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2019

Immunology and Infectious Disease

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Articles 1 - 30 of 117

Full-Text Articles in Life Sciences

Using Empirical And Theoretical Approaches To Control Outbreaks Of An Emerging Disease (Swimmer’S Itch) In The Midwest Of The U.S.A., Gregory J. Sandland, James Peirce Oct 2019

Using Empirical And Theoretical Approaches To Control Outbreaks Of An Emerging Disease (Swimmer’S Itch) In The Midwest Of The U.S.A., Gregory J. Sandland, James Peirce

Annual Symposium on Biomathematics and Ecology: Education and Research

No abstract provided.


Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice, Bradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Paul J. Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, Christopher Bebbington, Nenad Tomasevic Aug 2019

Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice, Bradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Paul J. Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm, Christopher Bebbington, Nenad Tomasevic

Open Access Articles

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and ...


Age-Based Dynamics Of A Stable Circulating Cd8 T Cell Repertoire Component, Elena N. Naumova, Maryam B. Yassai, Wendy Demos, Erica Reed, Melissa Unruh, Dipica Haribhai, Calvin B. Williams, Yuri N. Naumov, Jack Gorski Aug 2019

Age-Based Dynamics Of A Stable Circulating Cd8 T Cell Repertoire Component, Elena N. Naumova, Maryam B. Yassai, Wendy Demos, Erica Reed, Melissa Unruh, Dipica Haribhai, Calvin B. Williams, Yuri N. Naumov, Jack Gorski

Open Access Articles

T-cell memory to pathogens can be envisioned as a receptor-based imprint of the pathogenic environment on the naive repertoire of clonotypes. Recurrent exposures to a pathogen inform and reinforce memory, leading to a mature state. The complexity and temporal stability of this system in man is only beginning to be adequately described. We have been using a rank-frequency approach for quantitative analysis of CD8 T cell repertoires. Rank acts as a proxy for previous expansion, and rank-frequency, the number of clonotypes at a particular rank, as a proxy for abundance, with the relation of the two estimating the diversity of ...


Sustained Antigen Release Polyanhydride-Based Vaccine Platform For Immunization Against Bovine Brucellosis, Paola M. Boggiatto, Robert G. Schaut, Carly Kanipe, Sean M. Kelly, Balaji Narasimhan, Douglas E. Jones, Steven C. Olsen Aug 2019

Sustained Antigen Release Polyanhydride-Based Vaccine Platform For Immunization Against Bovine Brucellosis, Paola M. Boggiatto, Robert G. Schaut, Carly Kanipe, Sean M. Kelly, Balaji Narasimhan, Douglas E. Jones, Steven C. Olsen

Chemical and Biological Engineering Publications

Brucellosis is a bacterial zoonosis and a significant source of economic loss and a major public health concern, worldwide. Bovine brucellosis, as caused primarily by Brucella abortus, is an important cause of reproductive loss in cattle. Vaccination has been the most effective way to reduce disease prevalence contributing to the success of control and eradication programs. Currently, there are no human vaccines available, and despite the success of commercial vaccines for livestock, such as B. abortus strain RB51 (RB51), there is need for development of novel and safer vaccines against brucellosis. In the current study, we report the fabrication of ...


Combating Tuberculosis: Using Time-Dependent Sensitivity Analysis To Develop Strategies For Treatment And Prevention, Kendall B. Clark, Mayleen Cortez, Cristian Hernandez, Beth E. Thomas, Allison L. Lewis Jul 2019

Combating Tuberculosis: Using Time-Dependent Sensitivity Analysis To Develop Strategies For Treatment And Prevention, Kendall B. Clark, Mayleen Cortez, Cristian Hernandez, Beth E. Thomas, Allison L. Lewis

Spora: A Journal of Biomathematics

Although many organizations throughout the world have worked tirelessly to control tuberculosis (TB) epidemics, no country has yet been able to eradicate the disease completely. We present two compartmental models representing the spread of a TB epidemic through a population. The first is a general TB model; the second is an adaptation for regions in which HIV is prevalent, accounting for the effects of TB/HIV co-infection. Using active subspaces, we conduct time-dependent sensitivity analysis on both models to explore the significance of certain parameters with respect to the spread of TB. We use the results of this sensitivity analysis ...


