| Death by Protein Damage in Irradiated Cells |
Jan 2011 |
11 pages |
| Authors:
Michael J Daly; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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 | A founding concept of radiobiology that deals with X-rays, gamma-rays and ultraviolet light is that radiation indiscriminately damages cellular macromolecules. Mounting experimental evidence does not fit into this theoretical framework. Whereas DNA lesion-yields in cells exposed to a given dose and type of radiation appear to be fixed, protein lesion-yields are highly variable. Extremely radiation resistant bacteria such as Deinococcus radiodurans have evolved extraordinarily efficient antioxidant chemical defenses, which specifically ... |
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| Small-Molecule Antioxidant Proteome-Shields in Deinococcus Radiodurans |
Sep 2010 |
16 pages |
| Authors:
Michael J Daly; Elena K Gaidamakova; Vera Y Matrosova; Juliann G Kiang; Risaku Fukumoto; Duck-Yeon Lee; Nancy B Wehr; Gabriela A Viteri; Barbara S Berlett; Rodney L Levine; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| For Deinococcus radiodurans and other bacteria which are extremely resistant to ionizing radiation, ultraviolet radiation, and desiccation, a mechanistic link exists between resistance, manganese accumulation, and protein protection. We show that ultrafiltered, protein-free preparations of D. radiodurans cell extracts prevent protein oxidation at massive doses of ionizing radiation. In contrast, ultrafiltrates from ionizing radiation-sensitive bacteria were not protective. The D. radiodurans ultrafiltrate was enriched in Mn, phosphate, nucleosides and bases, ... |
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| Modulating Radiation Resistance: Novel Protection Paradigms Based on Defenses against Ionizing Radiation in the Extremophile Deinococcus radiodurans |
10 May 2010 |
11 pages |
| Authors:
Michael J Daly; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| For Deinococcus radiodurans and other bacteria which are extremely resistant to ionizing radiation (IR) and desiccation, a mechanistic link exists between resistance, manganese accumulation, and protein protection. We have demonstrated that ultrafiltered, protein-free preparations of D. radiodurans cell extracts prevent protein oxidation at massive doses of IR. In comparison, ultrafiltrates from IR-sensitive bacteria were not protective. The D. radiodurans ultrafiltrate was enriched in Mn, phosphate, nucleosides, and bases and peptides. ... |
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| Treatment of Hepatitis C Infections with Interferon: A Historical Perspective |
Jan 2010 |
5 pages |
| Authors:
Robert M Friedman; Sara Contente; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Interferons were first described in 1957, but it was not until 34 years after their discovery that sufficient quantities of it were available for treatment of hepatitis C virus (HCV) infections, Clinicians now have an excellent understanding of the basis for the effectiveness of interferon alpha (IFN-alpha) in the therapy of this disease. Treatment with IFN-alpha is more efficient when it complemented by the antiviral ribavirin and the IFN-alpha is ... |
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| A New Perspective on Radiation Resistance Based on Deinococcus radiodurans |
Mar 2009 |
10 pages |
| Authors:
Michael J Daly; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| In classical models of radiation toxicity, DNA is the molecule that is most affected by ionizing radiation (IR). However, recent data show that the amount of protein damage caused during irradiation of bacteria is better related to survival than to DNA damage. In this Opinion article, a new model is presented in which proteins are the most important target in the hierarchy of macromolecules affected by IR. A first line ... |
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| A Novel ICOS-Independent, but CD28- and SAP-Dependent, Pathway of T Cell-Dependent, Polysaccharide-Specific Humoral Immunity in Response to Intact Streptococcus pneumoniae versus Pneumococcal Conjugate Vaccine |
Jan 2008 |
10 pages |
| Authors:
