Medical Microbiology Commons^™

Il-1ri (Interleukin-1 Receptor Type I) Signalling Is Essential For Host Defence And Hemichannel Activity During Acute Central Nervous System Bacterial Infection., Juan Xiong, Maria Burkovetskaya, Nikolay Karpuk, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a common aetiological agent of bacterial brain abscesses. We have previously established that a considerable IL-1 (interleukin-1) response is elicited immediately following S. aureus infection, where the cytokine can exert pleiotropic effects on glial activation and blood-brain barrier permeability. To assess the combined actions of IL-1α and IL-1β during CNS (central nervous system) infection, host defence responses were evaluated in IL-1RI (IL-1 receptor type I) KO (knockout) animals. IL-1RI KO mice were exquisitely sensitive to intracerebral S. aureus infection, as demonstrated by enhanced mortality rates and bacterial burdens within the first 24 h following pathogen exposure compared …

Myd88-Dependent Signaling Influences Fibrosis And Alternative Macrophage Activation During Staphylococcus Aureus Biofilm Infection., Mark L. Hanke, Amanda Angle, Tammy Kielian

Journal Articles: Pathology and Microbiology

Bacterial biofilms represent a significant therapeutic challenge based on their ability to evade host immune and antibiotic-mediated clearance. Recent studies have implicated IL-1β in biofilm containment, whereas Toll-like receptors (TLRs) had no effect. This is intriguing, since both the IL-1 receptor (IL-1R) and most TLRs impinge on MyD88-dependent signaling pathways, yet the role of this key adaptor in modulating the host response to biofilm growth is unknown. Therefore, we examined the course of S. aureus catheter-associated biofilm infection in MyD88 knockout (KO) mice. MyD88 KO animals displayed significantly increased bacterial burdens on catheters and surrounding tissues during early infection, which …

A Shared Gene Expression Signature In Mouse Models Of Ebv-Associated And Non-Ebv-Associated Burkitt Lymphoma, Kathryn T. Bieging, Kamonwan Fish, Subbarao Bondada, Richard Longnecker

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional …

B1b Lymphocyte-Derived Antibodies Control Borrelia Hermsii Independent Of Fcα/Μ Receptor And In The Absence Of Host Cell Contact., Matthew J. Colombo, David Abraham, Akira Shibuya, Kishore R. Alugupalli

Department of Microbiology and Immunology Faculty Papers

The critical role of IgM in controlling pathogen burden has been demonstrated in a variety of infection models. In the murine model of Borrelia hermsii infection, IgM is necessary and sufficient for the rapid clearance of bacteremia. Convalescent, but not naïve, B1b cells generate a specific IgM response against B. hermsii, but the mechanism of IgM-mediated protection is unknown. Here, we show that neither Fcα/μR, a high-affinity receptor for IgM, nor IgM-dependent complement activation is required for controlling B. hermsii. Bacteria in diffusion chambers with a pore size impermeable to cells were killed when diffusion chambers were implanted into either …

Step-Wise Loss Of Bacterial Flagellar Torsion Confers Progressive Phagocytic Evasion, Rustin R. Lovewell, Ryan M. Collins, Julie L. Acker, George A. O'Toole, Matthew J. Wargo, Brent Berwin, Craig R. Roy

Dartmouth Scholarship

Phagocytosis of bacteria by innate immune cells is a primary method of bacterial clearance during infection. However, the mechanisms by which the host cell recognizes bacteria and consequentially initiates phagocytosis are largely unclear. Previous studies of the bacterium Pseudomonas aeruginosa have indicated that bacterial flagella and flagellar motility play an important role in colonization of the host and, importantly, that loss of flagellar motility enables phagocytic evasion. Here we use molecular, cellular, and genetic methods to provide the first formal evidence that phagocytic cells recognize bacterial motility rather than flagella and initiate phagocytosis in response to this motility. We demonstrate …

Rip1-Dependent And Independent Effects Of Necrostatin-1 In Necrosis And T Cell Activation., Youngsik Cho, Thomas Mcquade, Haibing Zhang, Jianke Zhang, Francis Ka-Ming Chan

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Programmed necrosis/necroptosis is an emerging form of cell death that plays important roles in mammalian development and the immune system. The pro-necrotic kinases in the receptor interacting protein (RIP) family are crucial mediators of programmed necrosis. Recent advances in necrosis research have been greatly aided by the identification of chemical inhibitors that block programmed necrosis. Necrostatin-1 (Nec-1) and its derivatives were previously shown to target the pro-necrotic kinase RIP1/RIPK1. The protective effect conferred by Nec-1 and its derivatives in many experimental model systems was often attributed to the inhibition of RIP1 function.

