Biochemistry Commons^™

Enhancement Of Reactive Oxygen Species Production And Chlamydial Infection By The Mitochondrial Nod-Like Family Member Nlrx1, Ali A. Abdul-Sater, Najwene Saïd-Sadier, Verissa M. Lam, Bhavni Singh, Matthew A. Pettengill, Fraser Soares, Ivan Tattoli, Simone Lipinski, Stephen E. Girardin, Philip Rosenstiel, David M. Ojcius

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Chlamydia trachomatis infections cause severe and irreversible damage that can lead to infertility and blindness in both males and females. Following infection of epithelial cells, Chlamydia induces production of reactive oxygen species (ROS). Unconventionally, Chlamydiae use ROS to their advantage by activating caspase-1, which contributes to chlamydial growth. NLRX1, a member of the Nod-like receptor family that translocates to the mitochondria, can augment ROS production from the mitochondria following Shigella flexneri infections. However, in general, ROS can also be produced by membrane-bound NADPH oxidases. Given the importance of ROS-induced caspase-1 activation in growth of the chlamydial vacuole, we investigated the …

Preeclampsia, Autoimmunity And The At1 Receptor, Roxanna A. Irani

Dissertations and Theses (Open Access)

Preeclampsia (PE) is a disease of late pregnancy characterized by maternal hypertension and proteinuria. It is associated with preterm delivery and significant perinatal morbidity and mortality. Despite affecting ~7% of first pregnancies, there is no effective screening method to identify women at risk, nor is there a definitive treatment other than delivery of the baby and placenta. Though the pathogenesis of PE remains unclear, an imbalance in the renin-angiotensin and immune systems are thought to be major contributors. Bridging these two concepts, it has recently been shown that women with PE harbor specific autoantibodies: the angiotensin II type 1 receptor …

Aspergillus Fumigatus Stimulates The Nlrp3 Inflammasome Through A Pathway Requiring Ros Production And The Syk Tyrosine Kinase, Najwane Saïd-Sadier, Eduardo V. Padilla, Gordon Langsley, David M. Ojcius

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Invasive aspergillosis (IA) is a life-threatening disease that occurs in immunodepressed patients when infected with Aspergillus fumigatus. This fungus is the second most-common causative agent of fungal disease after Candida albicans. Nevertheless, much remains to be learned about the mechanisms by which A. fulmigatus activates the innate immune system. We investigated the inflammatory response to conidia and hyphae of A. fumigatus and specifically, their capacity to trigger activation of an inflammasome. Our results show that in contrast to conidia, hyphal fragments induce NLRP3 inflammasome assembly, caspase-1 activation and IL-1β release from a human monocyte cell line. The ability of Aspergillus …

Chloroquine Susceptibility And Reversibility In A Plasmodium Falciparum Genetic Cross, Jigar J. Patel, Drew Thacker, John C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig

Biological Sciences Faculty Publications

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT) are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 x Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the South-East Asia-derived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute …

The Danger Signal Adenosine Induces Persistence Of Chlamydial Infection Through Stimulation Of A2b Receptors, Matthew A. Pettengill, Verissa W. Lam, David M. Ojcius

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Infections with intracellular bacteria such as chlamydiae affect the majority of the world population. Infected tissue inflammation and granuloma formation help contain the short-term expansion of the invading pathogen, leading also to local tissue damage and hypoxia. However, the effects of key aspects of damaged inflamed tissues and hypoxia on continued infection with intracellular bacteria remain unknown. We find that development of Chlamydia trachomatis is reversibly retarded by prolonged exposure of infected cells to extracellular adenosine, a hallmark of hypoxia and advanced inflammation. In epithelial cells, this effect was mediated by the A2b adenosine receptor, unique in the adenosine receptor …

Inactivation Of The Fliy Gene Encoding A Flagellar Motor Switch Protein Attenuates Mobility And Virulence Of Leptospira Interrogans Strain Lai, Sumei Liao, Ai-Hua Sun, David M. Ojcius, Senlin Wu, Jinfang Zhao, Jie Yan

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Background: Pathogenic Leptospira species cause leptospirosis, a zoonotic disease of global importance. The spirochete displays active rotative mobility which may contribute to invasion and diffusion of the pathogen in hosts. FliY is a flagellar motor switch protein that controls flagellar motor direction in other microbes, but its role in Leptospira, and paricularly in pathogenicity remains unknown.