Quanyi Chen; Jennifer L Cannons; James C Paton; Hisaya Akiba; Pamela L Schwartzberg; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Polysaccharide (PS)- and protein-specific murine IgG responses to intact Streptococcus pneumoniae (Pn) are both dependent on CD4 T cell help, B7-dependent costimulation, and CD40/CD40 ligand interactions. However, the primary PS-specific, relative to protein-specific, IgG response terminates more rapidly, requires a shorter period of T cell help and B7-dependent costimulation, and fails to generate memory. In light of the critical role for ICOS/ICOS ligand interactions in sustaining T cell-dependent Ig responses ... |
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| Dendritic Cell-Derived Exosomes Express a Streptococcus pneumoniae Capsular Polysaccharide Type 14 Cross-Reactive Antigen That Induces Protective Immunoglobulin Responses against Pneumococcal Infection in Mice |
Jan 2007 |
12 pages |
| Authors:
Jesus Colino; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Exosomes activate T cells in vivo, but whether exosomes are able to induce humoral immune responses is still unknown. We found that dendritic cells, but not other immune cells, constitutively release an exosome-associated glycoconjugate that is cross-reactive with the capsular polysaccharide of Streptococcus pneumoniae type 14 (Cps14-CRA). Cps14-CRA was localized to the cholesterol-enriched microdomains or rafts of the exosomes and was mapped to the Beta1--6 branched N-acetyl-lactosamine derivatives of the ... |
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| Transgenic Expression of Bcl-xL or Bcl-2 by Murine B Cells Enhances the In Vivo Antipolysaccharide, but Not Antiprotein, Response to Intact Streptococcus pneumoniae |
2007 |
13 pages |
| Authors:
Gouri Chattopadhyay; Abdul Q. Khan; Goutam Sen; Jesus Colino; Wendy duBois; Anatoly Rubtsov; Raul M. Torres; Michael Potter; Clifford M. Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| IgG antipolysaccharide (PS) and antiprotein responses to Streptococcus pneumoniae (Pn) are both CD4 T cell dependent. However, the primary IgG anti-PS response terminates more quickly, uses a shorter period of T cell help, fails to generate memory, and is more dependent on membrane Ig (mIg) signaling. We thus determined whether this limited anti-PS response to Pn reflected a greater propensity of PS-specific B cells to undergo apoptosis. We used mice ... |
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| Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to Intact Streptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine |
Aug 2006 |
9 pages |
| Authors:
Quanyi Chen; Goutam Sen; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Interleukin-1 and IL-1 are proinflammatory cytokines that exert largely overlapping biological effects, both inducing cell signaling exclusively through IL-1R1 (1). Soluble IL-1R antagonist also binds to IL-1R1 but does not exert agonistic activity, serving instead to block IL-1 and IL- activity (2). IL-1RII also binds IL-1 but does not mediate signaling. IL-1 plays a key role in mediating innate host protection in response to pathogens, but is also a major ... |
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| Immunization of Aged Mice with a Pneumococcal Conjugate Vaccine Combined with an Unmethylated CpG-Containing Oligodeoxynucleotide Restores Defective Immunoglobulin G Antipolysaccharide Responses and Specific CD4+-T-Cell Priming to Young Adult Levels |
Apr 2006 |
11 pages |
| Authors:
Goutam Sen; Quanyi Chen; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Polysaccharide (PS)-protein conjugate vaccines, in contrast to purified PS vaccines, recruit CD4+ T-cell help and restore defective PS-specific humoral immunity in the immature host. Surprisingly, in the immunocompromised, aged host, anti-PS responses to conjugate vaccines are typically no better than those elicited by purified PS vaccines. Although aging leads to defects in multiple immune cell types, diminished CD4+ T-cell helper function has recently been shown to play a dominant role. ... |
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| Induction of In Vivo Antipolysaccharide Immunoglobulin Responses to Intact Streptococcus pneumoniae Is More Heavily Dependent on Btk-Mediated B-Cell Receptor Signaling than Antiprotein Responses |
