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Articles 1 - 18 of 18
Full-Text Articles in Medicine and Health Sciences
The Vibrio Cholerae Minor Pilin Tcpb Initiates Assembly And Retraction Of The Toxin-Coregulated Pilus, Dixon Ng, Tony Harn, Tuba Altindal, Subramania Kolappan, Jarrad Marles, Rajan Lala, Ingrid Spielman, Yang Gao, Caitlyn Hauke, Gabriela Kovacikova
The Vibrio Cholerae Minor Pilin Tcpb Initiates Assembly And Retraction Of The Toxin-Coregulated Pilus, Dixon Ng, Tony Harn, Tuba Altindal, Subramania Kolappan, Jarrad Marles, Rajan Lala, Ingrid Spielman, Yang Gao, Caitlyn Hauke, Gabriela Kovacikova
Dartmouth Scholarship
Type IV pilus (T4P) systems are complex molecular machines that polymerize major pilin proteins into thin filaments displayed on bacterial surfaces. Pilus functions require rapid extension and depolymerization of the pilus, powered by the assembly and retraction ATPases, respectively. A set of low abundance minor pilins influences pilus dynamics by unknown mechanisms. The Vibrio cholerae toxin-coregulated pilus (TCP) is among the simplest of the T4P systems, having a single minor pilin TcpB and lacking a retraction ATPase. Here we show that TcpB, like its homolog CofB, initiates pilus assembly. TcpB co-localizes with the pili but at extremely low levels, equivalent …
Global Role Of Cyclic Amp Signaling In Ph-Dependent Responses In Candida Albicans, Jeffrey M. Hollomon, Nora Grahl, Sven D. Willger, Katja Koeppen, Deborah A. Hogan
Global Role Of Cyclic Amp Signaling In Ph-Dependent Responses In Candida Albicans, Jeffrey M. Hollomon, Nora Grahl, Sven D. Willger, Katja Koeppen, Deborah A. Hogan
Dartmouth Scholarship
Candida albicans behaviors are affected by pH, an important environmental variable. Filamentous growth is a pH-responsive behavior, where alkaline conditions favor hyphal growth and acid conditions favor growth as yeast. We employed filamentous growth as a tool to study the impact of pH on the hyphal growth regulator Cyr1, and we report that downregulation of cyclic AMP (cAMP) signaling by acidic pH contributes to the inhibition of hyphal growth in minimal medium with GlcNAc. Ras1 and Cyr1 are generally required for efficient hyphal growth, and the effects of low pH on Ras1 proteolysis and GTP binding are consistent with diminished …
Signaling Through Lrg1, Rho1 And Pkc1 Governs Candida Albicans Morphogenesis In Response To Diverse Cues, Jinglin L. Xie, Nora Grahl, Trevor Sless, Michelle Leach, Sang Hu Kim, Deborah Hogan
Signaling Through Lrg1, Rho1 And Pkc1 Governs Candida Albicans Morphogenesis In Response To Diverse Cues, Jinglin L. Xie, Nora Grahl, Trevor Sless, Michelle Leach, Sang Hu Kim, Deborah Hogan
Dartmouth Scholarship
The capacity to transition between distinct morphological forms is a key virulence trait for diverse fungal pathogens. A poignant example of a leading opportunistic fungal pathogen of humans for which an environmentally responsive developmental program underpins virulence is Candida albicans. C. albicans mutants that are defective in the transition between yeast and filamentous forms typically have reduced virulence. Although many positive regulators of C. albicans filamentation have been defined, there are fewer negative regulators that have been implicated in repression of filamentation in the absence of inducing cues. To discover novel negative regulators of filamentation, we screened …
Immune- And Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants Of Herpes Simplex Virus-Induced Generalized Infections And Acute Liver Failure, Zachary M. Parker, Tracy Jo Pasieka, George A. Parker, David A. Leib
Immune- And Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants Of Herpes Simplex Virus-Induced Generalized Infections And Acute Liver Failure, Zachary M. Parker, Tracy Jo Pasieka, George A. Parker, David A. Leib
Dartmouth Scholarship
The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN-αβγR-/- mice are exquisitely susceptible to liver infection following corneal infection with HSV-1. In this study, we used bone marrow chimeras of IFN-αβγR-/- (AG129) and wild-type (WT; 129SvEv) mice …
Heterogeneity Among Isolates Reveals That Fitness In Low Oxygen Correlates With Aspergillus Fumigatus Virulence, Caitlin H. Kowalski, Sarah R. Beattie, Kevin K. Fuller, Elizabeth A. Mcgurk, Yi-Wei Tang, Tobias Hohl, Joshua Obar, Robert Cramer Jr.