Results: A suicide plasmid for the fliY gene of Leptospira interrogans serogroup Icterohaemorrhagiae serovar Lai strain Lai that was disrupted by inserting the ampicillin resistance gene (bla) was constructed, and the inactivation of fliY gene in a mutant (fliY-) was confirmed by PCR and …

Inflammasome-Dependent Caspase-1 Activation In Cervical Epithelial Cells Stimulates Growth Of The Intracellular Pathogen Chlamydia Trachomatis, Ali A. Abdul-Sater, Evonne Koo, Georg Hacker, David M. Ojcius

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Inflammasomes have been extensively characterized in monocytes and macrophages, but not in epithelial cells, which are the preferred host cells for many pathogens. Here we show that cervical epithelial cells express a functional inflammasome. Infection of the cells by Chlamydia trachomatis leads to activation of caspase-1, through a process requiring the NOD-like receptor family member NLRP3 and the inflammasome adaptor protein ASC. Secretion of newly synthesized virulence proteins from the chlamydial vacuole through a type III secretion apparatus results in efflux of K+ through glibenclamide-sensitive K+ channels, which in turn stimulates production of reactive oxygen species. Elevated levels of reactive …

An Iterative Strategy Combining Biophysical Criteria And Duration Hidden Markov) Models For Structural Predictions Of Chlamydia Trachomatis S66 Promoters, Ronna R. Mallios, David M. Ojcius, David H. Ardell

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Background: Promoter identification is a first step in the quest to explain gene regulation in bacteria. It has been demonstrated that the initiation of bacterial transcription depends upon the stability and topology of DNA in the promoter region as well as the binding affinity between the RNA polymerase σ-factor and promoter. However, promoter prediction algorithms to date have not explicitly used an ensemble of these factors as predictors. In addition, most promoter models have been trained on data from Escherichia coli. Although it has been shown that transcriptional mechanisms are similar among various bacteria, it is quite possible that the …

Effects Of Spaceflight On Phagocytic Function And Immune-Neural Interaction, Farnaz P. Baqai

Loma Linda University Electronic Theses, Dissertations & Projects

In spaceflight, astronauts will be exposed to several environmental risk factors that may lead to disturbances in homeostasis maintained by the central nervous system (CNS) and immune system. Low Earth orbit (LEO) spaceflight studies have shown that microgravity changes virtually all immune parameters that have been evaluated. Similarly, ground based studies have shown that low-dose radiation can also significantly impact immune function. Finally, as most spacecrafts are ecologically and environmentally closed systems, astronauts may be at increased risk for exposure to aerosolized infectious agents. The hypothesis of this study is: Exposure to spaceflight environment (microgravity and radiation) can influence immune …

Pathogenic Adaptation Of Intracellular Bacteria By Rewiring A Cis-Regulatory Input Function, Suzanne E. Osborne, Don Walthers, Ana M. Tomljenovic, David T. Mulder, Uma Silphaduang, Nancy Duong, Michael J. Lowden

Dartmouth Scholarship

The acquisition of DNA by horizontal gene transfer enables bacteria to adapt to previously unexploited ecological niches. Although horizontal gene transfer and mutation of protein-coding sequences are well-recognized forms of pathogen evolution, the evolutionary significance of cis-regulatory mutations in creating phenotypic diversity through altered transcriptional outputs is not known. We show the significance of regulatory mutation for pathogen evolution by mapping and then rewiring a cis-regulatory module controlling a gene required for murine typhoid. Acquisition of a binding site for the Salmonella pathogenicity island-2 regulator, SsrB, enabled the srfN gene, ancestral to the Salmonella genus, to play a …