Feb 2006 |
7 pages |
| Authors:
Abdul Q Khan; Goutam Sen; Shuling Guo; Owen N Witte; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| The relative role of Btk-dependent B-cell receptor (BCR) signaling in the induction of antipolysaccharide (anti-PS) and antiprotein immunoglobulin (Ig) responses to an intact extracellular bacterium in vivo is unknown. Btk(exp low) mice exhibit reduced BCR signaling but largely restore B-cell development. Btk(exp low) mice immunized with intact Streptococcus pneumoniae elicit reduced anti-PS but normal antiprotein Ig responses. Immunization of Btk(exp low) mice with PS-protein conjugate in saline results in an ... |
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| Differential Regulation of Protein- and Polysaccharide-Specific Ig Isotype Production In Vivo in Response to Intact Streptococcus pneumoniae |
Jan 2006 |
43 pages |
| Authors:
Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Adaptive humoral immunity to extracellular bacteria is largely mediated by antibody specific for both protein and polysaccharide antigens. Proteins and polysaccharides are biochemically distinct, and as a result are processed differently by the immune system, leading to different mechanistic pathways for eventual elicitation of specific Ig isotypes. Much of our current knowledge concerning the parameters underlying anti-protein and anti-polysaccharide Ig responses have come from studies using soluble, purified antigens. However, ... |
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| In Vivo Humoral Immune Responses to Isolated Pneumococcal Polysaccharides Are Dependent on the Presence of Associated TLR Ligands |
Jan 2005 |
9 pages |
| Authors:
Goutam Sen; Abdul Q Khan; Quanyi Chen; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| We determined whether T cell-independent Ig isotype responses to isolated pneumococcal polysaccharides (PPS) required TLR signaling in vivo. IgG anti-PPS responses to PPS3, PPS14, and C-polysaccharide (C-PS) were virtually undetectable in TLR2-/- mice, whereas specific IgM induction was variably reduced compared with wild-type mice. All PPS-containing preparations induced IL-6 and TNF-alpha from wild-type, but not TLR2-/-, macrophages. TLR2 activity was distinct from that of PPS, in that it was phenol ... |
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| Both Innate Immunity and Type 1 Humoral Immunity to Streptococcus pneumoniae Are Mediated by MyD88 but Differ in Their Relative Levels of Dependence on Toll-Like Receptor 2 |
Jan 2005 |
11 pages |
| Authors:
Adbul Q Khan; Quanyi Chen; Zheng-Qi Wu; James C Paton; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Little is known regarding the role of Toll-like receptors (TLRs) in regulating protein- and polysaccharide-specific immunoglobulin (Ig) isotype production in response to an in vivo challenge with an extracellular bacterium. In this report we demonstrate that MyD88-/-, but not TLR2-/-, mice are markedly defective in their induction of multiple splenic proinflammatory cytokine- and chemokine-specific mRNAs after intraperitoneal (i.p.) challenge with heat-killed Streptococcus pneumoniae capsular type 14 (S. pneumoniae type 14). ... |
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| Insulin-Like Growth Factor-1 Controls Type 2 T Cell-Independent B Cell Response |
Jan 2005 |
11 pages |
| Authors:
Stephanie Baudler; Julia Baumgartl; Brigitte Hampel; Thorsten Buch; Ari Waisman; Clifford M Snapper; Wilhelm Krone; Jens C Bruning; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| The IGF-1 receptor (IGF-1R) is expressed on T and B lymphocytes, and the expression of the insulin- and IGF-1-signaling machinery undergoes defined changes throughout lineage differentiation, offering a putative role for IGF-1 in the regulation of immune responses. To study the role of the IGF-1R in lymphocyte differentiation and function in vivo, we have reconstituted immunodeficient RAG2-deficient mice with IGF-1R/ fetal liver cells. Despite the absence of IGF-1Rs, the development ... |