Heterogeneity Among Isolates Reveals That Fitness In Low Oxygen Correlates With Aspergillus Fumigatus Virulence, Caitlin H. Kowalski, Sarah R. Beattie, Kevin K. Fuller, Elizabeth A. Mcgurk, Yi-Wei Tang, Tobias Hohl, Joshua Obar, Robert Cramer Jr.
Dartmouth Scholarship
Previous work has shown that environmental and clinical isolates of Aspergillus fumigatus represent a diverse population that occupies a variety of niches, has extensive genetic diversity, and exhibits virulence heterogeneity in a number of animal models of invasive pulmonary aspergillosis (IPA). However, mechanisms explaining differences in virulence among A. fumigatus isolates remain enigmatic. Here, we report a significant difference in virulence of two common lab strains, CEA10 and AF293, in the murine triamcinolone immunosuppression model of IPA, in which we previously identified severe low oxygen microenvironments surrounding fungal lesions. Therefore, we hypothesize that the ability to thrive within these lesions …
Requirements For Pseudomonas Aeruginosa Type I-F Crispr-Cas Adaptation Determined Using A Biofilm Enrichment Assay, Gary E. Heussler, Jon L. Miller, Courtney E. Price, Alan J. Collins
Requirements For Pseudomonas Aeruginosa Type I-F Crispr-Cas Adaptation Determined Using A Biofilm Enrichment Assay, Gary E. Heussler, Jon L. Miller, Courtney E. Price, Alan J. Collins
Dartmouth Scholarship
CRISPR (clustered regularly interspaced short palindromic repeat)-Cas (CRISPR-associated protein) systems are diverse and found in many archaea and bacteria. These systems have mainly been characterized as adaptive immune systems able to protect against invading mobile genetic elements, including viruses. The first step in this protection is acquisition of spacer sequences from the invader DNA and incorporation of those sequences into the CRISPR array, termed CRISPR adaptation. Progress in understanding the mechanisms and requirements of CRISPR adaptation has largely been accomplished using overexpression of cas genes or plasmid loss assays; little work has focused on endogenous CRISPR-acquired immunity from viral predation. …
Effects Of Tcpb Mutations On Biogenesis And Function Of The Toxin-Coregulated Pilus, The Type Ivb Pilus Of Vibrio Cholerae, Yang Gao, Caitlyn A. Hauke, Jarrad M. Marles, Ronald K. Taylor
Effects Of Tcpb Mutations On Biogenesis And Function Of The Toxin-Coregulated Pilus, The Type Ivb Pilus Of Vibrio Cholerae, Yang Gao, Caitlyn A. Hauke, Jarrad M. Marles, Ronald K. Taylor
Dartmouth Scholarship
Vibrio cholerae is the etiological agent of the acute intestinal disorder cholera. The toxin-coregulated pilus (TCP), a type IVb pilus, is an essential virulence factor of V. cholerae. Recent work has shown TcpB is a large minor pilin encoded within the tcp operon. TcpB contributes to efficient pilus formation and is essential for all TCP functions. Here we have initiated a detailed, targeted mutagenesis approach to further characterize this salient TCP component. We have identified (thus far) 20 residues of TcpB, which affect either the steady state level of TcpB or alter one or more TCP functions. This study …
Microrna Mir-155 Is Necessary For Efficient Gammaherpesvirus Reactivation From Latency, But Not For Establishment Of Latency, Rebecca L. Crepeau, Peisheng Zhang, Edward J. Usherwood
Microrna Mir-155 Is Necessary For Efficient Gammaherpesvirus Reactivation From Latency, But Not For Establishment Of Latency, Rebecca L. Crepeau, Peisheng Zhang, Edward J. Usherwood
Dartmouth Scholarship
