Digital Commons Network^™

Pyrimidine Pathway-Dependent And -Independent Functions Of The Toxoplasma Gondii Mitochondrial Dihydroorotate Dehydrogenase, Miryam Andrea Hortua Triana, Daniela Cajiao Herrera, Barbara H. Zimmermann, Barbara A. Fox, David Bzik

Dartmouth Scholarship

Dihydroorotate dehydrogenase (DHODH) mediates the fourth step of de novo pyrimidine biosynthesis and is a proven drug target for inducing immunosuppression in therapy of human disease as well as a rapidly emerging drug target for treatment of malaria. In Toxoplasma gondii, disruption of the first, fifth, or sixth step of de novo pyrimidine biosynthesis induced uracil aux- otrophy. However, previous attempts to generate uracil auxotrophy by genetically deleting the mitochondrion-associated DHODH of T. gondii (Tg DHODH) failed. To further address the essentiality of Tg DHODH, mutant gene alleles deficient in Tg DHODH activity were designed to ablate the enzyme activity. …

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.

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

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. …

Incidence And Duration Of Type-Specific Human Papillomavirus Infection In High-Risk Hpv-Naïve Women: Results From The Control Arm Of A Phase Ii Hpv-16/18 Vaccine Trial, Agnihotram V. Ramanakumar, Paulo Naud, Cecilia M. Roteli-Martins, Newton S. De Carvalho, Paola C. De Borba, Julio C. Teixeira, Mark Blatter, Anna-Barbara Moscicki, Diane M. Harper, Barbara Romanowski, Stephen K. Tyring, Brian Ramjattan, Anne Schuind, Gary Dubin, Eduardo L. Franco

Dartmouth Scholarship

OBJECTIVES:

Persistence of human papillomaviruses (HPVs) is necessary for cervical carcinogenesis. We evaluated incidence and duration of type-specific HPV infections and the influence of age and number of sexual partners.

METHODS:

Data were obtained from 553 women (15-25 years), who were seronegative and DNA-negative for high-risk HPV (HR-HPV) types and were enrolled in the placebo arm of a randomised trial of the HPV-16/18 vaccine (NCT00689741/NCT00120848). They were followed for 6.3 years. Cervicovaginal samples were self-collected at 3-month intervals for up to 27 months, and cervical samples were collected by clinicians at 6-month intervals until study end. …

Building From The Hiv Response Toward Universal Health Coverage, Jonathon Jay, Kent Buse, Marielle Hart, Robert Marten, Scott Kellerman, Morolake Odetoyinbo, Jonathan D. Quick, Timothy Evans, Peter Piot, Mark Dybul, Agnes Binagwaho

Dartmouth Scholarship

Universal health coverage (UHC) has gained prominence as a global health priority. The UHC movement aims to increase access to quality, needed health services while reducing financial hardship from health spending, particularly in low- and middle- income countries.
As a policy agenda, UHC has been identified primarily with prepayment and risk-pool- ing programs. While financing policies provide important benefits, increasing access to health services will require broader reforms.
For lessons, the UHC movement should look to the global HIV response, which has confronted many of the same barriers to access in weak health systems. Considerable success on HIV has resulted …

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 …

Artificial Intelligence And Amikacin Exposures Predictive Of Outcomes In Multidrug-Resistant Tuberculosis Patients, Chawangwa Modongo, Jotam G. Pasipanodya, Shashikant Srivastava, Nicola Zetola, Scott Williams, Giorgio Sirugo, Tawanda Gumbo

Dartmouth Scholarship

Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR- TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0 –24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) pa- tients had sputum culture conversion during …

Ethics In Community-Based Research With Vulnerable Children: Perspectives From Rwanda, Theresa Betancourt, Mary C. Smith Fawzi, Anne Stevenson, Fredrick Kanyanganzi, Catherine Kirk, Lauren Ng, Christina Mushashi, Justin I. Bizimana, William Beardslee, Guiseppe Raviola, Stephanie Smith, Yvonne Kayiteshonga, Agnes Binagwaho

