV serotypes triggering antibody-dependent enhancement (ADE) upon infection with a heterologous serotype is a major risk factor for SD. The understanding of other determinants of SD has been limited, partly due to using bulk sample assays and relying on inadequate immunocompromised in vivo DENV models. Consequently, the question why children are more likely to progress to SD than adults remains unanswered. To overcome these challenges, the Einav lab has employed an integrated single cell systems immunology approach to profile the immune responses in SD vs. dengue (D) patients in blood samples from a subset of a cohort of ~550 patients enrolled in Colombia. A dysregulated NK cell response was identified as a key hallmark of SD progression, more pronounced in children than adults. Additionally, preliminary results in convalescent PBMC samples have recently provided evidence for trained immunity of NK cells following DENV infection. NK cells from BCG vaccinees or CMV seropositive subjects show long-lasting activation after restimulation. Epigenomic reprogramming is thought to enable short-lived cells to acquire an immune memory-like phenotype. Yet, it remains unknown whether trained immunity reflects a more general phenomenon in human viral, particularly acute, infections. While trained immunity has shown protection from re-challenge in animal models, it is also unknown if it plays a role in disease pathogenesis. The primary goals of this project are to functionally characterize global and DENV-specific NK cell subtype functions as well as memory NK cell responses; further, to define their roles in viral clearance and disease pathogenesis. Pursuing these aims will also further a 3D lymphoid tissue organoid model to study DENV pathogenesis and immune responses. The translational impact is that defining the receptors that mediate NK cell-induced pathogenesis may reveal candidate biomarkers of progression to SD and/or targets for immunomodulatory strategies to prevent it.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Shirit Einav