METHODOLOGY/PRINCIPAL FINDINGS: We compared the effect of …

Role Of Phosphoinositide 3-Kinase – Akt Signaling Pathway In The Age-Related Cytokine Dysregulation In Splenic Macrophages Stimulated Via Tlr-2 Or Tlr-4 Receptors, Mosoka Papa Fallah, R. Lakshman Chelvarajan, Beth A. Garvy, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Age-associated defects in both B-lymphocytes and macrophages in elderly result in a reduction in the efficacy of vaccines to many Gram positive bacteria like Streptococcus pneumoniae. Splenic macrophages from aged mice have been shown to have a defect in production of pro-inflammatory cytokines (IL-6, IL-12, IL-1β, TNF-α) but exhibit increased production of IL-10 upon TLR4 ligation. Here we showed that aged macrophages demonstrate similar cytokine dysregulation phenotype upon stimulation with TLR2 ligands, or killed S. pneumoniae. We hypothesized that an age-associated increase in activity of phosphatidyl inositol 3-kinase (PI3K)-Akt signaling pathway may be playing a causal role in …

Myd88 Is Pivotal For Immune Recognition Of Citrobacter Koseri And Astrocyte Activation During Cns Infection., Shuliang Liu, Tammy Kielian

Journal Articles: Pathology and Microbiology

Citrobacter koseri (C. koseri) is a Gram-negative bacterium that can cause a highly aggressive form of neonatal meningitis, which often progresses to establish multi-focal brain abscesses. The roles of Toll-like receptor 4 (TLR4) and its signaling adaptor MyD88 during CNS C. koseri infection have not yet been examined, which is important since recent evidence indicates that innate immune responses are tailored towards specific pathogen classes. Here TLR4 WT (C3H/FeJ) and TLR4 mutant (C3H/HeJ) mice as well as MyD88 KO animals were infected intracerebrally with live C. koseri, resulting in meningitis and ventriculitis with accompanying brain abscess formation. MyD88 KO mice …

In Vitro Amplification Of Misfolded Prion Protein Using Lysate Of Cultured Cells, Charles E. Mays, Jihyun Yeom, Hae-Eun Kang, Jifeng Bian, Vadim Khaychuk, Younghwan Kim, Jason C Bartz, Glenn C Telling, Chongsuk Ryou

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Protein misfolding cyclic amplification (PMCA) recapitulates the prion protein (PrP) conversion process under cell-free conditions. PMCA was initially established with brain material and then with further simplified constituents such as partially purified and recombinant PrP. However, availability of brain material from some species or brain material from animals with certain mutations or polymorphisms within the PrP gene is often limited. Moreover, preparation of native PrP from mammalian cells and tissues, as well as recombinant PrP from bacterial cells, involves time-consuming purification steps. To establish a convenient and versatile PMCA procedure unrestricted to the availability of substrate sources, we attempted to …

Neuroinflammation Leads To Region-Dependent Alterations In Astrocyte Gap Junction Communication And Hemichannel Activity., Nikolay Karpuk, Maria Burkovetskaya, Teresa Fritz, Amanda Angle, Tammy Kielian

Journal Articles: Pathology and Microbiology

Inflammation attenuates gap junction (GJ) communication in cultured astrocytes. Here we used a well-characterized model of experimental brain abscess as a tool to query effects of the CNS inflammatory milieu on astrocyte GJ communication and electrophysiological properties. Whole-cell patch-clamp recordings were performed on green fluorescent protein (GFP)-positive astrocytes in acute brain slices from glial fibrillary acidic protein-GFP mice at 3 or 7 d after Staphylococcus aureus infection in the striatum. Astrocyte GJ communication was significantly attenuated in regions immediately surrounding the abscess margins and progressively increased to levels typical of uninfected brain with increasing distance from the abscess proper. Conversely, …