MicroRNA-155 (miR-155) has been shown to play significant roles in the immune response, including in the formation of germinal centers (GC) and the development and maturation of T follicular helper (Tfh) cells. There is in vitro evidence to support a critical role for cellular miR-155 and viral miR-155 homologs in the establishment of gammaherpesvirus latency in B cells. We sought to determine the contribution of miR-155 to the establishment and maintenance of latency in vivousing murine gammaherpesvirus (MHV-68) infection. MHV-68-infected mice deficient in miR-155 exhibited decreases in GC B cells and Tfh cells. However, the frequencies of spleen cells …
Cyclic Di-Gmp-Regulated Periplasmic Proteolysis Of A Pseudomonas Aeruginosa Type Vb Secretion System Substrate, Richard B. Cooley, T. Jarrod Smith, Wilfred Leung, Valerie Tierney, Bradley Borlee, George A. O'Toole, Holger Sondermann
Cyclic Di-Gmp-Regulated Periplasmic Proteolysis Of A Pseudomonas Aeruginosa Type Vb Secretion System Substrate, Richard B. Cooley, T. Jarrod Smith, Wilfred Leung, Valerie Tierney, Bradley Borlee, George A. O'Toole, Holger Sondermann
Dartmouth Scholarship
We previously identified a second-messenger-regulated signaling system in the environmental bacterium Pseudomonas fluorescens which controls biofilm formation in response to levels of environmental inorganic phosphate. This system contains the transmembrane cyclic di-GMP (c-di-GMP) receptor LapD and the periplasmic protease LapG. LapD regulates LapG and controls the ability of this protease to process a large cell surface adhesin protein, LapA. While LapDG orthologs can be identified in diverse
The Pseudomonas Aeruginosa Efflux Pump Mexghi-Opmd Transports A Natural Phenazine That Controls Gene Expression And Biofilm Development, Hassan Sakhtah, Leslie Koyama, Yihan Zhang, Diana K. Morales, Blanche Fields, Alexa Price-Whelan, Deborah Hogan
The Pseudomonas Aeruginosa Efflux Pump Mexghi-Opmd Transports A Natural Phenazine That Controls Gene Expression And Biofilm Development, Hassan Sakhtah, Leslie Koyama, Yihan Zhang, Diana K. Morales, Blanche Fields, Alexa Price-Whelan, Deborah Hogan
Dartmouth Scholarship
Redox-cycling compounds, including endogenously produced phenazine antibiotics, induce expression of the efflux pump MexGHI-OpmD in the opportunistic pathogen Pseudomonas aeruginosa Previous studies of P. aeruginosa virulence, physiology, and biofilm development have focused on the blue phenazine pyocyanin and the yellow phenazine-1-carboxylic acid (PCA). In P. aeruginosa phenazine biosynthesis, conversion of PCA to pyocyanin is presumed to proceed through the intermediate 5-methylphenazine-1-carboxylate (5-Me-PCA), a reactive compound that has eluded detection in most laboratory samples. Here, we apply electrochemical methods to directly detect 5-Me-PCA and find that it is transported by MexGHI-OpmD in P. aeruginosa strain PA14 planktonic and biofilm cells. We …
Signaling In Effector Lymphocytes: Insights Toward Safer Immunotherapy, Kamalakannan Rajasekaran, Matthew J. Riese, Sridhar Rao, Li Wang, Monica Thakar, Charles Sentman, Subramaniam Malarkannan
Signaling In Effector Lymphocytes: Insights Toward Safer Immunotherapy, Kamalakannan Rajasekaran, Matthew J. Riese, Sridhar Rao, Li Wang, Monica Thakar, Charles Sentman, Subramaniam Malarkannan
Dartmouth Scholarship
Receptors on T and NK cells systematically propagate highly complex signaling cascades that direct immune effector functions, leading to protective immunity. While extensive studies have delineated hundreds of signaling events that take place upon receptor engagement, the precise molecular mechanism that differentially regulates the induction or repression of a unique effector function is yet to be fully defined. Such knowledge can potentiate the tailoring of signal transductions and transform cancer immunotherapies. Targeted manipulations of signaling cascades can augment one effector function such as antitumor cytotoxicity while contain the overt generation of pro-inflammatory cytokines that contribute to treatment-related toxicity such as …