Cxcr3 Chemokine Receptor Guides Trypanosoma Cruzi-Specific T-Cells Triggered By Dna/Adenovirus Asp2 Vaccine To Heart Tissue After Challenge, Camila Pontes Ferreira, Leonardo Moro Cariste, Barbara Ferri Moraschi, Bianca Ferrarini Zanetti, Sang Won Han, Daniel Araki Ribeiro, Alexandre Vieira Machado, Joseli Lannes-Vieira, Ricardo T. Gazzinelli, Jose Ronnie Vasconcelos Carvalho Jul 2019

Cxcr3 Chemokine Receptor Guides Trypanosoma Cruzi-Specific T-Cells Triggered By Dna/Adenovirus Asp2 Vaccine To Heart Tissue After Challenge, Camila Pontes Ferreira, Leonardo Moro Cariste, Barbara Ferri Moraschi, Bianca Ferrarini Zanetti, Sang Won Han, Daniel Araki Ribeiro, Alexandre Vieira Machado, Joseli Lannes-Vieira, Ricardo T. Gazzinelli, Jose Ronnie Vasconcelos Carvalho

Open Access Articles

CD8+ T lymphocytes play an important role in controlling infections by intracellular pathogens. Chemokines and their receptors are crucial for the migration of CD8+ T-lymphocytes, which are the main IFNgamma producers and cytotoxic effectors cells. Although the participation of chemokine ligands and receptors has been largely explored in viral infection, much less is known in infection by Trypanosoma cruzi, the causative agent of Chagas disease. After T. cruzi infection, CXCR3 chemokine receptor is highly expressed on the surface of CD8+ T-lymphocytes. Here, we hypothesized that CXCR3 is a key molecule for migration of parasite-specific CD8+ T-cells towards infected tissues, where ...


Alternative Splicing Regulates Stochastic Nlrp3 Activity, Florian Hoss, James L. Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-Alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Chris D. Putnam, Richard D. Kolodner, Stefan Canzar, Matthias Geyer, Hal M. Hoffman, Eicke Latz Jul 2019

Alternative Splicing Regulates Stochastic Nlrp3 Activity, Florian Hoss, James L. Mueller, Francisca Rojas Ringeling, Juan F. Rodriguez-Alcazar, Rebecca Brinkschulte, Gerald Seifert, Rainer Stahl, Lori Broderick, Chris D. Putnam, Richard D. Kolodner, Stefan Canzar, Matthias Geyer, Hal M. Hoffman, Eicke Latz

Open Access Articles

Leucine-rich repeat (LRR) domains are evolutionarily conserved in proteins that function in development and immunity. Here we report strict exonic modularity of LRR domains of several human gene families, which is a precondition for alternative splicing (AS). We provide evidence for AS of LRR domain within several Nod-like receptors, most prominently the inflammasome sensor NLRP3. Human NLRP3, but not mouse NLRP3, is expressed as two major isoforms, the full-length variant and a variant lacking exon 5. Moreover, NLRP3 AS is stochastically regulated, with NLRP3 exon 5 lacking the interaction surface for NEK7 and hence loss of activity. Our data thus ...


A Permethrin Metabolite Is Associated With Adaptive Immune Responses In Gulf War Illness, Utsav Joshi, Lawrence J. Stern, Laila Abdullah Jul 2019

A Permethrin Metabolite Is Associated With Adaptive Immune Responses In Gulf War Illness, Utsav Joshi, Lawrence J. Stern, Laila Abdullah

Open Access Articles

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood ...


