Funktionelle Analyse von Sly2-abhängigen adaptiven Immunantworten gegen Pneumokokken-Antigene

01/07/2019 to 31/12/2020

Invasive pneumococcal infections are amongst the leading causes of death worldwide, especially in young children and immune deficient patients like individuals with Down’s syndrome (DS). Differentially expressed chromosome 21 genes are suggested to substantially contribute to Trisomy 21 phenotypes. Expression analyses revealed that a very small group of nine identified genes were additionally amplified in DS patients. SLy2 (Samsn1) was the most markedly amplified gene within this distinct group.
The work program of the present application comprises the experimental examination of the role of the adaptor protein SLy2 during immune responses towards pneumococcal antigens. We aim to analyze the influence of SLy2 expression during invasive pneumococcal infection by using our SLy2 transgenic (TG) and SLy2 deficient (KO) mice. Our previous data show, that B-1 cell responses upon immunization with Pneumovax 23 (a pure polysaccharide vaccine) or Prevenar 13 (a conjugate-vaccine) are considerably reduced in SLy2 TG mice. By contrast, SLy2 KO mice exhibit enhanced numbers of B-1 cells and antibody-secreting cells (ASCs) as well as elevated levels of natural serum IgM. In order to further confirm the immunosuppressive role of SLy2 in B-cell driven immune responses, we now would like to infect our mice with Streptococcus pneumoniae and analyse both their survival and specific B-cell responses upon infection. In order to evaluate the effectiveness of currently available pneumococcal vaccines on the background of SLy2 deregulations, infection shall be additionally performed upon Pneumovax 23 (P23) or Prevenar 13 (PCV13) immunization. The identification of genotype-phenotype relationships using SLy2 mouse models will increase our understanding of the accompanying malignancies and susceptibilities in DS, which is a prerequisite for evolving novel therapeutic strategies that may improve the quality and expectancy of the life of DS patients.