Under physiological conditions, microglia (MG), the CNS macrophages, persist life-long without substantial cellular input from the bone marrow. Yet, in bacterial meningitis and meningoencephalitis, myeloid cells are recruited from the bone marrow to the CNS. Accordingly, the contribution of MG, as opposed to circulating myeloid cells, to inflammation in meningitis remains unclear, despite the established potent response of MG to bacteria such as group B streptococci (GBS) in vitro. A major obstacle has been the lack of animal models, where MG number and function can be specifically modulated. Here, we will use recently developed mouse models, where MG are targeted by Cx3cr1 promoter driven Cre recombinase, or ablated by ganciclovir (CD11b-HSVTK). Next, MG activation in GBS meningitis will be studied in transgenic ΝF-κΒ reporter mice by intravital imaging. Second, the capacity of the potent GBS effectors RNA and lipopeptides to activate MG and perturb the blood brain barrier in states of GBS colonization and invasive infection will be analyzed. Finally, we will explore the role of myeloid cells in containment and dissemination of GBS colonizing the mouse intestine. In summary, we aim at defining the role of MG and peripheral mononuclear phagocytes in CNS inflammation control by combining novel gene targeting and GBS meningitis models.