Intracerebral targets and immunomodulation of murine Listeria monocytogenes meningoencephalitis.

In humans, infection with Listeria monocytogenes (L. monocytogenes) can severely affect the central nervous system (CNS). In the present study we have employed a murine model of CNS listeriosis to characterize the intracerebral distribution of L. monocytogenes. Following intracerebral application of a low dose of L. monocytogenes (serovar 1/2a, EGD strain) a severe fatal leptomeningitis, ventriculitis, and encephalitis developed. Listeria were detectable both intracellularly in different cell types of the CNS and extracellularly in the cerebrospinal fluid. Ultrastructural analysis revealed macrophages, granulocytes, plexus epithelial cells, ependymal cells, and neurons as target cells. An inflammatory reaction with macrophages and granulocytes developed in the brains of these animals but was not sufficient to prevent the fatal outcome of the disease. However, active immunization of mice prior to an intracerebral challenge infection significantly reduced the mortality. Immunized animals showed an early recruitment of a significant number of CD8+ and, to a lesser degree, CD4+ T cells within 24 hours p.i. as well as a strong activation of microglial cells and macrophages. These findings may provide an interesting model for studies on the pathogenesis of cerebral listeriosis.

Systemic immunization induces protective CD4+ and CD8+ T cell-mediated immune responses in murine Listeria monocytogenes meningoencephalitis.

The immune mechanisms underlying immunization-induced protection of mice from lethal central nervous system (CNS) listeriosis were evaluated by immunohistochemistry, flow cytometry of leukocytes isolated from the brain, reverse transcription-polymerase chain reaction analysis of intracerebral (i.c.) tumor-necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-1 beta, IL-10, granulocyte/macrophage colony-stimulating factor, and inducible nitric oxide synthase mRNA expression, and T cell depletion experiments. The data demonstrate that active immunization of mice prior to an i.c. infection with Listeria monocytogenes prevents the development of a fatal necrotizing encephalitis and accelerates the recruitment of an increased number of alpha beta T cell receptor (TcR)+ CD4+ and CD8+ T cells, gamma delta TcR+ T cells, B cells, granulocytes and macrophages to the brain compared to non-immunized animals. In addition, immunization induced a pronounced activation of i.c. macrophages and microglial cells as shown by an increased expression of MHC class II antigens. In parallel, transcript levels for all cytokine mRNA analyzed were higher in the brains of immunized mice. The protective effects of immunization were completely abolished by depletion of CD4+, CD8+, or both T cell subsets. All groups of T cell-depleted immunized mice developed a fatal necrotizing encephalitis with an increased i.c. bacterial load. In addition, cytokine mRNA synthesis was significantly impaired. The severity of disease was only slightly different between CD4+, CD8+ and CD4+/CD8+ T cell depleted mice, indicating that both subsets of T cells are required for an effective i.c. immune response to L. monocytogenes. This is in marked contrast to systemic listeriosis, and points to CNS-specific features of the immune response.