Association Between Chronic Liver And Colon Inflammation During The Development Of Murine Syngeneic Graft-Versus-Host Disease, Jason Anthony Brandon, Jacqueline Perez-Rodriguez, C. Darrell Jennings, Donald A. Cohen, Vishal J. Sindhava, Subbarao Bondada, Alan M. Kaplan, J. Scott Bryson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The murine model of cyclosporine A (CsA)-induced syngeneic graft-versus-host disease (SGVHD) is a bone marrow (BM) transplantation model that develops chronic colon inflammation identical to other murine models of CD4⁺ T cell-mediated colitis. Interestingly, SGVHD animals develop chronic liver lesions that are similar to the early peribiliary inflammatory stages of clinical chronic liver disease, which is frequently associated with inflammatory bowel disease (IBD). Therefore, studies were initiated to investigate the chronic liver inflammation that develops in the SGVHD model. To induce SGVHD, mice were lethally irradiated, reconstituted with syngeneic BM, and treated with CsA. All of the SGVHD animals …

Rabies Virus Infection Induces Type I Interferon Production In An Ips-1 Dependent Manner While Dendritic Cell Activation Relies On Ifnar Signaling., Elizabeth J Faul, Celestine N Wanjalla, Mehul S Suthar, Michael Gale, Christoph Wirblich, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

As with many viruses, rabies virus (RABV) infection induces type I interferon (IFN) production within the infected host cells. However, RABV has evolved mechanisms by which to inhibit IFN production in order to sustain infection. Here we show that RABV infection of dendritic cells (DC) induces potent type I IFN production and DC activation. Although DCs are infected by RABV, the viral replication is highly suppressed in DCs, rendering the infection non-productive. We exploited this finding in bone marrow derived DCs (BMDC) in order to differentiate which pattern recognition receptor(s) (PRR) is responsible for inducing type I IFN following infection …

Role Of Flgt In Anchoring The Flagellum Of Vibrio Cholerae, Raquel M. Martinez, Brooke A. Jude, Thomas J. Kirn, Karen Skorupski, Ronald K. Taylor

Dartmouth Scholarship

Flagellar motility has long been regarded as an important virulence factor. In Vibrio cholerae, the single polar flagellum is essential for motility as well as for proper attachment and colonization. In this study, we demonstrate that the novel flagellar protein FlgT is involved in anchoring the flagellum to the V. cholerae cell. A screen for novel colonization factors by use of TnphoA mutagenesis identified flgT. An in-frame deletion of flgT established that FlgT is required for attachment, colonization, and motility. Transmission electron microscopy revealed that while the flgT mutant is capable of assembling a phenotypically normal flagellum, …

Anomalous Constitutive Src Kinase Activity Promotes B Lymphoma Survival And Growth, Jiyuan Ke, R. Lakshman Chelvarajan, Vishal Sindhava, Darrell A. Robertson, Lazaros Lekakis, C. Darrell Jennings, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background: Previously we have shown that B cell receptor (BCR) expression and B cell receptor signaling pathways are important for the basal growth of B lymphoma cells. In particular we have shown that the activation of Syk, a non-src family protein tyrosine kinase and the mitogen activated protein kinases (MAPK), ERK and JNK that mediate BCR signals are required for the constitutive growth of B lymphoma cells. Since src family protein tyrosine kinases (SFKs) like Lyn are known to be needed for the phosphorylation of BCR co-receptors, Ig-alpha and Ig-beta, we hypothesized that one or more SFKs will be constitutively …

Gbdr Regulates Pseudomonas Aeruginosa Plch And Pchp Transcription In Response To Choline Catabolites, Matthew J. Wargo, Tiffany C. Ho, Maegan J. Gross, Laurie A. Whittaker, Deborah A. Hogan

