Abstracts (complete list) - Wissenschaft Online

Susanne Kirschnek, Robert Paul, Bianca Obermaier, Georg Häcker, Uwe Koedel
Contribution of cell death in phagocytes and resident cells to
the outcome of pneumococcal meningitis in mice
Efficient uptake and elimination of bacteria by neutrophil granulocytes and macrophages
is a crucial step in the defence against bacterial infections. We observed phagocytosisassociated
apoptosis of macrophages and granulocytes after uptake and digestion of
bacteria, which proceeds via the mitochondrial pathway and is at least in part
dependent on the BH3-only protein Bim. To investigate the significance of bacteriainduced
phagocyte apoptosis for infection, a mouse model of pneumococcal meningitis
was used. Phagocyte and/or resident tissue apoptosis was inhibited by Bcl-2
overexpression or Bim deficiency. In this model, neutrophil granulocyte function is
known to be crucial for efficient defence against bacterial infection. Mice overexpressing
Bcl-2 in the hematopoietic compartment had more severe symptoms and higher
lethality than wild type littermates. We observed a similar recruitment of leukocytes into
the brain at early time points during infection but a significantly higher leukocyte count
in the cerebrospinal fluid at later stages. This was accompagnied by a loss of bloodbrain-barrier
function and impaired clearance of bacteria in the blood in Bcl-2transgenic
mice. In addition, more pronounced histopathological alterations, indicative
of enhanced inflammation, were observed. Experiments with bim-/- mice further
indicate that the loss of the pro-apoptotic Bcl-2 family protein Bim leads to a different
phenotype where higher leukocyte counts in the cerebrospinal fluid are correlated with
lower bacterial load in the brain and better maintenance of the blood-brain-barrier.
Thus, in contrast to Bcl-2 overexpression (which was restricted to the hematopoetic
compartment), Bim deficiency in all cell types conferred enhanced resistance to
pneumococcal meningitis. These results indicate a physiological function for phagocyte
apoptosis in the control of bacterial infections and suggest that cell death in nonhematopoetic
cells contributes to the outcome of pneumococcal meningitis.