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Search Results: 1 - 10 of 302476 matches for " Mary X. D. O'Riordan "
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More Than a Pore: The Cellular Response to Cholesterol-Dependent Cytolysins
Sara K. B. Cassidy,Mary X. D. O'Riordan
Toxins , 2013, DOI: 10.3390/toxins5040618
Abstract: Targeted disruption of the plasma membrane is a ubiquitous form of attack used in all three domains of life. Many bacteria secrete pore-forming proteins during infection with broad implications for pathogenesis. The cholesterol-dependent cytolysins (CDC) are a family of pore-forming toxins expressed predominately by Gram-positive bacterial pathogens. The structure and assembly of some of these oligomeric toxins on the host membrane have been described, but how the targeted cell responds to intoxication by the CDCs is not as clearly understood. Many CDCs induce lysis of their target cell and can activate apoptotic cascades to promote cell death. However, the extent to which intoxication causes cell death is both CDC- and host cell-dependent, and at lower concentrations of toxin, survival of intoxicated host cells is well documented. Additionally, the effect of CDCs can be seen beyond the plasma membrane, and it is becoming increasingly clear that these toxins are potent regulators of signaling and immunity, beyond their role in intoxication. In this review, we discuss the cellular response to CDC intoxication with emphasis on the effects of pore formation on the host cell plasma membrane and subcellular organelles and whether subsequent cellular responses contribute to the survival of the affected cell.
Caspase-2 mediates a Brucella abortus RB51-induced hybrid cell death having features of apoptosis and pyroptosis
Denise N. Bronner,Mary X. D. O'Riordan,Yongqun He
Frontiers in Cellular and Infection Microbiology , 2013, DOI: 10.3389/fcimb.2013.00083
Abstract: Programmed cell death (PCD) can play a crucial role in tuning the immune response to microbial infection. Although PCD can occur in different forms, all are mediated by a family of proteases called caspases. Caspase-2 is the most conserved caspase, however, its function in cell death is ill-defined. Previously we demonstrated that live attenuated cattle vaccine strain Brucella abortus RB51 induces caspase-2-mediated and caspase-1-independent PCD of infected macrophages. We also discovered that rough attenuated B. suis strain VTRS1 induces a caspase-2-mediated and caspase-1-independent proinflammatory cell death in infected macrophages, which was tentatively coined “caspase-2-mediated pyroptosis”. However, the mechanism of caspase-2-mediated cell death pathway remained unclear. In this study, we found that caspase-2 mediated proinflammatory cell death of RB51-infected macrophages and regulated many genes in different PCD pathways. We show that the activation of proapoptotic caspases-3 and -8 was dependent upon caspase-2. Caspase-2 regulated mitochondrial cytochrome c release and TNFα production, both of which are known to activate caspase-3 and caspase-8, respectively. In addition to TNFα, RB51-induced caspase-1 and IL-1β production was also driven by caspase-2-mediated mitochondrial dysfunction. Interestingly, pore formation, a phenomenon commonly associated with caspase-1-mediated pyroptosis, occurred; however, unlike its role in S. typhimurium-induced pyroptosis, pore formation did not contribute to RB51-induced proinflammatory cell death. Our data suggest that caspase-2 acts as an initiator caspase that mediates a novel RB51-induced hybrid cell death that simulates but differs from typical non-proinflammatory apoptosis and caspase-1-mediated proinflammatory pyroptosis. The initiator role of the caspase-2-mediated cell death was also conserved in cellular stress-induced cell death of macrophages treated with etoposide, naphthalene, or anti-Fas. Caspase-2 also regulated caspase-3 and -8 activation, as well as cell death in macrophages treated with each of the three reagents. Taken together, our data has demonstrated that caspase-2 can play an important role in mediating a proinflammatory response and a hybrid cell death that demonstrates features of both apoptosis and pyroptosis.
Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacterial infections  [PDF]
Yu Qiao, Brian M. Gray, Mohammed H. Sofi, Laura D. Bauler, Kathryn A. Eaton, Mary X. D. ORiordan, Cheong-Hee Chang
Open Journal of Immunology (OJI) , 2012, DOI: 10.4236/oji.2012.21004
Abstract: We have reported a new innate-like CD4 T cell population that expresses cell surface makers of effector/memory cells and produce Th1 and Th2 cytokines immediately upon activation. Unlike conventional CD4 T cells that are selected by thymic epithelial cells, these CD4 T cells, named T-CD4 T cells, are selected by MHC class II expressing thymocytes. Previously, we showed that the presence of T-CD4 T cells protected mice from airway inflammation suggesting an immune regulatory role of T-CD4 T cells. To further understand the function of T-CD4 T cells, we investigated immune responses mediated by T-CD4 T cells during bacterial infection because the generation of antigen specific CD4 T cells contributes to clearance of infection and for the development of immune memory. The current study shows a suppressive effect of T-CD4 T cells on both CD8 and CD4 T cell-mediated immune responses during Listeria and Helicobacter infections. In the mouse model of Listeria monocytogenes infection, T-CD4 T cells resulted in decreasedfrequency of Listeria-specific CD8 T cells and the killing activity of them. Furthermore, mice with T-CD4 T cells developed poor immune memory, demonstrated by reduced expansion of antigen-specific T cells and high bacterial burden upon re-infection. Similarly, the presence of T-CD4 T cells suppressed the generation of antigen-specific CD4 T cells in Helicobacter pylori infected mice. Thus, our studies reveal a novel function of T-CD4 T cells in sup-pressing anti-bacterial immunity.
XIAP Regulates Cytosol-Specific Innate Immunity to Listeria Infection
Laura D. Bauler,Colin S. Duckett,Mary X. D. O'Riordan
PLOS Pathogens , 2008, DOI: 10.1371/journal.ppat.1000142
Abstract: The inhibitor of apoptosis protein (IAP) family has been implicated in immune regulation, but the mechanisms by which IAP proteins contribute to immunity are incompletely understood. We show here that X-linked IAP (XIAP) is required for innate immune control of Listeria monocytogenes infection. Mice deficient in XIAP had a higher bacterial burden 48 h after infection than wild-type littermates, and exhibited substantially decreased survival. XIAP enhanced NF-κB activation upon L. monocytogenes infection of activated macrophages, and prolonged phosphorylation of Jun N-terminal kinase (JNK) specifically in response to cytosolic bacteria. Additionally, XIAP promoted maximal production of pro-inflammatory cytokines upon bacterial infection in vitro or in vivo, or in response to combined treatment with NOD2 and TLR2 ligands. Together, our data suggest that XIAP regulates innate immune responses to L. monocytogenes infection by potentiating synergy between Toll-like receptors (TLRs) and Nod-like receptors (NLRs) through activation of JNK- and NF-κB–dependent signaling.
TBK1 Protects Vacuolar Integrity during Intracellular Bacterial Infection
Andrea L Radtke,Laura M Delbridge,Siddharth Balachandran,Glen N Barber,Mary X. D O'Riordan
PLOS Pathogens , 2007, DOI: 10.1371/journal.ppat.0030029
Abstract: TANK-binding kinase-1 (TBK1) is an integral component of Type I interferon induction by microbial infection. The importance of TBK1 and Type I interferon in antiviral immunity is well established, but the function of TBK1 in bacterial infection is unclear. Upon infection of murine embryonic fibroblasts with Salmonella enterica serovar Typhimurium (Salmonella), more extensive bacterial proliferation was observed in tbk1?/? than tbk1+/+ cells. TBK1 kinase activity was required for restriction of bacterial infection, but interferon regulatory factor-3 or Type I interferon did not contribute to this TBK1-dependent function. In tbk1?/?cells, Salmonella, enteropathogenic Escherichia coli, and Streptococcus pyogenes escaped from vacuoles into the cytosol where increased replication occurred, which suggests that TBK1 regulates the integrity of pathogen-containing vacuoles. Knockdown of tbk1 in macrophages and epithelial cells also resulted in increased bacterial localization in the cytosol, indicating that the role of TBK1 in maintaining vacuolar integrity is relevant in different cell types. Taken together, these data demonstrate a requirement for TBK1 in control of bacterial infection distinct from its established role in antiviral immunity.