Dartmouth Scholarship

Pseudomonas aeruginosa hemolytic phospholipase C, PlcH, can degrade phosphatidylcholine (PC) and sphingomyelin in eukaryotic cell membranes and extracellular PC in lung surfactant. Numerous studies implicate PlcH in P. aeruginosa virulence. The phosphorylcholine released by PlcH activity on phospholipids is hydrolyzed by a periplasmic phosphorylcholine phosphatase, PchP. Both plcH gene expression and PchP enzyme activity are positively regulated by phosphorylcholine degradation products, including glycine betaine. Here we report that the induction of plcH and pchP transcription by glycine betaine is mediated by GbdR, an AraC family transcription factor. Mutants that lack gbdR are unable to induce plcH and pchP in media …

Germinal Center Reutilization By Newly Activated B Cells., Tanja A Schwickert, Boris Alabyev, Tim Manser, Michel C Nussenzweig

Department of Microbiology and Immunology Faculty Papers

Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude …

Il-4(-/-) Mice With Lethal Mesocestoides Corti Infections--Reduced Th2 Cytokines And Alternatively Activated Macrophages., A. E. O'Connell, L. A. Kerepesi, G. L. Vandergrift, D. R. Herbert, T J. Van Winkle, D. C. Hooper, E J. Pearce, D. Abraham

Department of Microbiology and Immunology Faculty Papers

Protection against Mesocestoides corti, a cestode that invades vital organs, is dependent on the production of IL-4, as IL-4(-/-) mice were found to have higher parasite burdens when compared with wild-type mice. The goal of this study was to investigate the role of IL-4 in immunity to M. corti, focusing on the immunological profile and on potential mediators of pathology. IL-4(-/-) mice infected with M. corti showed 100% mortality by 32 days, whereas wild-type mice survived for approximately 1 year. Parasite burdens were significantly increased in the liver, peritoneal, and thoracic cavities of IL-4(-/-) mice, associated with impaired recruitment of …

Detection Of Sub-Clinical Cwd Infection In Conventional Test-Negative Deer Long After Oral Exposure To Urine And Feces From Cwd+ Deer, Nicholas J. Haley, Candace K. Mathiason, Mark D. Zabel, Glenn C. Telling, Edward A Hoover

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: Chronic wasting disease (CWD) of cervids is a prion disease distinguished by high levels of transmissibility, wherein bodily fluids and excretions are thought to play an important role. Using cervid bioassay and established CWD detection methods, we have previously identified infectious prions in saliva and blood but not urine or feces of CWD+ donors. More recently, we identified very low concentrations of CWD prions in urine of deer by cervid PrP transgenic (Tg[CerPrP]) mouse bioassay and serial protein misfolding cyclic amplification (sPMCA). This finding led us to examine further our initial cervid bioassay experiments using sPMCA.

OBJECTIVES: We sought …

Development Of A Mouse Monoclonal Antibody Cocktail For Post-Exposure Rabies Prophylaxis In Humans., Thomas Müller, Bernhard Dietzschold, Hildegund Ertl, Anthony R Fooks, Conrad Freuling, Christine Fehlner-Gardiner, Jeannette Kliemt, Francois X Meslin, Charles E Rupprecht, Noël Tordo, Alexander I Wanderler, Marie Paule Kieny

Department of Microbiology and Immunology Faculty Papers

As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used …

Characterization Of Two Outer Membrane Proteins, Flgo And Flgp, That Influence Vibrio Cholerae Motility, Raquel M. Martinez, Madushini N. Dharmasena, Thomas J. Kirn, Ronald K. Taylor

Dartmouth Scholarship

Vibrio cholerae is highly motile by the action of a single polar flagellum. The loss of motility reduces the infectivity of V. cholerae, demonstrating that motility is an important virulence factor. FlrC is the sigma-54-dependent positive regulator of flagellar genes. Recently, the genes VC2206 (flgP) and VC2207 (flgO) were identified as being regulated by FlrC via a microarray analysis of an flrC mutant (D. C. Morris, F. Peng, J. R. Barker, and K. E. Klose, J. Bacteriol. 190:231-239, 2008). FlgP is reported to be an outer membrane lipoprotein required for motility that functions as a colonization factor. The study reported …

Cd19 Signaling Is Impaired In Murine Peritoneal And Splenic B-1 B Lymphocytes, Trivikram Dasu, Vishal Sindhava, Stephen H. Clarke, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