Leptospira Interrogans Induces Apoptosis In Macrophages Via Caspase-8- And -3-Dependent Pathways, Dandan Jin, David M. Ojcius, Dexter Sun, Haiyan Dong, Yihui Luo, Yafei Mao, Jie Yan

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Apoptosis of host cells plays an important role in modulating the pathogenesis of many infectious diseases. It has been reported that Leptospira interrogans, the causal agent of leptospirosis, induces apoptosis in macrophages and hepatocytes. However, the molecular mechanisms responsible for host cell death remained largely unknown. Here we demonstrate that L. interrogans induced apoptosis in a macrophage-like cell line, J774A.1, and primary murine macrophages in a time- and dose-dependent manner. Apoptosis was associated with the activation of cysteine aspartic acid-specific proteases (caspase-3, caspase-6, and caspase-8), the increased expression of Fas-associated death domain (FADD), and the cleavage of the caspase substrates …

Characterization Of The Ompl1 Gene Of Pathogenic Leptospira Species In China And Cross-Immunogenicity Of The Ompl1 Protein, Haiyan Dong, Ye Hu, Feng Xue, Dexter Sun, David M. Ojcius, Yafei Mao, Jie Yan

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Background: The usefulness of available vaccine and serological tests for leptospirosis is limited by the low cross-reactivity of antigens from numerous serovars of pathogenic Leptospira spp. Identification of genus-specific protein antigens (GP-Ag) of Leptospira would be important for development of universal vaccines and serodiagnostic methods. OmpL1, a transmembrane porin of pathogenic leptospires, was identified as a possible GP-Ag, but its sequence diversity and immune cross-reactivity among different serovars of pathogenic leptospires remains largely unknown.

Results: PCR analysis demonstrated that the ompL1 gene existed in all 15 official Chinese standard strains as well as 163 clinical strains of pathogenic leptospires isolated …

Critical Involvement Of The Atm-Dependent Dna Damage Response In The Apoptotic Demise Of Hiv-1-Elicited Syncytia, Jean-Luc Perfettini, Roberta Nardacci, Mehdi Bourouba, Frederic Subra, Laurent Gros, Claire Séror, Gwenola Manic, Filippo Rosselli, Alessandra Amendola, Peggy Masdehors, Luciana Chessa, Giuseppe Novelli, David M. Ojcius, Jan Konrad Siwicki, Magdalena Chechlinska, Christian Auclair, Jose R. Regueiro, Hughes De Thé, Marie-Lise Gougeon, Mauro Piacentini, Guido Kroemer

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DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown …

Susceptibility Of Chlamydia Trachomatis To The Excipient Hydroxy-Ethylcellulose: Ph And Concentration Dependence Of Antimicrobial Activity, Ali A. Abdul-Sater, David M. Ojcius, M. P. Meyer

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Hydroxyethyl cellulose (HEC) is used as a neutral excipient in microbicides used against sexually transmitted pathogens. However, HEC inhibits the infection of cervical epithelial cells by Chlamydia trachomatis at pH 5 in a concentration-dependent manner. At pH 7, infection is inversely dependent on the concentration of HEC, possibly due to pH-dependent calcium sequestration.

Immunoadjuvanticity Of Chlorophyll, Jocelyn Helen Parks Ramos

All-Inclusive List of Electronic Theses and Dissertations

Background: Vaccines are formulations containing antigenic determinants (from non-self organic matters) and immuno-enhancers called adjuvants. Together, they evoke protective immune responses in hosts. Adjuvants are substances that further vaccines' capability to induce a robust immune response. Common side effects with conventional adjuvants used in most vaccines are toxicity, inflammation and granulomas. In this study we investigated the pigment chlorophyll (Chl) for immunoadjuvanticity. The selection of chlorophyll is based on the fact that it is a component in foods such as spinach, and that it contains an isoprenoid structure that is a feature of many conventional adjuvants, Pristane and Squalene. Chl …