Membrane Damage during Listeria monocytogenes Infection Triggers a Caspase-7 Dependent Cytoprotective Response
Sara K. B. Cassidy,Jon A. Hagar,Thirumala Devi Kanneganti,Luigi Franchi,Gabriel Nu?ez,Mary X. D. O'Riordan
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002628
Abstract: The cysteine protease caspase-7 has an established role in the execution of apoptotic cell death, but recent findings also suggest involvement of caspase-7 during the host response to microbial infection. Caspase-7 can be cleaved by the inflammatory caspase, caspase-1, and has been implicated in processing and activation of microbial virulence factors. Thus, caspase-7 function during microbial infection may be complex, and its role in infection and immunity has yet to be fully elucidated. Here we demonstrate that caspase-7 is cleaved during cytosolic infection with the intracellular bacterial pathogen, Listeria monocytogenes. Cleavage of caspase-7 during L. monocytogenes infection did not require caspase-1 or key adaptors of the primary pathways of innate immune signaling in this infection, ASC, RIP2 and MyD88. Caspase-7 protected infected macrophages against plasma membrane damage attributable to the bacterial pore-forming toxin Listeriolysin O (LLO). LLO-mediated membrane damage could itself trigger caspase-7 cleavage, independently of infection or overt cell death. We also detected caspase-7 cleavage upon treatment with other bacterial pore-forming toxins, but not in response to detergents. Taken together, our results support a model where cleavage of caspase-7 is a consequence of toxin-mediated membrane damage, a common occurrence during infection. We propose that host activation of caspase-7 in response to pore formation represents an adaptive mechanism by which host cells can protect membrane integrity during infection.
Chemical Derivatives of a Small Molecule Deubiquitinase Inhibitor Have Antiviral Activity against Several RNA Viruses
Marta J. Gonzalez-Hernandez, Anupama Pal, Kofi E. Gyan, Marie-Eve Charbonneau, Hollis D. Showalter, Nicholas J. Donato, Mary O'Riordan, Christiane E. Wobus
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094491
Abstract: Most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. A good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. The small molecule WP1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other RNA viruses. In this study, we screened a library of 31 small molecule derivatives of WP1130 to identify compounds that retained the broad-spectrum antiviral activity of the parent compound in vitro but exhibited improved drug-like properties, particularly increased aqueous solubility. Seventeen compounds significantly reduced murine norovirus infection in murine macrophage RAW 264.7 cells, with four causing decreases in viral titers that were similar or slightly better than WP1130 (1.9 to 2.6 log scale). Antiviral activity was observed following pre-treatment and up to 1 hour postinfection in RAW 264.7 cells as well as in primary bone marrow-derived macrophages. Treatment of the human norovirus replicon system cell line with the same four compounds also decreased levels of Norwalk virus RNA. No significant cytotoxicity was observed at the working concentration of 5 μM for all compounds tested. In addition, the WP1130 derivatives maintained their broad-spectrum antiviral activity against other RNA viruses, Sindbis virus, LaCrosse virus, encephalomyocarditis virus, and Tulane virus. Thus, altering structural characteristics of WP1130 can maintain effective broad-spectrum antiviral activity while increasing aqueous solubility.