B-1 cells reside predominantly within the coelomic cavities, tonsils, Peyer's patches, spleen (a minor fraction – ∼5%) and are absent in the lymph nodes. They are the primary sources of natural IgM in the body. B-1 cells express polyreactive B cell receptors (BCRs) that cross react with self-antigens and are thus implicated in auto-immune disorders. Previously, we reported that peritoneal B-1 cells are deficient in CD19-mediated intracellular signals leading to Ca²⁺ mobilization. Here, we find that splenic B-1 cells, like peritoneal B-1 cells, are defective in Ca²⁺ release upon B cell activation by co-cross-linking BCR and CD19. In …

Il-9 As A Mediator Of Th17-Driven Inflammatory Disease, Elizabeth C. Nowak, Casey T. Weaver, Henrietta Turner, Sakhina Begum-Haque, Burkhard Becher, Bettina Schreiner, Anthony J. Coyle, Lloyd H. Kasper, Randolph J. Noelle

Dartmouth Scholarship

We report that like other T cells cultured in the presence of transforming growth factor (TGF) beta, Th17 cells also produce interleukin (IL) 9. Th17 cells generated in vitro with IL-6 and TGF-beta as well as purified ex vivo Th17 cells both produced IL-9. To determine if IL-9 has functional consequences in Th17-mediated inflammatory disease, we evaluated the role of IL-9 in the development and progression of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. The data show that IL-9 neutralization and IL-9 receptor deficiency attenuates disease, and this correlates with decreases in Th17 cells and IL-6-producing macrophages in …

Detection Of Cwd Prions In Urine And Saliva Of Deer By Transgenic Mouse Bioassay, Nicholas J. Haley, Davis M. Seelig, Mark D. Zabel, Glenn C. Telling, Edward A. Hoover

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chronic wasting disease (CWD) is a prion disease affecting captive and free-ranging cervids (e.g. deer, elk, and moose). The mechanisms of CWD transmission are poorly understood, though bodily fluids are thought to play an important role. Here we report the presence of infectious prions in the urine and saliva of deer with chronic wasting disease (CWD). Prion infectivity was detected by bioassay of concentrated, dialyzed urine and saliva in transgenic mice expressing the cervid PrP gene (Tg[CerPrP] mice). In addition, PrP(CWD) was detected in pooled and concentrated urine by protein misfolding cyclic amplification (PMCA). The concentration of abnormal prion protein …

Accelerated High Fidelity Prion Amplification Within And Across Prion Species Barriers, Kristi M. Green, Joaquín Castilla, Tanya S. Seward, Dana L. Napier, Jean E. Jewell, Claudio Soto, Glenn C. Telling

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Experimental obstacles have impeded our ability to study prion transmission within and, more particularly, between species. Here, we used cervid prion protein expressed in brain extracts of transgenic mice, referred to as Tg(CerPrP), as a substrate for in vitro generation of chronic wasting disease (CWD) prions by protein misfolding cyclic amplification (PMCA). Characterization of this infectivity in Tg(CerPrP) mice demonstrated that serial PMCA resulted in the high fidelity amplification of CWD prions with apparently unaltered properties. Using similar methods to amplify mouse RML prions and characterize the resulting novel cervid prions, we show that serial PMCA abrogated a transmission barrier …

Cd5 Plays An Inhibitory Role In The Suppressive Function Of Murine Cd4(+) Cd25(+) T(Reg) Cells., Trivikram Dasu, Joseph E Qualls, Halide Tuna, Chander Raman, Donald A Cohen, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

A subset of CD4(+) T cells, the CD4(+) CD25(+) regulatory T (T(reg)) cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T(reg)) cells' and for activation of the effector function of CD4(+) CD25(+) regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator …

Cd5 Plays An Inhibitory Role In The Suppressive Function Of Murine Cd4+ Cd25+ TReg Cells, Trivikram Dasu, Joseph E. Qualls, Halide Tuna, Chander Raman, Donald A. Cohen, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