Dartmouth Scholarship

A “risk of harm” protocol to identify youth in need of immediate emergency assistance in a study on mental health and HIV in Rwanda among 680 youth ages 10–17 is described. Cases are presented that describe the experience in using this protocol to ensure safety of participants, with ethical and logistical challenges considered. Among the population of the study, 3.2% were deemed "risk of harm.” The most prevalent presenting problem was non-fatal suicidal behavior (91% of risk of harm cases), with 36% having a history of a reported previous attempt. Challenges included: acute food insecurity/significant poverty; lack of support/adequate supervision …

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

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 …

Human Papillomavirus Infection In Rwanda At The Moment Of Implementation Of A National Hpv Vaccination Programme, Fidele Ngabo, Silvia Franceschi, Iacopo Baussano, M. Chantal Umulisa, Peter Snijders, Anne Uyterlinde, Fulvio Lazzarato, Vanessa Tenet, Maurice Gatera, Agnes Binagwaho, Gary Clifford

Dartmouth Scholarship

Cervical cancer is the most common female cancer in Rwanda that, in 2011, became the first African country to implement a national vaccination programme against human papillomavirus (HPV). To provide a robust baseline for future evaluations of vaccine effectiveness, cervical cell specimens were obtained from 2508 women aged 18–69 years from the general population in Kigali, Rwanda, during 2013/14. 20 % of women were HIV-positive. Samples were used for liquid-based cytology and HPV testing (44 types) with GP5+/6+ PC.

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

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 …

Horizontal Gene Acquisitions, Mobile Element Proliferation, And Genome Decay In The Host-Restricted Plant Pathogen Erwinia Tracheiphila, Lori R. Shapiro, Erin D. Scully, Timothy J. Straub, Jihye Park, Andrew G. Stephenson, Gwyn A. Beattie, Mark L. Gleason, Roberto Kolter, Miguel C. Coelho, Consuelo M. De Moraes, Mark C. Mescher, Olga Zhaxybayeva

Dartmouth Scholarship

Modern industrial agriculture depends on high-density cultivation of genetically similar crop plants, creating favorable conditions for the emergence of novel pathogens with increased fitness in managed compared with ecologically intact settings. Here, we present the genome sequence of six strains of the cucurbit bacterial wilt pathogen Erwinia tracheiphila (Enterobacteriaceae) isolated from infected squash plants in New York, Pennsylvania, Kentucky, and Michigan. These genomes exhibit a high proportion of recent horizontal gene acquisitions, invasion and remarkable amplification of mobile genetic elements, and pseudogenization of approximately 20% of the coding sequences. These genome attributes indicate that E. tracheiphila recently emerged as a …

Expression Of Complement And Toll-Like Receptor Pathway Genes Is Associated With Malaria Severity In Mali: A Pilot Case Control Study, Rafal S. Sobota, Antoine Dara, Jessica E. Manning, Amadou Niangaly

Dartmouth Scholarship

Background: The host response to infection by Plasmodium falciparum, the parasite most often responsible for severe malaria, ranges from asymptomatic parasitaemia to death. The clinical trajectory of malaria is influenced by host genetics and parasite load, but the factors determining why some infections produce uncomplicated malaria and some proceed to severe disease remain incompletely understood.

Methods: To identify molecular markers of severe falciparum malaria, human gene expression patterns were compared between children aged 6 months to 5 years with severe and uncomplicated malaria who were enrolled in a case–control study in Bandiagara, Mali. Microarrays were used to obtain expression …

Rbdb, A Rhomboid Protease Critical For Srebp Activation And Virulence In Aspergillus Fumigatus, Sourabh Dhingra, Caitlin H. Kowlaski, Arsa Thammahong, Sarah R. Beattie, Katherine M. Bultman, Robert A. Cramer

Dartmouth Scholarship

SREBP transcription factors play a critical role in fungal virulence; however, the mechanisms of sterol regulatory element binding protein (SREBP) activation in pathogenic fungi remains ill-defined. Screening of the Neurospora crassa whole-genome deletion collection for genes involved in hypoxia responses identified a gene for an uncharacterized rhomboid protease homolog, rbdB, required for growth under hypoxic conditions. Loss of rbdB in Aspergillus fumigatus also inhibited growth under hypoxic conditions. In addition, the A. fumigatus ΔrbdB strain also displayed phenotypes consistent with defective SREBP activity, including increased azole drug susceptibility, reduced siderophore production, and full loss of virulence. Expression of …