Hiv/Aids In Pakistan: The Battle Begins, Mohammad A. Rai, Haider J. Warraich, Syed H. Ali, Vivek R. Nerurkar

Department of Biological & Biomedical Sciences

Pakistan, the second most populous Muslim nation in the world, has started to finally experience and confront the HIV/AIDS epidemic. The country had been relatively safe from any indigenous HIV cases for around two decades, with most of the infections being attributable to deported HIV positive migrants from the Gulf States. However, the virus finally seems to have found a home-base, as evidenced by the recent HIV outbreaks among the injection drug user community. Extremely high-risk behavior has also been documented among Hijras (sex workers) and long-distance truck drivers. The weak government response coupled with the extremely distressing social demographics …

Atp Activates A Reactive Oxygen Species-Dependent Oxidative Stress Response And Secretion Of Pro-Inflammatory Cytokines In Macrophages, Christiane M. Cruz, Alessandra Rinna, Henry Jay Forman, Ana L. M. Ventura, Pedro M. Persechini, David M. Ojcius

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Secretion of the proinflammatory cytokines, interleukin (IL)-1β and IL-18, usually requires two signals. The first, due to microbial products such as lipopolysaccharide, initiates transcription of the cytokine genes and accumulation of the precursor proteins. Cleavage and secretion of the cytokines is mediated by caspase-1, in association with an inflammasome containing Nalp3, which can be activated by binding of extracellular ATP to purinergic receptors. We show that treatment of macrophages with ATP results in production of reactive oxygen species (ROS), which stimulate the phosphatidylinositol 3-kinase (PI3K) pathway and subsequent Akt and ERK1/2 activation. ROS exerts its effect through glutathionylation of PTEN …

Characterization Of Host Cell Death Induced By Chlamydia Trachomatis, Songmin Ying, Silke F. Fischer, Matthew A. Pettengill, Debye Conte, Stefan A. Paschen, David M. Ojcius, Georg Hacker

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Chlamydia are obligate intracellular bacteria that modulate apoptosis of the host cell. Strikingly, chlamydial infection has been reported both to inhibit and to induce apoptosis. Although the ability to inhibit apoptosis has been corroborated by the identification of cellular targets, confirmation of cell death induction has been complicated by a mixture of apoptotic features and atypical cell death during infection, as well as by differences in the experimental techniques used to measure cell death. Here we use a panel of well-established approaches in the study of apoptosis to define the form of cell death induced by Chlamydia trachomatis infection. Infected …

In Vivo Mature Immunological Synapses Forming Smacs Mediate Clearance Of Virally Infected Astrocytes From The Brain, Carlos Barcia, Clare Thomas, James Curtin, Gwendalyn King, Kolja Wawrowsky, Marianela Candolfi, Weidong Xiong, Chunyan Liu, Kurt Kroeger, Olivier Boyer, Jerzy Kupiec-Weglinski, David Klatzmann, Maria Castro, Pedro Lowenstein

Articles

The microanatomy of immune clearance of infected brain cells remains poorly understood. Immunological synapses are essential anatomical structures that channel information exchanges between T cell–antigen-presenting cells (APC) during the priming and effector phases of T cells' function, and during natural killer–target cell interactions. The hallmark of immunological synapses established by T cells is the formation of the supramolecular activation clusters (SMACs), in which adhesion molecules such as leukocyte function-associated antigen 1 segregate to the peripheral domain of the immunological synapse (p-SMAC), which surrounds the T cell receptor–rich or central SMAC (c-SMAC). The inability so far to detect SMAC formation in …

Immunogenicity Of Terephthalate, A Constituent Of Synthetic Polymers, And Its Modulation By Adjuvants, Youssef Aachoui

All-Inclusive List of Electronic Theses and Dissertations

Objective: In this study we have focused on the potential immunotoxicity resulting from exposure to phthalate compounds which are widely present as basic constituents of many synthetic polymers.

