Staphylococcus aureus is an important human pathogen commonly infecting nearly every host tissue. The ability of S. aureus to resist innate immunity is critical to its success as a pathogen, including its propensity to grow in the presence of host nitric oxide (NO·). Upon exogenous NO· exposure, S. aureus immediately excretes copious amounts of L-lactate to maintain redox balance. However, after prolonged NO·-exposure, S. aureus reassimilates L-lactate specifically and in this work, we identify the enzyme responsible for this L-lactate-consumption as a L-lactate-quinone oxidoreductase (Lqo, SACOL2623). Originally annotated as Mqo2 and thought to oxidize malate, we show that this enzyme exhibits no affinity for malate but reacts specifically with L-lactate (KM = ∼330 μM). In addition to its requirement for reassimilation of L-lactate during NO·-stress, Lqo is also critical to respiratory growth on L-lactate as a sole carbon source. Moreover, Δlqo mutants exhibit attenuation in a murine model of sepsis, particularly in their ability to cause myocarditis. Interestingly, this cardiac-specific attenuation is completely abrogated in mice unable to synthesize inflammatory NO· (iNOS−/−). We demonstrate that S. aureus NO·-resistance is highly dependent on the availability of a glycolytic carbon sources. However, S. aureus can utilize the combination of peptides and L-lactate as carbon sources during NO·-stress in an Lqo-dependent fashion. Murine cardiac tissue has markedly high levels of L-lactate in comparison to renal or hepatic tissue consistent with the NO·-dependent requirement for Lqo in S. aureus myocarditis. Thus, Lqo provides S. aureus with yet another means of replicating in the presence of host NO·.

Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG-immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization. Diminished degradation of IgG-ICs prolongs the intracellular residency of nucleic acids, leading to the activation of Toll-like receptors. It also promotes phagosomal membrane permeabilization, allowing dsDNA and IgG to leak into the cytosol and activate AIM2 and TRIM21. Collectively, these events promote the accumulation of nuclear antigens and activate innate sensors that drive IFNα production and heightened cell death. These data identify a previously unidentified defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus.

Kit regulation of mast cell proliferation and differentiation has been intimately linked to the activation of phosphatidylinositol 3-OH kinase (PI3K). The activating D816V mutation of Kit, seen in the majority of mastocytosis patients, causes a robust activation of PI3K signals. However, whether increased PI3K signaling in mast cells is a key element for their in vivo hyperplasia remains unknown. Here we report that dysregulation of PI3K signaling in mice by deletion of the phosphatase and tensin homolog (Pten) gene (which regulates the levels of the PI3K product, phosphatidylinositol 3,4,5-trisphosphate) caused mast cell hyperplasia and increased numbers in various organs. Selective deletion of Pten in the mast cell compartment revealed that the hyperplasia was intrinsic to the mast cell. Enhanced STAT5 phosphorylation and increased expression of survival factors, such as Bcl-XL, were observed in PTENdeficient mast cells, and these were further enhanced by stem cell factor stimulation. Mice carrying PTEN-deficient mast cells also showed increased hypersensitivity as well as increased vascular permeability. Thus, Pten deletion in the mast cell compartment results in a mast cell proliferative phenotype in mice, demonstrating that dysregulation of PI3K signals is vital to the observed mast cell hyperplasia.(Blood. 2011;118(20): 5466-5475) IntroductionMast cells (MCs) are innate immune cells that also serve to amplify adaptive immunity. 1 They are best known for their role as effector cells in allergic disease, 2 but there is considerable evidence of a beneficial role for these cells in host defense and immune regulation. 3 In various pathologic circumstances, MC numbers can be increased because of hyperplasia or neoplastic transformation. 4,5 Mastocytosis is a term used to collectively describe MC hyperplasia/ neoplasia in one or more organs. Systemic mastocytosis normally involves one or more visceral organs with or without skin involvement. The majority of patients with mastocytosis carry a somatic mutation in the Kit proto-oncogene, the receptor for SCF that is central to MC proliferation and differentiation. Substitution of D for V at position 816 in the kinase domain of the receptor results in constitutive (SCF-independent) activation of Kit and enhanced MC proliferation. 6 It is well known that signals generated by SCF engagement of Kit are highly dependent on the activity of phosphatidylinositol 3-OH kinase (PI3K). [7][8][9][10] In addition, PI3K activity is also increased by the D816V mutation of Kit. 9 Proliferation of murine MCs is also partly dependent on IL-3 and its receptor (IL-3R). 11,12 Human intestinal MCs also express functional IL-3R, and IL-3 stimulation causes enhanced growth rates and effector responses. 13 Interestingly, IL-3R activity and its role in regulating proliferative responses are also tightly coupled to the activation of PI3K. 14 In addition, STAT5 is also important to the transcriptional activity induced by the IL-3R and c-Kit, and STAT5-PI3K-Akt signals are known to be essenti...

Only four cases of Type I odontoid fracture have been previously described in the English literature. Most authors consider this lesion to be stable, although the mechanism(s) of injury has not been clearly elucidated. A case of Type I odontoid fracture in association with atlanto-occipital and atlantoaxial dislocation resulting in death is presented. The normal ligamentous anatomy is reviewed and proposed mechanisms for this injury are discussed. The radiographic features of all reported cases of this type are reviewed. It is proposed that the Type I odontoid fracture is a likely manifestation of atlanto-occipital instability and rarely occurs as an isolated or stable injury.

Two patients with altered hemostatic mechanisms developed spinal subarachnoid hemorrhage after difficult lumbar punctures. One patient had received anticoagulation therapy soon after lumbar puncture and the other had a low platelet count (63,000/mm3) at the time of lumbar puncture. In both patients a hematoma evolved, producing blockage of cerebrospinal fluid flow. Clinical manifestations consisted of severe back and radicular pain with sphincteric disturbances followed by rapidly developing severe paraparesis. Of the methods of radiographic evaluation that were used, including computed tomography (CT) without contrast enhancement, myelography, CT with intrathecally administered contrast medium, and magnetic resonance imaging, we found the best study to be myelography via lateral cervical puncture followed by CT. Unfortunately, diagnosis was delayed, and surgical evacuation of the hematomas did not substantially improve the patients' conditions. The salient clinical and radiographic features of this disorder and its pathophysiology are reviewed. Prompt recognition of these lesions is necessary so that surgical intervention may maximize chances of recovery.