A subset of CD4⁺ T cells, the CD4⁺ CD25⁺ regulatory T (T_reg) cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such ‘natural regulatory (T_reg) cells’ and for activation of the effector function of CD4⁺ CD25⁺ regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, …

A Novel Inhibitory Mechanism Of Mitochondrion-Dependent Apoptosis By A Herpesviral Protein, Pinghui Feng, Chengyu Liang, Young C. Shin, Xiaofei E, Weijun Zhang, Robyn Gravel, Ting-Ting Wu, Ren Sun, Edward Usherwood, Jae U. Jung

Dartmouth Scholarship

Upon viral infection, cells undergo apoptosis as a defense against viral replication. Viruses, in turn, have evolved elaborate mechanisms to subvert apoptotic processes. Here, we report that a novel viral mitochondrial anti-apoptotic protein (vMAP) of murine gamma-herpesvirus 68 (gammaHV-68) interacts with Bcl-2 and voltage-dependent anion channel 1 (VDAC1) in a genetically separable manner. The N-terminal region of vMAP interacted with Bcl-2, and this interaction markedly increased not only Bcl-2 recruitment to mitochondria but also its avidity for BH3-only pro-apoptotic proteins, thereby suppressing Bax mitochondrial translocation and activation. In addition, the central and C-terminal hydrophobic regions of vMAP interacted with VDAC1. …

All-Trans Retinoic Acid Mediates Enhanced T Reg Cell Growth, Differentiation, And Gut Homing In The Face Of High Levels Of Co-Stimulation, Micah J. Benson, Karina Pino-Lagos, Mario Rosemblatt, Randolph J. Noelle

Dartmouth Scholarship

We demonstrate that all-trans retinoic acid (RA) induces FoxP3(+) adaptive T regulatory cells (A-Tregs) to acquire a gut-homing phenotype (alpha 4 beta 7(+) CC chemokine receptor 9(+)) and the capacity to home to the lamina propria of the small intestine. Under conditions that favor the differentiation of A-Tregs (transforming growth factor-beta1 and interleukin 2) in vitro, the inclusion of RA induces nearly all activated CD4(+) T cells to express FoxP3 and greatly increases the accumulation of these cells. In the absence of RA, A-Treg differentiation is abruptly impaired by proficient antigen presenting cells or through direct co-stimulation. In the presence …

Phenotypic Alterations In Type Ii Alveolar Epithelial Cells In Cd4+ T Cell Mediated Lung Inflammation, Marcus Gereke, Lothar Gröbe, Silvia Prettin, Michael Kasper, Stefanie Deppenmeier, Achim D. Gruber, Richard I. Enelow, Jan Buer, Dunja Bruder

Dartmouth Scholarship

Although the contribution of alveolar type II epithelial cell (AEC II) activities in various aspects of respiratory immune regulation has become increasingly appreciated, our understanding of the contribution of AEC II transcriptosome in immunopathologic lung injury remains poorly understood. We have previously established a mouse model for chronic T cell-mediated pulmonary inflammation in which influenza hemagglutinin (HA) is expressed as a transgene in AEC II, in mice expressing a transgenic T cell receptor specific for a class II-restricted epitope of HA. Pulmonary inflammation in these mice occurs as a result of CD4+ T cell recognition of alveolar antigen. This model …

The Flagellum Of Pseudomonas Aeruginosa Is Required For Resistance To Clearance By Surfactant Protein A, Shiping Zhang, Francis X. Mccormack, Roger C. Levesque, George A. O'Toole, Gee W. Lau

Dartmouth Scholarship

Surfactant protein A (SP-A) is an important lung innate immune protein that kills microbial pathogens by opsonization and membrane permeabilization. We investigated the basis of SP-A-mediated pulmonary clearance of Pseudomonas aeruginosa using genetically-engineered SP-A mice and a library of signature-tagged P. aeruginosa mutants. A mutant with an insertion into flgE, the gene that encodes flagellar hook protein, was preferentially cleared by the SP-A(+/+) mice, but survived in the SP-A(-/-) mice. Opsonization by SP-A did not play a role in flgE clearance. However, exposure to SP-A directly permeabilized and killed the flgE mutant, but not the wild-type parental strain. P. aeruginosa …