Involvement of Mitogen-Activated Protein Kinase Pathways inStaphylococcus aureusInvasion of Normal Osteoblasts

Abstract

Staphylococcus aureus invades osteoblasts and can persist in the intracellular environment. The present study examined the role of osteoblast mitogen-activated protein kinase (MAPK) pathways in bacterial invasion. S. aureus infection of normal human and mouse osteoblasts resulted in an increase in the phosphorylation of the extracellular signal-regulated protein kinases (ERK 1 and 2). This stimulation of ERK 1 and 2 correlated with the time course of S. aureus invasion, and bacterial adherence induced the MAPK pathway. ERK 1 and 2 phosphorylation was time and dose dependent and required active S. aureus gene expression for maximal induction. The nonpathogenic Staphylococcus carnosus was also able to induce ERK 1 and 2 phosphorylation, albeit at lower levels than S. aureus. Phosphorylation of the stress-activated protein kinases was increased in both infected human and mouse osteoblasts; however, the p38 MAPK pathway was not activated in response to S. aureus. Finally, the transcription factor c-Jun, but not Elk-1 or ATF-2, was phosphorylated in response to S. aureus infection.Osteomyelitis (OM) is an infection of bone that results from hematogenous seeding, spread of infection from a contiguous area such as the skin adjacent to a wound, surgical inoculation of bacteria into bone, or trauma coincident with staphylococcal infection (57). The presence of an inert, prosthetic orthopedic device increases the likelihood of disease, and removal of the implant may be required (16). Chronic or recurring OM can be a persistent clinical problem that is difficult to treat effectively and results in abnormal bone remodeling, leading to a vascular compromise in the infected area. Long periods of antibiotic treatment are utilized in an attempt to control OM recurrences; however, methicillin-resistant staphylococci are now commonplace, and therapeutic levels of antibiotics in necrotic bone are difficult to achieve unless antibiotic-impregnated beads or implants are used (9).Staphylococcus aureus is a capable bone pathogen because it possesses several cell surface adhesion molecules that facilitate its binding to the bone matrix. These include fibronectin-binding proteins (18, 30), fibrinogen-binding proteins (6, 10, 36), elastin-binding adhesin (42), collagen-binding adhesin (43), and a broad-specificity adhesin (MAP) which facilitates lowaffinity binding of S. aureus to several proteins, including osteopontin, collagen, bone sialoprotein, fibronectin, fibrinogen, and vitronectin (37). In addition, S. aureus contains surface proteins that are able to stimulate bone resorption (39) via increasing osteoclast activity (4). The resultant bone destruction facilitates bacterial invasiveness. S. aureus not only colonizes bone matrix but is internalized in vitro (17,28,29) and in vivo (49) by osteoblasts (bone-forming cells). With the notable exception of Listeria monocytogenes, very little work has been done to examine mechanisms of invasion and intracellular survival by gram-positive bacteria. The ability of S. aureus to invade osteo...

Agenesis of paranasal sinuses and nasal nitric oxide in primary ciliary dyskinesia

“…The fact that only the development of those paranasal sinuses which have post-natal growth (frontal and sphenoidal) is compromised might indicate that this effect is secondary to chronic post-natal upper airways infection and inflammation [16,17], and hypothetically related to the premature ossification of the cartilage surrounding the paranasal recesses [16, 17.] The higher than normal prevalence in SCD would support this hypothesis. In animal models it has been demonstrated that airfilled spaces in the cranium are formed by invasion of nasal mucous epithelium into neighbouring nasal capsule cartilages [18].…”

High Mobility Group Nucleosomal Binding Domain 2 Protein Protects Bladder Epithelial Cells from Klebsiella pneumoniae Invasion

“…30) Mitogen-activated protein kinase (MAPK) family members are involved in host cell invasion by several pathogenic bacteria. [17][18][19][20][21] Invasion of epithelial cells represents a potential pathogenic mechanism for K. pneumoniae. We explored the role of mitogen-activated protein kinase kinases (MEK 1/2) and the extracellular signalregulated kinases (ERK 1/2) in K. pneumoniae invasion.…”

“…[17][18][19][20][21] Pretreatment with the MEK1/2 inhibitor PD98059 significantly reduced K. pneumoniae 03183 uptake by T 24 cells (Fig. 1).…”

Staphylococcus aureusInduces Expression of Receptor Activator of NF-κB Ligand and Prostaglandin E2in Infected Murine Osteoblasts

“…Staphylococcus aureus strain UAMS-1 (ATCC 49230) is a human osteomyelitis clinical isolate (15). Staphylococcus carnosus (ATCC 51365) is a nonpathogenic species with a reduced ability to invade osteoblasts (11). Strains N1, N2, N3, N4, and N5 are Staphylococcus aureus nasopharyngeal isolates kindly provided by Vance G. Fowler, Jr. (Duke University Medical Center).…”

“…Although both constitutive COX (COX-1) and inducible COX (COX-2) are expressed in mouse osteoblasts, the expression of COX-2 is markedly induced by several proinflammatory cytokines, such as interleukin 6 (IL-6). Bost et al (5,11) have reported that S. aureus-infected osteoblasts produce high levels of IL-6, which have been shown to modulate the activity of bone-resorptive osteoclasts either directly or indirectly (21,45). It has also been determined that PGE 2 can upregulate RANK-L expression in osteoblasts (16,17,54,57).…”