Friendly Fire: Biological Functions And Consequences Of Chromosomal Targeting By Crispr-Cas Systems, Gary E. Heussler, George A. O'Toole
Friendly Fire: Biological Functions And Consequences Of Chromosomal Targeting By Crispr-Cas Systems, Gary E. Heussler, George A. O'Toole
Dartmouth Scholarship
Clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) systems in bacteria and archaea target foreign elements, such as bacteriophages and conjugative plasmids, through the incorporation of short sequences (termed spacers) from the foreign element into the CRISPR array, thereby allowing sequence-specific targeting of the invader. Thus, CRISPR-Cas systems are typically considered a microbial adaptive immune system. While many of these incorporated spacers match targets on bacteriophages and plasmids, a noticeable number are derived from chromosomal DNA. While usually lethal to the self-targeting bacteria, in certain circumstances, these self-targeting spacers can have profound effects in regard to microbial biology, including functions …
Pilz Domain Protein Flgz Mediates Cyclic Di-Gmp-Dependent Swarming Motility Control In Pseudomonas Aeruginosa, Amy Baker, Andreas Diepold, Sherry Kuchma, Jessie Scott, Dae Gon Ha, Giulia Orazi, Judith Armitage, George A. O'Toole
Pilz Domain Protein Flgz Mediates Cyclic Di-Gmp-Dependent Swarming Motility Control In Pseudomonas Aeruginosa, Amy Baker, Andreas Diepold, Sherry Kuchma, Jessie Scott, Dae Gon Ha, Giulia Orazi, Judith Armitage, George A. O'Toole
Dartmouth Scholarship
The second messenger cyclic diguanylate (c-di-GMP) is an important regulator of motility in many bacterial species. In Pseudomonas aeruginosa, elevated levels of c-di-GMP promote biofilm formation and repress flagellum-driven swarming motility. The rotation of P. aeruginosa's polar flagellum is controlled by two distinct stator complexes, MotAB, which cannot support swarming motility, and MotCD, which promotes swarming motility. Here we show that when c-di-GMP levels are elevated, swarming motility is repressed by the PilZ domain-containing protein FlgZ and by Pel polysaccharide production. We demonstrate that FlgZ interacts specifically with the motility-promoting stator protein MotC in a c-di-GMP-dependent manner and that a …
The Inhibitory Site Of A Diguanylate Cyclase Is A Necessary Element For Interaction And Signaling With An Effector Protein, Kurt M. Dahlstrom, Krista M. Giglio, Holger Sondermann, George A. O'Toole
The Inhibitory Site Of A Diguanylate Cyclase Is A Necessary Element For Interaction And Signaling With An Effector Protein, Kurt M. Dahlstrom, Krista M. Giglio, Holger Sondermann, George A. O'Toole
Dartmouth Scholarship
Many bacteria contain large cyclic diguanylate (c-di-GMP) signaling networks made of diguanylate cyclases (DGCs) and phosphodiesterases that can direct cellular activities sensitive to c-di-GMP levels. While DGCs synthesize c-di-GMP, many DGCs also contain an autoinhibitory site (I-site) that binds c-di-GMP to halt excess production of this small molecule, thus controlling the amount of c-di-GMP available to bind to target proteins in the cell. Many DGCs studied to date have also been found to signal for a specific c-di-GMP-related process, and although recent studies have suggested that physical interaction between DGCs and target proteins may provide this signaling fidelity, the importance …
Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib
Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib
