Exploration of molecular defense mechanisms against viral infections exemplified in COVID-19

Abstract

Studying the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been an international research focus ever since the start of the pandemic in early 2020. In the first part of this thesis, the antibody response to both infection with and vaccination against SARS-CoV-2 was analysed; while multiple vaccines exist, with regard to resulting antibody titres and short-term inflammatory response, no large differences between the immunization approaches exist. Initial antibody responses waned after 6 months but were restored robustly by booster vaccinations. Antibody responses were weaker against variants of SARS-CoV-2, with the beta-variant showing the strongest immune evasion. In the second section, the T cell exhaustion characteristic for liver cirrhosis was found to be driven by Interleukin-10 (IL-10), which was itself caused by bacterial translocation-induced type I interferon derived from myeloid cells in the liver. Interestingly, this T cell exhaustion was critical for vaccine responses, including the vaccine response to SARS-CoV-2, and could be repressed using IL-10 blockade, restoring vaccine responsiveness. The third part of the thesis is focused on the interactions of T cells and antigen presenting cells (APCs): while preconditioning through Interferon is necessary and leads to an immune activation, for an optimal response, an additional trigger via interaction between cluster of differentiation (CD) 40 and CD40 ligand (CD40L) is essential: thus, myeloid cells need T cell help to participate to their fullest extent. A signature of important immune activators, including IL-15 and several other cytokines, as well as driving transcription factors like p65, IRF1 and FOS, could only become activated by the combinatorial signals. In severe forms of Coronavirus disease 2019 (COVID-19), APCs lack either one or both parts of this activation, rendering the immune response less directed and effective.