|Titel:||Natural Killer Cell-Mediated Target Cell Killing in the Context of Viral Infections||Sprache:||Englisch||Autor*in:||Hagemann, Kerri||Erscheinungsdatum:||2022||Tag der mündlichen Prüfung:||2023-01-13||Zusammenfassung:||
Viral infections are a constant threat for our health, requiring adequate immune responses. Thus, an effective interaction between innate and adaptive immunity determines disease severity and recovery outcome. Natural killer (NK) cells are among the first immune cells that are activated upon viral infection, contributing to the immune response with a variety of germline-encoded receptors, cytokine release, NK cell-mediated target cell killing and interactions with adaptive cellular and humoral components. This is not only of importance in acute infections as described for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but also determines the progression of chronic and latent infections, including human immunodeficiency virus type 1 (HIV-1) infection. For a better understanding of antiviral mechanisms mediated by NK cells, we investigated different pathways of receptor-mediated detection of virally infected cells that result in target cell killing. The recently emerged SARS-CoV-2 caused the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, with little initial understanding of disease progression, treatment options and viral impact on immune responses. However, studies comparing SARS-CoV-2 to the former SARS-CoV and endemic human coronaviruses (hCoV) identified cross-reactive antibodies against the novel coronavirus. Here we investigated the impact of cross-reactive antibodies, and antibodies resulting from natural SARS-CoV-2 infection or mRNA vaccination, on NK cell activation and, in turn, on target cell killing mediated by antibody-dependent cellular cytotoxicity (ADCC). We show that the low-affinity FcRIIIa (CD16) triggers NK cell activation against SARS-CoV-2 spike and nucleocapsid protein analyzed by CD107a surface expression, and that vaccine-induced responses were significantly higher than after natural infection. In addition, we were able to confirm an ADCC-dependent killing of receptor-binding domain (RBD)-expressing target cells. Using a different viral infection model, we focused on killer cell immunoglobulin-like receptor (KIR)-mediated NK cell responses. The newly identified KIR2DL5 ligand CD155 is associated with HIV-1 infection and downmodulated during infection. We were therefore interested in defining the impact of KIR2DL5+ NK cells on viral inhibition in HIV-1 infection and determining the viral mechanism involved in modulation of CD155 expression. In our study we demonstrate a Nef-dependent alteration of CD155 surface expression on HIV-1-infected target cells in vitro. We further observed an increased antiviral activity of KIR2DL5+ NK cells against wild-type virus strains compared to Nef-deficient virus strains. Our data therefore gives novel and important insights in the diversity of antiviral mechanisms mediated by NK cells. We highlight their role in SARS-CoV-2 infection and, to our knowledge, for the first time show that Nef-dependent downregulation of CD155 impacts KIR2DL5-mediated target cell recognition in HIV-1 infection.
|Enthalten in den Sammlungen:||Elektronische Dissertationen und Habilitationen|
geprüft am 08.02.2023
geprüft am 08.02.2023