Recruitment Of Bad By The Chlamydia Trachomatis Vacuole Correlates With Host-Cell Survival, Philippe Verbeke, Lynn Welter-Stahl, S. Ying, J. Hansen, Georg Hacker, Toni Darville, David M. Ojcius

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Chlamydiae replicate intracellularly in a vacuole called an inclusion. Chlamydial-infected host cells are protected from mitochondrion-dependent apoptosis, partly due to degradation of BH3-only proteins. The host-cell adapter protein 14-3-3β can interact with host-cell apoptotic signaling pathways in a phosphorylation-dependent manner. In Chlamydia trachomatis-infected cells, 14-3-3β co-localizes to the inclusion via direct interaction with a C. trachomatis-encoded inclusion membrane protein. We therefore explored the possibility that the phosphatidylinositol-3 kinase (PI3K) pathway may contribute to resistance of infected cells to apoptosis. We found that inhibition of PI3K renders C. trachomatis-infected cells sensitive to staurosporine-induced apoptosis, which is accompanied by mitochondrial cytochrome c …

Intercellular Spreading Of Porphyromonas Gingivalis Infection In Primary Gingival Epithelial Cells, Özlem Yilmaz, Philippe Verbeke, Richard J. Lamont, David M. Ojcius

All Dugoni School of Dentistry Faculty Articles

Porphyromonas gingivalis, an important periodontal pathogen, is an effective colonizer of oral tissues. The organism successfully invades, multiplies in, and survives for extended periods in primary gingival epithelial cells (GECs). It is unknown whether P. gingivalis resides in the cytoplasm of infected cells throughout the infection or can spread to adjacent cells over time. We developed a technique based on flow cytofluorometry and fluorescence microscopy to study propagation of the organism at different stages of infection of GECs. Results showed that P. gingivalis spreads cell to cell and that the amount of spreading increases gradually over time. There was a …

A Role For Mitogen-Activated Protein Kinase (Erk1/2) Activation And Non-Selective Pore Formation In P2x7 Receptor-Mediated Thymocyte Death, Rodolphe Auger, Iris Motta, Karim Benihoud, David M. Ojcius, Jean M. Kanellopoulos

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Extracellular ATP (ATPe) binds to P2X7 receptors (P2X7R) expressed on the surface of cells of hematopoietic lineage, including murine thymocytes. Activation of P2X7R by ATPe results in the opening of cation-specific channels, and prolonged ATPe exposure leads to the formation of non-selective pores enabling transmembrane passage of solutes up to 900 Da. In the presence of ATPe, P2X7R-mediated thymocyte death is due primarily to necrosis/lysis and not apoptosis, as measured by the release of lactate dehydrogenase indicative of a loss of plasma membrane integrity. The present study is focused on the identification of P2X7R signaling mediators in ATP-induced thymocyte necrosis/lysis. …

Defensin In The Ticks Dermacentor Variabilis And Ixodes Scapularis, Shane Michael Ceraul

Theses and Dissertations in Biomedical Sciences

This dissertation presents the identification, molecular structure and expression of defensin, an antimicrobial peptide, in the ticks, Dermacentor variabilis and Ixodes scapularis. A 624 bp cDNA molecule for defensin was cloned and sequenced from hemocytes, fat body and midgut of unstimulated D. variabilis ticks. Defensin peptide was detected only in the hemocyte lysates. These results suggest that the defensin from D. variabilis is synthesized and stored in the hemocytes, although the role of other tissues is not excluded.

The ability of the juvenile stage ticks to express the defensin gene was confirmed. Detection of the defensin transcript in all …

Association Between Coinfection Of Porphyromonas Gingivalis, Actinobacillus Actinomycetemcomitans And Treponema Denticola And Periodontal Tissue Destruction In Chronic Periodontitis, L. L. Chen, Y. M. Wu, J. Yan, W. L. Sun, Y. Z. Sun, David M. Ojcius

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No abstract provided.

