Interaction ofNeisseria meningitidiswith Human Meningeal Cells Induces the Secretion of a Distinct Group of Chemotactic, Proinflammatory, and Growth-Factor Cytokines

Abstract

The interactions of Neisseria meningitidis with cells of the leptomeninges are pivotal events in the progression of bacterial leptomeningitis. An in vitro model based on the culture of human meningioma cells was used to investigate the role of the leptomeninges in the inflammatory response. Following challenge with meningococci, meningioma cells secreted specifically the proinflammatory cytokine interleukin-6 (IL-6), the CXC chemokine IL-8, the CC chemokines monocyte chemoattractant protein 1 (MCP-1) and regulated-upon-activation, normal-T-cell expressed and secreted protein (RANTES), and the cytokine growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). A temporal pattern of cytokine production was observed, with early secretion of IL-6, IL-8, and MCP-1 followed by later increases in RANTES and GM-CSF levels. IL-6 was induced equally by the interactions of piliated and nonpiliated meningococci, whereas lipopolysaccharide (LPS) had a minimal effect, suggesting that other, possibly secreted, bacterial components were responsible. Induction of IL-8 and MCP-1 also did not require adherence of bacteria to meningeal cells, but LPS was implicated. In contrast, efficient stimulation of RANTES by intact meningococci required pilus-mediated adherence, which served to deliver increased local concentrations of LPS onto the surface of meningeal cells. Secretion of GM-CSF was induced by pilus-mediated interactions but did not involve LPS. In addition, capsule expression had a specific inhibitory effect on GM-CSF secretion, which was not observed with IL-6, IL-8, MCP-1, or RANTES. Thus, the data demonstrate that cells of the leptomeninges are not inert but are active participants in the innate host response during leptomeningitis and that there is a complex relationship between expression of meningococcal components and cytokine induction.Meningitis, which is an inflammation of the meninges that surround the brain within the skull and the spinal cord within the spinal canal (56), is the most common infection of the central nervous system. In humans, the meninges comprise the pachymenix or dura mater (hard mother) and the leptomeninges, which consist of the arachnoid mater and pia mater together with the trabeculae that traverse the cerebrospinal fluid (CSF)-filled subarachnoid space (SAS) (2, 9, 56). Classical bacterial meningitis is predominantly a leptomeningitis, with little or no involvement of the dura mater or the underlying brain. The bacterial etiology of leptomeningitis is broad, and a wide variety of bacteria that gain access to the SAS can initiate an inflammatory response. Susceptibility to the various causative agents is age dependent, and a distinct group of species affect neonates compared to the species that affect subjects over 1 month old (13). After the neonatal period, the most common bacterial agents that cause pyogenic leptomeningitis are Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis (meningococci). In affluent countries, vaccines developed against H. inf...

Interactions ofHaemophilus parasuisand its LOS with porcine brain microvascular endothelial cells

“…Moreover, we observed that purified LOS was a relatively poor cytokine inducer suggesting that other cell-associated or heat-resistant bacterial component(s) are also involved in stimulating cytokine production. These results are consistent with other studies showing that pro-inflammatory responses elicited by N. meningitidis are mediated by LOS as well as non-LOS components [8,31]. Further studies are needed to identify other surface structures involved in PBMEC stimulation by H. parasuis.…”

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

“…In general, the host defense against the pathogen includes cytokines, chemokines, and oxidative burst. Among the genes expressed following infection, we found genes involved in the immunological responses, such as those encoding IL-6 and TNF-␣, both described to be induced after N. meningitidis infection (7,51,57,64). However, absent from the transcriptional profile was IL-1␤, which is involved in the pathogenesis of bacterial meningitis.…”

Interaction of Neisseria meningitidis with human brain microvascular endothelial cells: role of MAP- and tyrosine kinases in invasion and inflammatory cytokine release

“…A various number of bacterial surface components -in particular the lipooligosaccharide (LOS) -have been implicated in the release of cytokines induced by N. meningitidis in different cell types (Dixon et al, 2001;Kolb-Mäurer et al, 2001;Christodoulides et al, 2002;Unkmeir et al, 2002b). Cytokines were initially thought to be produced solely by cells of the immune system; however, it is now evident that many non-immune cells produce them.…”