Iiv-6 Inhibits Nf-Kappab Responses In Drosophila, Cara C. West, Florentina Rus, Ying Chen, Anni Kleino, Monique Gangloff, Don B. Gammon, Neal S. Silverman Jul 2019

Iiv-6 Inhibits Nf-Kappab Responses In Drosophila, Cara C. West, Florentina Rus, Ying Chen, Anni Kleino, Monique Gangloff, Don B. Gammon, Neal S. Silverman

Neal Silverman

The host immune response and virus-encoded immune evasion proteins pose constant, mutual selective pressure on each other. Virally encoded immune evasion proteins also indicate which host pathways must be inhibited to allow for viral replication. Here, we show that IIV-6 is capable of inhibiting the two Drosophila NF-kappaB signaling pathways, Imd and Toll. Antimicrobial peptide (AMP) gene induction downstream of either pathway is suppressed when cells infected with IIV-6 are also stimulated with Toll or Imd ligands. We find that cleavage of both Imd and Relish, as well as Relish nuclear translocation, three key points in Imd signal transduction, occur ...


Control Of Antiviral Innate Immune Response By Protein Geranylgeranylation, Shigao Yang, Zhaozhao Jiang, Katherine A. Fitzgerald, Donghai Wang Jul 2019

Control Of Antiviral Innate Immune Response By Protein Geranylgeranylation, Shigao Yang, Zhaozhao Jiang, Katherine A. Fitzgerald, Donghai Wang

Katherine A. Fitzgerald

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS' interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates ...


Persistent Inflammation During Anti-Tuberculosis Treatment With Diabetes Comorbidity, Nathella Pavan Kumar, Kiyoshi F. Fukutani, Basavaradhya S. Shruthi, Thabata Alves, Paulo S. Silveira-Mattos, Michael S. Rocha, Kim West, Mohan Natarajan, Vijay Viswanathan, Subash Babu, Bruno B. Andrade, Hardy Kornfeld Jul 2019

Persistent Inflammation During Anti-Tuberculosis Treatment With Diabetes Comorbidity, Nathella Pavan Kumar, Kiyoshi F. Fukutani, Basavaradhya S. Shruthi, Thabata Alves, Paulo S. Silveira-Mattos, Michael S. Rocha, Kim West, Mohan Natarajan, Vijay Viswanathan, Subash Babu, Bruno B. Andrade, Hardy Kornfeld

Open Access Articles

Diabetes mellitus (DM) increases risk for pulmonary tuberculosis (TB) and adverse treatment outcomes. Systemic hyper-inflammation is characteristic in people with TB and concurrent DM (TBDM) at baseline, but the impact of TB treatment on this pattern has not been determined. We measured 17 plasma cytokines and growth factors in longitudinal cohorts of Indian and Brazilian pulmonary TB patients with or without DM. Principal component analysis revealed virtually complete separation of TBDM from TB individuals in both cohorts at baseline, with hyper-inflammation in TBDM that continued through treatment completion at six months. By one year after treatment completion, there was substantial ...


The Expression Of Connexin-43 By Cd11c+ Dendritic Cells Is Required To Maintain Cd4+ Foxp3+ Regulatory T Cell Population In Peripheral Lymphoid Organs, Caroline Titus Miller Jul 2019

The Expression Of Connexin-43 By Cd11c+ Dendritic Cells Is Required To Maintain Cd4+ Foxp3+ Regulatory T Cell Population In Peripheral Lymphoid Organs, Caroline Titus Miller

Biological Sciences Theses & Dissertations

Foxp3+ regulatory T cells (TR) are an immunosuppressive subset of CD4+ T cells that maintain homeostasis of the immune system. They are sustained by the interaction between the Major Histocompatibility Complex (MHC) molecules present on antigen presenting dendritic cells and the T Cell Receptor (TCR) expressed on TR cells that is specific for the MHC loaded with an antigenic peptide. Here, we show that in addition to MHC/TCR interaction, Connexin-43 (Cx43) expression by dendritic cells is required to maintain the TR cell population. CD11c+ dendritic cells represent a major subset of antigen presenting cells. Using flow cytometry ...