Activation Of The Phosphatidylinositol 3-Kinase/Akt Pathway Contributes To Survival Of Primary Epithelial Cells Infected With The Periodontal Pathogen Porphyromonas Gingivalis, Özlem Yilmaz, Thomas Jungas, Philippe Verbeke, David M. Ojcius

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Porphyromonas gingivalis, an important periodontal pathogen, infects primary gingival epithelial cells (GECs). Despite the large number of bacteria that replicate inside the GECs, the host cell remains viable. We demonstrate that P. gingivalis triggers rapid and reversible surface phosphatidylserine exposure through a mechanism requiring caspase activation. However, after 1 day of infection, the bacteria no longer induce phosphatidylserine externalization and instead protect infected cells against apoptosis. Infection exerts its effect at the level of mitochondria, as P. gingivalis also blocks depolarization of the mitochondrial transmembrane potential and cytochrome c release. Interestingly, protein kinase B/Akt is phosphorylated during infection, which can …

Tolerance Of The Fetus By The Maternal Immune System: Role Of Inflammatory Mediators At The Feto-Maternal Interface, Colette Kanellopoulos-Langevin, Stephane M. Caucheteux, Philippe Verbeke, David M. Ojcius

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The adaptive immune system of placental mammals has evolved to tolerate the fetus. Rejection of the fetus by adaptive immune responses is therefore a rare event, with abortion being caused more frequently by inflammation in the placenta. This review will cover recent aspects of immune privilege and the innate immune system at the feto-maternal interface, citing examples of the role played by microbial infections in fetal demise.

Lysosomal Membrane Permeabilization Induces Cell Death In A Mitochondrion-Dependent Fashion, Patricia Boya, Karine Andreau, Delphine Poncet, Naoufal Zamzami, Jean-Luc Perfettini, Didier Metivier, David M. Ojcius, Marja Jäättelä, Guido Kroemer

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A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on …

Role Of Proapoptotic Bax In Propagation Of Chlamydia Muridarum (The Mouse Pneumonitis Strain Of Chlamydia Trachomatis) And The Host Inflammatory Response, Jean-Luc Perfettini, David M. Ojcius, Charles W. Andrews Jr., Stanley J. Korsmeyer, Roger G. Rank, Toni Darville

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The BCL-2 family member BAX plays a critical role in regulating apoptosis. Surprisingly, bax-deficient mice display limited phenotypic abnormalities. Here we investigate the effect of BAX on infection by the sexually transmitted pathogen,Chlamydia muridarum (the mouse pneumonitis strain ofChlamydia trachomatis). Bax −/−cells are relatively resistant to Chlamydia-induced apoptosis, and fewer bacteria are recovered after two infection cycles from Bax −/− cells than from wild-type cells. These results suggest that BAX-dependent apoptosis may be used to initiate a new round of infection, most likely by releasingChlamydia-containing apoptotic bodies from infected cells that could be internalized by neighboring uninfected cells. Nonetheless, infected …

Characterization Of A Gene Encoding Two Isoforms Of A Mitochondrial Protein Upregulated By Cyclosporin A In Activated T Cells, Laurent Mascarell, Rodolphe Auger, Andres Alcover, David M. Ojcius, Thomas Jungas, Veronique Cadet-Daniel, Jean M. Kanellopoulos, Paolo Truffa-Bacchi

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Cyclosporin A (CSA) is an immunosuppressor used in organ transplantation. A recent proteomic analysis has revealed that activation of T cells in the presence of CSA induces the synthesis of hundreds of new proteins. Here we used representational difference analysis to characterize some of the corresponding induced genes. After cDNA bank screening we focused on one of these genes, which we named CSA-conditional, T cell activation-dependent (CSTAD) gene. This gene produces two mRNAs resulting from alternative splicing events. They encode two proteins of 104 and 141 amino acids, CSTADp-S and CSTADp-L, for the short and long forms, respectively. FK506 had …