Metabolic Stress Drives Keratinocyte Defenses against Staphylococcus aureus Infection.

Human skin is commonly colonized and infected by Staphylococcus aureus. Exactly how these organisms are sensed by keratinocytes has not been clearly delineated. Using a combination of metabolic and transcriptomic methodologies, we found that S.

Necroptosis Promotes Staphylococcus aureus Clearance by Inhibiting Excessive Inflammatory Signaling.

Staphylococcus aureus triggers inflammation through inflammasome activation and recruitment of neutrophils, responses that are critical for pathogen clearance but are associated with substantial tissue damage. We postulated that necroptosis, cell death mediated by the RIPK1/RIPK3/MLKL pathway, would function to limit pathological inflammation. In models of skin infection or sepsis, Mlkl-/- mice had high bacterial loads, an inability to limit interleukin-1b (IL-1b) production, and excessive inflammation.

Methicillin-resistant Staphylococcus aureus adaptation to human keratinocytes.

Unlabelled: Skin is the most common site of Staphylococcus aureus infection. While most of these infections are self-limited, recurrent infections are common. Keratinocytes and recruited immune cells participate in skin defense against infection.

Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.

The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S.

Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes.

The USA300 strains of Staphylococcus aureus are the major cause of skin and soft tissue infection in the United States. Invasive USA300 infection has been attributed to several virulence factors, including protein A and the α-hemolysin (Hla), which cause pathology by activating host signaling cascades. Here we show that S.

Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity.

Staphyococcus aureus and especially the epidemic methicillin-resistant S. aureus strains cause severe necrotizing pneumonia. The mechanisms whereby these organisms invade across the mucosal epithelial barrier to initiate invasive infection are not well understood.

Streptococcus pneumoniae DNA initiates type I interferon signaling in the respiratory tract.

Unlabelled: The mucosal epithelium is the initial target for respiratory pathogens of all types. While type I interferon (IFN) signaling is traditionally associated with antiviral immunity, we demonstrate that the extracellular bacterial pathogen Streptococcus pneumoniae activates the type I IFN cascade in airway epithelial and dendritic cells. This response is dependent upon the pore-forming toxin pneumolysin.

Participation of CD11c(+) leukocytes in methicillin-resistant Staphylococcus aureus clearance from the lung.

Staphylococcus aureus causes especially severe pulmonary infection, associated with high morbidity and mortality. In addition to the effects of specific virulence factors, it appears that the intensity of the host proinflammatory response, particularly in the initial stages of infection, contributes substantially to pulmonary damage. We tested the hypothesis that the CD11c(+) leukocytes are important in the host response to pulmonary infection with methicillin-resistant S.

Visual field size criteria for mobility rehabilitation referral.

Purpose: To investigate evidence-based visual field size criteria for referral of low-vision (LV) patients for mobility rehabilitation.

Methods: One hundred and nine participants with LV and 41 age-matched participants with normal sight (NS) were recruited. The LV group was heterogeneous with diverse causes of visual impairment.

Staphylococcus aureus activates type I IFN signaling in mice and humans through the Xr repeated sequences of protein A.

The activation of type I IFN signaling is a major component of host defense against viral infection, but it is not typically associated with immune responses to extracellular bacterial pathogens. Using mouse and human airway epithelial cells, we have demonstrated that Staphylococcus aureus activates type I IFN signaling, which contributes to its virulence as a respiratory pathogen. This response was dependent on the expression of protein A and, more specifically, the Xr domain, a short sequence-repeat region encoded by DNA that consists of repeated 24-bp sequences that are the basis of an internationally used epidemiological typing scheme.

The NanA neuraminidase of Streptococcus pneumoniae is involved in biofilm formation.

Streptococcus pneumoniae remains a major cause of bacteremia, pneumonia, and otitis media despite vaccines and effective antibiotics. The neuraminidase of S. pneumoniae, which catalyzes the release of terminal sialic acid residues from glycoconjugates, is involved in host colonization in animal models of infection and may provide a novel target for preventing pneumococcal infection.

Macular structure and vision of patients with macular heterotopia secondary to retinopathy of prematurity.

Purpose: To examine if vision in subjects with macular heterotopia (MH) secondary to retinopathy of prematurity (ROP) is related to anatomical macular structure.

Methods: Six subjects with MH who were between 18 years and 65 years of age and three age-matched subjects with normal vision were recruited for the study. Vision and macular structure of the better eye of the subjects with MH and the dominant eye of age-matched subjects with normal vision were assessed.

The type III toxins of Pseudomonas aeruginosa disrupt epithelial barrier function.

The type III secreted toxins of Pseudomonas aeruginosa are important virulence factors associated with clinically important infection. However, their effects on bacterial invasion across mucosal surfaces have not been well characterized. One of the most commonly expressed toxins, ExoS, has two domains that are predicted to affect cytoskeletal integrity, including a GTPase-activating protein (GAP) domain, which targets Rho, a major regulator of actin polymerization; and an ADP-ribosylating domain that affects the ERM proteins, which link the plasma membrane to the actin cytoskeleton.

Vision and self-reported mobility performance in patients with low vision.