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 Economic Burden Attributable To A Child’S Inpatient Admission For Diarrheal Disease In Rwanda, Fidele Ngabo, Mercy Mvundura, Lauren Gazley, Maurice Gatera, Celse Rugambwa, Eugene Kayonga, Yvette Tuyishme, Jeanne Niyibaho, Jason M. Mwenda, Philippe Donnen, Philippe Lepage, Agnes Binagwaho, Deborah Atherly

Dartmouth Scholarship

Backround:

Diarrhea is one of the leading causes of childhood morbidity and mortality. Hospitalization for diarrhea can pose a significant burden to health systems and households. The objective of this study was to estimate the economic burden attributable to hospitalization for diarrhea among children less than five years old in Rwanda. These data can be used by decision-makers to assess the impact of interventions that reduce diarrhea morbidity, including rotavirus vaccine introduction.

Methods:

This was a prospective costing study where medical records and hospital bills for children admitted with diarrhea at three hospitals were collected to estimate resource use and …

Identification Of Medicare Recipients At Highest Risk For Clostridium Difficile Infection In The Us By Population Attributable Risk Analysis, Erik R. Dubberke, Margaret A. Olsen, Dustin Stwalley, Ciarán P. Kelly, Dale N. Gerding, Yinong Young-Xu, Cedric Mahé

Dartmouth Scholarship

Background: Population attributable risk percent (PAR%) is an epidemiological tool that provides an estimate of the percent reduction in total disease burden if that disease could be entirely eliminated among a subpopulation. As such, PAR% is used to efficiently target prevention interventions. Due to significant limitations in current Clostridium difficile Infection (CDI) prevention practices and the development of new approaches to prevent CDI, such as vaccina- tion, we determined the PAR% for CDI in various subpopulations in the Medicare 5% random sample. Methods: This was a retrospective cohort study using the 2009 Medicare 5% random sample. Comorbidities, infections, and healthcare …

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). …

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 MazF_sa 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 MazF_sa. 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 …

Patterns Of Human Herpesvirus-8 Oral Shedding Among Diverse Cohorts Of Human Herpesvirus-8 Seropositive Persons, Rachel A. Bender Ignacio, Jason D. Goldman, Amalia S. Magaret, Stacy Selke, Meei-Li Huang, Soren Gantt, Christine Johnston, Warren Phipps, Joshua Schiffer, Richard Zuckerman

Dartmouth Scholarship

Human herpesvirus-8 (HHV-8), the etiologic agent of Kaposi sarcoma (KS), establishes lifelong latent infection with periodic lytic replication (“shedding”) at mucosal sites, especially the oropharynx. Patterns of HHV-8 shedding are not well understood, and require elucidation to better predict risk of HHV-8 related malignancies in those infected. We sought to characterize patterns of HHV-8 oropharyngeal shedding among diverse cohorts that enrolled HHV-8 seropositive persons.

Characterization Of The Paracoccidioides Hypoxia Response Reveals New Insights Into Pathogenesis Mechanisms Of This Important Human Pathogenic Fungus, Patrícia De Sousa Lima, Dawoon Chung, Alexandre Melo Bailão, Robert A. Cramer, Célia Maria De Almeida Soares

Dartmouth Scholarship

Background: Hypoxic microenvironments are generated during fungal infection. It has been described that to survive in the human host, fungi must also tolerate and overcome in vivo microenvironmental stress conditions including low oxygen tension; however nothing is known how Paracoccidioides species respond to hypoxia. The genus Paracoccidioides comprises human thermal dimorphic fungi and are causative agents of paracoccidioidomycosis (PCM), an important mycosis in Latin America.