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| The critical DNA flanking sequences of a CpG Oligodeoxynucleotide, but not the 6 base CpG motif, can be replaced with RNA without quantitative or qualitative changes in Toll-like receptor 9-mediated activity |
Jan 2004 |
12 pages |
| Authors:
Goutam Sen; Michael Flora; Gouri Chattopadhyay; Dennis M Klinman; Andrew Lees; James J Mond; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Double- and single-stranded oligodeoxynucleotides containing unmethylated cytosine-guanosine (CpG) dinucleotides (CpG-ODN) activate immune cells via TLR9. In this report we synthesized hybrid DNA-RNA molecules (HDR) in order to further explore the structure-immune function relationship of CpG-ODN in TLR9 signaling and the potential immunomodulatory properties of RNA. We demonstrate that replacement of the deoxyadenosine flanking sequences, critical for the immune activating properties of CpG-ODN, with a similar number of adenosines, although not ... |
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| Differential Regulation of IgG Anti-Capsular Polysaccharide and Antiprotein Responses to Intact Streptococcus pneumoniae in the Presence of Cognate CD4+ T Cell Help |
Jan 2004 |
9 pages |
| Authors:
Abdul Q Khan; Andrew Lees; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| The relative lack of memory for IgG antipolysaccharide responses is believed to be secondary to the inability of polysaccharides to associate with MHC class II molecules and thus a failure to recruit cognate CD4+T cell help. However, little is known concerning the role of T cells and the generation of memory for antipolysaccharide Ig responses to intact extracellular bacteria. We used heat-killed, intact Streptococcus pneumoniae, capsular type 14 (Pn14), to ... |
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| Antiapoptotic Action of Hypoxia-Inducible Factor-1Alpha in Human Endothelial Cells |
15 DEC 2003 |
10 pages |
| Authors:
Erik Z. Yu; Ying-Yue Li; Xiu-Huai Liu; Elliott Kagan; Richard M. McCarron; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Hypoxia-inducible factor-1 (HIF-1) is the major transcription factor involved in the adaptive response to hypoxia and consists of HIF-1a and HIF-1b subunits. Indirect evidence suggests that HIF-1a may exert both proapoptotic and antiapoptotic actions in response to hypoxia. In this study, we evaluated the effects of RNA interference (RNAi) targeting HIF-1a messenger RNA (mRNA) on apoptosis in primary cultured human umbilical vascular endothelial cells (HUVECs) exposed to anoxia and reoxygenation ... |
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| Opposing Signals from Pathogen-Associated Molecular Patterns and IL-10 Are Critical for Optimal Dendritic Cell Induction of In Vivo Humoral Immunity to Streptococcus pneumoniae |
Jul 2003 |
13 pages |
| Authors:
Jesus Colino; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Interleukin10 is widely regarded as an inhibitor of immunity in part through its ability to inhibit dendritic cell (DC) function. The present study suggests a modification of this view by demonstrating instead that a critical balance exists between signals mediated by pathogen-associated molecular patterns and IL-10 for optimization of DC induction of an in vivo humoral immune response. Bone marrow-derived, CD8 DC pulsed with Streptococcus pneumoniae in vitro induce in ... |
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| Two Distinct Mechanisms for Induction of Dendritic Cell Apoptosis in Response to Intact Streptococcus pneumoniae |
Jan 2003 |
13 pages |
| Authors:
Jesus Colino; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Apoptotic dendritic cells (DCs) are ineffective at inducing immunity. Thus, parameters that regulate DC viability during a primary infection will help to determine the outcome of the subsequent immune response. In this regard, pathogens have developed strategies to promote DC apoptosis to counterbalance the nascent primary immune response. We demonstrate, using cultured bone marrow-derived DCs, that Streptococcus pneumoniae can induce DC apoptosis through two distinct mechanisms: 1) a rapid, caspase-independent ... |
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| Tunicamycin Enhances Neuroinvasion and Pathogenicity in Mice with Venezuelan Equine Encephalitis Virus |