Background: As vision plays a significant role in mobility performance, it is usual to refer low vision patients, particularly those who complain of mobility difficulties, for orientation and mobility (O&M) training to help them maintain safe independent travel. Our study aimed to determine whether there was a relationship between measures of vision and self-reported mobility, and the applicability of a patient-based mobility assessment in patients with heterogeneous causes of visual loss.

Method: We assessed the high and low contrast visual acuity, visual field and scanning ability of 30 patients with low vision.

Immunostimulatory properties of the emerging pathogen Stenotrophomonas maltophilia.

Stenotrophomonas maltophilia is a multiple-antibiotic-resistant opportunistic pathogen that is being isolated with increasing frequency from patients with health-care-associated infections and especially from patients with cystic fibrosis (CF). While clinicians feel compelled to treat infections involving this organism, its potential for virulence is not well established. We evaluated the immunostimulatory properties and overall virulence of clinical isolates of S.

Bacterial neuraminidase facilitates mucosal infection by participating in biofilm production.

Many respiratory pathogens, including Hemophilus influenzae, Streptococcus pneumoniae, and Pseudomonas aeruginosa, express neuraminidases that can cleave alpha2,3-linked sialic acids from glycoconjugates. As mucosal surfaces are heavily sialylated, neuraminidases have been thought to modify epithelial cells by exposing potential bacterial receptors. However, in contrast to neuraminidase produced by the influenza virus, a role for bacterial neuraminidase in pathogenesis has not yet been clearly established.

Effects of azithromycin on clinical isolates of Pseudomonas aeruginosa from cystic fibrosis patients.

There is considerable interest in the use of azithromycin for the treatment of lung disease in patients with cystic fibrosis (CF). Although its mechanism of action as an inhibitor of bacterial protein synthesis has been well-established, it is less clear how azithromycin ameliorates the lung disease associated with Pseudomonas aeruginosa, which is considered to be resistant to the drug. We tested the effects of azithromycin on clinical isolates (CIs) from CF patients and compared them with laboratory reference strains to establish how this drug might interfere with the production of bacterial virulence factors that are relevant to the pathogenesis of airway disease in CF patients.

Bacterial induction of TNF-alpha converting enzyme expression and IL-6 receptor alpha shedding regulates airway inflammatory signaling.

Airway epithelial cells have a major role in initiating inflammation in response to bacterial pathogens. Through the immediate induction of CXCL8 and cytokine expression, polymorphonuclear cells are mobilized and activated to eradicate the infecting organisms. However, the influx of polymorphonuclear cells and the effects of their toxic exoproducts impede respiratory function.

The effect of cyclosporin A on airway cell proinflammatory signaling and pneumonia.

Cyclosporin A (CsA) blocks T cell activation by interfering with the Ca2+-dependent phosphatase, calcineurin. Proinflammatory responses to bacteria that are activated by Ca2+-fluxes in airway cells are a potential target for CsA. Although local immunosuppression may be advantageous to control airway inflammation, it could also increase susceptibility to bacterial pneumonia and invasive infection.

Facilitation of contrast detection in near-peripheral vision.

Foveal detection of a Gabor patch (target) is facilitated by collinear, displaced high-contrast flankers. Polat and Sagi reported that the same phenomenon occurred in the periphery, but no data were presented [Proc. Natl.

Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1.

Staphylococcus aureus is a major human pathogen that is associated with diverse types of local and systemic infection characterized by inflammation dominated by polymorphonuclear leukocytes. Staphylococci frequently cause pneumonia, and these clinical isolates often have increased expression of protein A, suggesting that this protein may have a role in virulence. Here we show that TNFR1, a receptor for tumor-necrosis factor-alpha (TNF-alpha) that is widely distributed on the airway epithelium, is a receptor for protein A.

TLR2 is mobilized into an apical lipid raft receptor complex to signal infection in airway epithelial cells.

Toll-like receptors (TLRs) mediate host responses to bacterial gene products. As the airway epithelium is potentially exposed to many diverse inhaled bacteria, TLRs involved in defense of the airways must be broadly responsive, available at the exposed apical surface of the cells, and highly regulated to prevent activation following trivial encounters with bacteria. We demonstrate that TLR2 is enriched in caveolin-1-associated lipid raft microdomains presented on the apical surface of airway epithelial cells after bacterial infection.

Toll-like receptors in normal and cystic fibrosis airway epithelial cells.

Toll-like receptors (TLRs) mediate cellular responses to diverse microbial ligands. The distribution and function of TLRs in airway cells were studied to identify which are available to signal the presence of inhaled pathogens and to establish if differences in TLR expression are associated with the increased proinflammatory responses seen in cystic fibrosis (CF). Isogenic, polarized CF and control bronchial epithelial cell lines, human airway cells in primary culture, and cftr null and wild-type mice were compared.

Pseudomonas aeruginosa flagella activate airway epithelial cells through asialoGM1 and toll-like receptor 2 as well as toll-like receptor 5.

The distribution of specific toll-like receptors and components of the signaling pathways activated by Pseudomonas aeruginosa flagella were studied in airway epithelial cells. Initially flagella bound to the apical surface of polarized epithelial cells, where they prominently colocalized with asialoGM1. By 4 h of exposure to flagella, toll-like receptor (TLR)5 expression was induced, mobilized to the apical surface of the cells, and colocalized with superficial flagella.