A Forward Genetic Screen Reveals Novel Independent Regulators Of Ulbp1, An Activating Ligand For Natural Killer Cells, Benjamin G Gowen, Bryan Chim, Caleb D. Marceau, Trever T Greene, Patrick Burr, Jeanmarie R. Gonzalez, Charles Hesser, Peter A. Dietzen, Teal Russell, Alexandre Iannello, Laurent Coscoy, Charles L. Sentman

Dartmouth Scholarship

Recognition and elimination of tumor cells by the immune system is crucial for limiting tumor growth. Natural killer (NK) cells become activated when the receptor NKG2D is engaged by ligands that are frequently upregulated in primary tumors and on cancer cell lines. However, the molecular mechanisms driving NKG2D ligand expression on tumor cells are not well defined. Using a forward genetic screen in a tumor-derived human cell line, we identified several novel factors supporting expression of the NKG2D ligand ULBP1. Our results show stepwise contributions of independent pathways working at multiple stages of ULBP1 biogenesis. Deeper investigation of selected hits …

Pleiotropic Effects Of Immune Responses Explain Variation In The Prevalence Of Fibroproliferative Diseases, Shirley B. Russell, Joan C. Smith, Minjun Huang, Joel S. Trupin, Scott M. Williams

Dartmouth Scholarship

Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to …

Dendritic Cell Autophagy Contributes To Herpes Simplex Virus-Driven Stromal Keratitis And Immunopathology, Yike Jiang, Xiaotang Yin, Patrick M. Stuart, David A. Leib

Dartmouth Scholarship

Herpetic stromal keratitis (HSK) is a blinding ocular disease that is initiated by HSV-1 and characterized by chronic inflammation in the cornea. Although HSK immunopathology of the cornea is well documented in animal models, events preceding this abnormal inflammatory cascade are poorly understood. In this study, we have examined the activation of pathological CD4T cells in the development of HSK. Dendritic cell autophagy (DC-autophagy) is an important pathway regulating ma- jor histocompatibility complex class II (MHCII)-dependent antigen presentation and proper CD4T cell activation during infectious diseases. Using DC-autophagy-deficient mice, we found that DC-autophagy significantly and specifically contributes to HSK disease …

The Fungal Exopolysaccharide Galactosaminogalactan Mediates Virulence By Enhancing Resistance To Neutrophil Extracellular Traps, Mark J. Lee, Hong Liu, Bridget M. Barker, Brendan D. Snarr, Fabrice M. Gravelat, Qusai Al Abdallah, Christina Gavino, Shane R. Baistrocchi, Hanna Ostapska, Tianli Xiao, Benjamin Ralph, Norma V. Solis, Melanie Lehoux, Stefanie D. Baptista, Arsa Thammahong

Dartmouth Scholarship

Of the over 250 Aspergillus species, Aspergillus fumigatus accounts for up to 80% of invasive human infections. A. fumigatus produces galactosaminogalactan (GAG), an exopolysaccharide composed of galactose and N-acetyl-galactosamine (GalNAc) that mediates adherence and is required for full virulence. Less pathogenic Aspergillus species were found to produce GAG with a lower GalNAc content than A. fumigatus and expressed minimal amounts of cell wall-bound GAG. Increasing the GalNAc content of GAG of the minimally pathogenic A. nidulans, either through overexpression of the A. nidulans epimerase UgeB or by heterologous expression of the A. fumigatus epimerase …

Workplace Safety Concerns Among Co-Workers Of Responder Returning From Ebola-Affected Country, Benjamin P. Chan, Elizabeth R. Daly, Elizabeth A. Talbot

Dartmouth Scholarship

We surveyed public health co-workers regarding attitudes toward a physician who returned to New Hampshire after volunteering in the West African Ebola outbreak. An unexpectedly large (18.0%) proportion of staff expressed discomfort with the Ebola responder returning to work. Employers should take proactive steps to address employee fears and concerns.

Parasite Manipulation Of The Invariant Chain And The Peptide Editor H2-Dm Affects Major Histocompatibility Complex Class Ii Antigen Presentation During Toxoplasma Gondii Infection, Louis-Philippe Leroux, Manami Nishi, Sandy El-Hage, Barbara A. Fox, David I Bzik, Florence Dzierszinsk

Dartmouth Scholarship

Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, …