Pathogenic Mechanisms and Host Interactions in Staphylococcus epidermidis Device-Related Infection

Staphylococcus epidermidis is a permanent member of the normal human microbiota, commonly found on skin and mucous membranes. By adhering to tissue surface moieties of the host via specific adhesins, S. epidermidis is capable of establishing a lifelong commensal relationship with humans that begins early in life. In its role as a commensal organism, S. epidermidis is thought to provide benefits to human host, including out-competing more virulent pathogens. However, largely due to its capacity to form biofilm on implanted foreign bodies, S. epidermidis has emerged as an important opportunistic pathogen in patients receiving medical devices. S. epidermidis causes approximately 20% of all orthopedic device-related infections (ODRIs), increasing up to 50%in late-developing infections. Despite this prevalence, it remains underrepresented in the scientific literature, in particular lagging behind the study of the S. aureus. This review aims to provide an overview of the interactions of S. epidermidis with the human host, both as a commensal and as a pathogen. The mechanisms retained by S. epidermidis that enable colonization of human skin as well as invasive infection, will be described, with a particular focus upon biofilm formation. The host immune responses to these infections are also described, including how S. epidermidis seems to trigger low levels of pro-inflammatory cytokines and high levels of interleukin-10, which may contribute to the sub-acute and persistent nature often associated with these infections. The adaptive immune response to S. epidermidis remains poorly described, and represents an area which may provide significant new discoveries in the coming years

Proteomic Modeling for HIV-1 Infected Microglia-Astrocyte Crosstalk

Background: HIV-1-infected and immune competent brain mononuclear phagocytes (MP; macrophages and microglia) secrete cellular and viral toxins that affect neuronal damage during advanced disease. In contrast, astrocytes can affect disease by modulating the nervous system’s microenvironment. Interestingly, little is known how astrocytes communicate with MP to influence disease. Methods and Findings: MP-astrocyte crosstalk was investigated by a proteomic platform analysis using vesicular stomatitis virus pseudotyped HIV infected murine microglia. The microglial-astrocyte dialogue was significant and affected microglial cytoskeleton by modulation of cell death and migratory pathways. These were mediated, in part, through F-actin polymerization and filament formation. Astrocyte secretions attenuated HIV-1 infected microglia neurotoxicity and viral growth linked to the regulation of reactive oxygen species. Conclusions: These observations provide unique insights into glial crosstalk during disease by supporting astrocytemediated regulation of microglial function and its influence on the onset and progression of neuroAIDS. The results open new insights into previously undisclosed pathogenic mechanisms and open the potential for biomarker discovery an

Abstract 15878: GSK-3α in Fibroblasts Attenuates Cardiac Fibrosis and Dysfunction Induced by Pressure Overload Through Modulation of TGFβ1

Glycogen synthase kinase-3α (GSK-3α) is a ubiquitously expressed S/T kinase that has versatile functions. Cardiac-specific loss of GSK-3α has outcomes that contrast with those of systemic deletion of GSK-3α after myocardial infarction, indicating cell type-specific roles of GSK-3α. However, the role of GSK-3α in fibroblasts (FB) remains to be defined. We hypothesized that GSK-3α in FB attenuates cardiac fibrosis (CF) and dysfunction in response to pressure overload (PO), and subjected FB-specific GSK-3α knockout mice (GSK-3αf/f/FSP-Cre, KO) and littermate GSK-3αf/f mice (CT) to 4 weeks of PO induced by transverse aortic constriction. The CF (%) was greater in KO than in CT (1.9±0.2 vs 1.1±0.1, p&lt;0.01) after sham operation, showing that loss of GSK-3α in FB causes CF at baseline. After PO, CF was increased in both KO and CT, and there was much more in KO than in CT (7.9±1.3 vs 3.8±0.4, p&lt;0.01). There was significantly more type I and type III collagen in KO than in CT after PO. Cardiac FB (%) measured by positive HSP47 staining area was more in KO than in CT after PO (22±1 vs 11±1, p&lt;0.005). These data suggest that loss of GSK-3α in FB promotes CF. The lung weight/body weight (mg/g) was greater in KO than in CT (11.3±1.8 vs 7.7±0.7, p&lt;0.05) after PO, indicating that KO had more severe lung congestion. Left ventricular (LV) ejection fraction (EF) and fractional shortening (FS) were not significantly different between sham KO and CT. The EF (45±5% vs 58±3%, p&lt;0.05) and FS (19±2% vs 25±2%, p&lt;0.05) were lower in KO than in CT after PO. LV ±dP/dts (mmHg/s) were lower in KO than in CT after PO (+dP/dt, 5306±358 vs 7536±541, p&lt;0.01; -dP/dt, 6250±404 vs 8893±353, p&lt;0.001) although they were not significantly different between sham KO and CT. LV end-diastolic pressure was higher in KO than in CT (15±2 vs 9±2, p&lt;0.05) after PO. These data show that loss of GSK-3α in FB exacerbates PO-induced cardiac dysfunction. More TGFβ1 was observed in cardiac FB in KO than in CT after PO. In neonatal rat cardiac FB, knockdown of GSK-3α increased the levels of TGFβ1, phospho-Smad3, α-smooth muscle actin, and Ki67-positive cells, showing that GSK-3α inhibits proliferation and myofibroblast transformation of FB. In conclusion, GSK-3α in FB protects against PO-induced CF and dysfunction through inhibition of TGFβ1.</jats:p