2003 |
134 pages |
| Authors:
Keith E. Steele; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Venezuelan equine encephalitis (VEE) virus infects horses and humans and is a potential biothreat pathogen. Agents that alter the blood-brain barrier (BBB) may enhance viral encephalitides. The current studies explored whether tunicamycin (TM) and other agents affect the pathogenesis of VEE. Following infection with the molecularly-cloned virulent V3000 virus TM-treated mice had a significantly (p < .05) decreased mean survival time (MST) of 7.3 days versus 9. 9 days in ... |
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| The Mechanism Underlying T Cell Help for Induction of an Antigen-Specific In Vivo Humoral Immune Response to Intact Streptococcus pneumoniae Is Dependent on the Type of Antigen |
Mar 2002 |
8 pages |
| Authors:
Zheng-Qi Wu; Yi Shen; Abdul Q Khan; Ching-Liang Chu; Richard Riese; Harold A Chapman; Osami Kanagawa; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Little is known concerning the role of T cells in regulating an anti-polysaccharide Ig response to an intact pathogen. We previously reported that the in vivo Ig responses to Streptococcus pneumoniae (strain R36A), specific for pneumococcal surface protein A (PspA) and for the phosphorylcholine (PC) determinant of C-polysaccharide, were both dependent on TCR-alpha beta T cells and B7-dependent costimulation, although only PspA-specific memory was generated. In this report, we show ... |
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| Endogenous Pro- and Anti-Inflammatory Cytokines Differentially Regulate an In Vivo Humoral Response to Streptococcus pneumoniae |
Feb 2002 |
14 pages |
| Authors:
Abdul Q Khan; Yi Shen; Zheng-Qi Wu; Thomas A Wynn; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Proinflammatory cytokines play a critical role in innate host defense against extracellular bacteria. However, little is known regarding the effects of these cytokines on the adaptive humoral response. Mice injected with a neutralizing anti-tumor necrosis factor alpha (TNF-a) monoclonal antibody (MAb) at the time of primary immunization with intact Streptococcus pneumoniae (strain R36A) showed a substantial reduction in both the primary immunoglobulin G (IgG) response specific for the cell wall ... |
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| Dendritic Cells Pulsed with Intact Streptococcus pneumoniae Elicit both Protein- and Polysaccharide-specific Immunoglobulin Isotype Responses In Vivo through Distinct Mechanisms |
07 Jan 2002 |
14 pages |
| Authors:
Jesus Colino; Yi Shen; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| Immature bone marrow-derived myeloid dendritic cells (BMDCs) are induced to undergo phenotypic maturation and secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-12 and IL-10 when pulsed in vitro with intact Streptococcus pneumoniae. After transfer to naive mice pulsed BMDCs induce immunoglobulin (Ig) isotype responses specific for both protein and polysaccharide pneumococcal antigens, having in common the requirement for viable BMDCs T cells, and B7-dependent costimulation in the recipient mice. ... |
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| B7 Requirements for Primary and Secondary Protein- and Polysaccharide-Specific Ig Isotype Responses to Streptococcus pneumoniae |
Sep 2000 |
10 pages |
| Authors:
Zheng-Qi Wu; Abdul Q Khan; Yi Shen; Jerome Schartman; Robert Peach; Andrew Lees; James J Mond; William C Gause; Clifford M Snapper; UNIFORMED SERVICES UNIV OF THE HEALTH SCIENCES BETHESDA MD DEPT OF PATHOLOGY
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| The requirements for B7 costimulation during an in vivo humoral response to an intact extracellular bacteria have not been reported. In this study we immunized mice with Streptococcus pneumoniae (R36A) to determine the B7 requirements for induction of Ig, specific for two determinants on R36A, the phosphorylcholine (PC) determinant of C-polysaccharide and pneumococcal surface protein A (PspA). We show that the primary anti-PspA response, the development of PspA-specific memory, and ... |
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