Dartmouth Scholarship
Herpes simplex virus 1 (HSV-1) establishes lifelong infection in the neurons of trigeminal ganglia (TG), cycling between productive infection and latency. Neuronal antiviral responses are driven by type I interferon (IFN) and are crucial to controlling HSV-1 virulence. Autophagy also plays a role in this neuronal antiviral response, but the mechanism remains obscure. In this study, HSV-1 infection of murine TG neurons triggered unusual clusters of autophagosomes, predominantly in neurons lacking detectable HSV-1 antigen. Treatment of neurons with IFN-β induced a similar response, and cluster formation by infection or IFN treatment was dependent upon an intact IFN-signaling pathway. The autophagic …
The Gras Sensor In Staphylococcus Aureus Mediates Resistance To Host Defense Peptides Differing In Mechanisms Of Action, Siyang Chaili, Ambrose L. L. Cheung, Arnold S. Bayer, Yan Q. Xiong, Alan Waring, Guido Memmi, Niles Donegan
The Gras Sensor In Staphylococcus Aureus Mediates Resistance To Host Defense Peptides Differing In Mechanisms Of Action, Siyang Chaili, Ambrose L. L. Cheung, Arnold S. Bayer, Yan Q. Xiong, Alan Waring, Guido Memmi, Niles Donegan
Dartmouth Scholarship
Staphylococcus aureus uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (ΔgraS) or its EL (ΔEL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil α-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous β-defensin (human β-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). …
The 40-Residue Insertion In Vibrio Cholerae Fadr Facilitates Binding Of An Additional Fatty Acyl-Coa Ligand, Wei Shi, Gabriela Kovacikova, Wei Lin, Ronald. K. Taylor, Karen Skorupski, F. Jon Kull
The 40-Residue Insertion In Vibrio Cholerae Fadr Facilitates Binding Of An Additional Fatty Acyl-Coa Ligand, Wei Shi, Gabriela Kovacikova, Wei Lin, Ronald. K. Taylor, Karen Skorupski, F. Jon Kull
Dartmouth Scholarship
FadR is a master regulator of fatty acid metabolism and influences virulence in certain members of Vibrionaceae. Among FadR homologues of the GntR family, the Vibrionaceae protein is unusual in that it contains a C-terminal 40-residue insertion. Here we report the structure of Vibrio cholerae FadR (VcFadR) alone, bound to DNA, and in the presence of a ligand, oleoyl-CoA. Whereas Escherichia coli FadR (EcFadR) contains only one acyl-CoA-binding site in each monomer, crystallographic and calorimetric data indicate that VcFadR has two. One of the binding sites resembles that of EcFadR, whereas the other, comprised residues from the insertion, has not …
Characterization Of Rna Helicase Csha And Its Role In Protecting Mrnas And Small Rnas Of Staphylococcus Aureus Strain Newman, Samin Kim, Anna-Rita Corvaglia, Stefano Léo, Ambrose Cheung, Patrice Francois
Characterization Of Rna Helicase Csha And Its Role In Protecting Mrnas And Small Rnas Of Staphylococcus Aureus Strain Newman, Samin Kim, Anna-Rita Corvaglia, Stefano Léo, Ambrose Cheung, Patrice Francois
Dartmouth Scholarship
The toxin MazFsa in Staphylococcus aureus is a sequence-specific endoribonuclease that cleaves the majority of the mRNAs in vivo but spares many essential mRNAs (e.g., secY mRNA) and, surprisingly, an mRNA encoding a regulatory protein (i.e., sarA mRNA). We hypothesize that some mRNAs may be protected by RNA-binding protein(s) from degradation by MazFsa. Using heparin-Sepharose-enriched fractions that hybridized to sarA mRNA on Northwestern blots, we identified among multiple proteins the DEAD box RNA helicase CshA (NWMN_1985 or SA1885) by mass spectroscopy. Purified CshA exhibits typical RNA helicase activities, as exemplified by RNA-dependent ATPase activity and unwinding of …