Die Wirkung von Bactericidal/Permeability-Increasing Protein (BPI) auf Listeria monocytogenes und seine Funktion im Rahmen einer Listerieninfektion

The antimicrobial action of bactericidal/permeability-increasing protein (BPI) against gramnegative bacteria is known for decades. BPI is mainly expressed in azurophilic granules of neutrophil granulocytes (nGr). It is able to neutralize LPS as wells as to opsonize bacteria leading to enhanced phagocytosis of the bound bacteria. During this work we provided first evidence that BPI has also antimicrobial function against grampositive bacteria, especially Listeria monocytogenes (L.m.). On the one hand we could show that human nGr secrete BPI after stimulation with listeria, on the other hand that BPI binds to the bacteria. This binding leads to an antimicrobial action of BPI against L.m.. Intragastral infection of wild type (WT) mice led to an increased expression of BPI mRNA in the small intestine, suggesting a role for BPI during listeriosis. Independent on the application route BPI deficient (BPI-/-) mice were more susceptible against an infection with L.m.. This was signified by an enhanced bacterial burden in the infected tissue as well as hightened systemic inflammation. Nevertheless, BPI mice finally were able to control the infection. To clarify, which cells are responsible for the stronger susceptibility of BPI-/- mice ex vivo generated immune cells belonging to the first line of defense were analysed. Neither isolated macrophages nor DCs derived from BPI-/- mice were able to recapitulate the in vivo phenotype of the mice. However the stimulation of nGr of WT- and BPI-/- mice with UV-inactivated listeria displayed significant differences for TNF- and ROS-production. BPI-/- nGr were hyperresponsive towards the stimulation with L.m.. The phagocytosis effectivity of living bacteria via nGr of both genotypes was comparable, but clear differences for their ability to kill the bacteria after 24 h were observed. The BPI-/- nGr harbored a threefold higher bacterial load compared to WT-nGr after 24 h. These in vitro data lead us to conclude, that nGr seem to be responsible for the increased susceptibility of the BPI-/- mice during a listeriosis. Since BPI-/- mice are able to combat the listeria-infection effectively one can assume that a protective adaptive immune response is independent on the expression of BPI.