Autonomic Testing in Functional Gastrointestinal Disorders: Implications of Reproducible Gastrointestinal Complaints during Tilt Table Testing
Shaista Safder,Thomas C. Chelimsky,Mary Ann O'Riordan,Gisela Chelimsky
Gastroenterology Research and Practice , 2009, DOI: 10.1155/2009/868496
Abstract: Background: The pathophysiology of functional abdominal pain (FAP) is unknown. The upright portion of a tilt table test triggers typical symptoms in certain children. Aim: To compare the pathophysiology and treatment response of children with FAP whose gastrointestinal symptoms (GI) were replicated (RGI) by tilt table testing (TTT) to those in whom TTT did not have this effect (NRGI). Methods: An IRB-approved retrospective review of the autonomic laboratory database identified all children tested for GI complaints. We compared results of TTT, Valsalva maneuver, deep breathing and the axon reflex sweat test. Overall treatment response and that specific to fludrocortisone was ranked from 1 to 5, with 1 “much worse,” 3 “neutral,” and 5 “much better.” Results: 32/76 identified children had reproducible symptoms on TTT (RGI) and 44 did not (NRGI). The RGI group was younger, had a shorter duration of symptoms, more postural tachycardia syndrome (POTS) and benefited more from fludrocortisone (73% in RGI vs. 25% in NRGI). Conclusion: Dividing patients with FAP according to the effect of TTT on their symptoms appears to delineate 2 fundamentally different groups, with potentially different pathophysiologies and treatment responses. A prospective study is needed.
Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations
Donald R VanDevanter, Mary A O'Riordan, Jeffrey L Blumer, Michael W Konstan
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-137
Abstract: We have retrospectively analyzed pulmonary function response data (as forced expiratory volume in one second; FEV1) from a previous blinded controlled CF exacerbation management study of intravenous ceftazidime/tobramycin and meropenem/tobramycin in which spirometry was conducted daily to assess the time course of pulmonary function response.Ninety-five patients in the study received antibiotics for at least 4 days and were included in our analyses. Patients received antibiotics for an average of 12.6 days (median = 13, SD = 3.2 days), with a range of 4 to 27 days. No significant differences were observed in mean or median treatment durations as functions of either treatment group or baseline lung disease stage. Average time from initiation of antibiotic treatment to highest observed FEV1 was 8.7 days (median = 10, SD = 4.0 days), with a range of zero to 19 days. Patients were treated an average of 3.9 days beyond the day of peak FEV1 (median = 3, SD = 3.8 days), with 89 patients (93.7%) experiencing their peak FEV1 improvement within 13 days. There were no differences in mean or median times to peak FEV1 as a function of treatment group, although the magnitude of FEV1 improvement differed between groups.Our results suggest that antibiotic response to exacerbation as assessed by pulmonary function is essentially complete within 2 weeks of treatment initiation and relatively independent of the magnitude of pulmonary function response observed.Cystic Fibrosis (CF) is a life-shortening genetic disease in which ~80% of deaths result from loss of lung function linked to inflammation caused by chronic bacterial lung infection (principally Pseudomonas aeruginosa) [1,2]. Pulmonary exacerbations (intermittent episodes during which symptoms of lung infection increase and lung function decreases) can cause substantial resource utilization [3], morbidity [4], and irreversible loss of lung function [5].A number of different signs, symptoms, and test results can contribute to the
Hall A Annual Report 2013
M. M. Dalton,K. Allada,K. Aniol,W. Boeglin,A. Camsonne,E. Chudakov,M. Cummings,D. Flay,M. Friedman,O. Glamazdin,J. Gomez,C. Keppel,H. P. Khanal,R. Lindgren,E. Long,R. Michaels,M. Mihovilovi?,C. Mu?oz Camacho,S. Nanda,R. Pomatsalyuk,S. Riordan,S. ?irca,C. Smith,P. Solvignon,N. F. Sparveris,V. Vereshchaka,X. Yan,Z. Ye,Y. X. Zhao,Jefferson Lab Hall A Collaboration
Physics , 2014,
Abstract: Report over the experimental activities in Hall A at Thomas Jefferson National Accelerator Facility during 2013.
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