Mtorc2/Akt Activation In Adipocytes Is Required For Adipose Tissue Inflammation In Tuberculosis, Nuria Martinez, Catherine Y. Cheng, Natkunam Ketheesan, Aidan Cullen, Yuefeng Tang, Josephine Lum, Kim West, Michael Poidinger, David A. Guertin, Amit Singhal, Hardy Kornfeld Jul 2019

Mtorc2/Akt Activation In Adipocytes Is Required For Adipose Tissue Inflammation In Tuberculosis, Nuria Martinez, Catherine Y. Cheng, Natkunam Ketheesan, Aidan Cullen, Yuefeng Tang, Josephine Lum, Kim West, Michael Poidinger, David A. Guertin, Amit Singhal, Hardy Kornfeld

Open Access Articles

BACKGROUND: Mycobacterium tuberculosis has co-evolved with the human host, adapting to exploit the immune system for persistence and transmission. While immunity to tuberculosis (TB) has been intensively studied in the lung and lymphoid system, little is known about the participation of adipose tissues and non-immune cells in the host-pathogen interaction during this systemic disease.

METHODS: C57BL/6J mice were aerosol infected with M. tuberculosis Erdman and presence of the bacteria and the fitness of the white and brown adipose tissues, liver and skeletal muscle were studied compared to uninfected mice.

FINDINGS: M. tuberculosis infection in mice stimulated immune cell infiltration ...


Tethering Of Vesicles To The Golgi By Gmap210 Controls Lat Delivery To The Immune Synapse, Andres Ernesto Zucchetti, Laurence Bataille, Jean-Marie Carpier, Stephanie Dogniaux, Mabel San Roman-Jouve, Mathieu Maurin, Michael W. Stuck, Rosa M. Rios, Cosima T. Baldari, Gregory J. Pazour, Claire Hivroz Jun 2019

Tethering Of Vesicles To The Golgi By Gmap210 Controls Lat Delivery To The Immune Synapse, Andres Ernesto Zucchetti, Laurence Bataille, Jean-Marie Carpier, Stephanie Dogniaux, Mabel San Roman-Jouve, Mathieu Maurin, Michael W. Stuck, Rosa M. Rios, Cosima T. Baldari, Gregory J. Pazour, Claire Hivroz

Open Access Articles

The T cell immune synapse is a site of intense vesicular trafficking. Here we show that the golgin GMAP210, known to capture vesicles and organize membrane traffic at the Golgi, is involved in the vesicular transport of LAT to the immune synapse. Upon activation, more GMAP210 interact with LAT-containing vesicles and go together with LAT to the immune synapse. Regulating LAT recruitment and LAT-dependent signaling, GMAP210 controls T cell activation. Using a rerouting and capture assay, we show that GMAP210 captures VAMP7-decorated vesicles. Overexpressing different domains of GMAP210, we also show that GMAP210 allows their specific delivery to the immune ...


The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer Jun 2019

The Wet Bridge Transfer System: An Novel In Vitro Tool For Assessing Exogenous Surfactant As A Pulmonary Drug Delivery Vehicle, Brandon J. Baer

Western Research Forum

Background:

Due to its complex branching structure, direct drug delivery to the remote areas of the lung is a major challenge. Consequently, most therapies, such as those treating pulmonary infection and inflammation, must utilize large systemic dosing, with the potential for adverse side effects. A novel alternative strategy is to use exogenous surfactant, a material capable of distributing throughout the lung, as a pulmonary drug delivery vehicle.

Objective:

Utilize an in vitro transferring system to assess exogenous surfactant (BLES) as a pulmonary delivery vehicle for different therapeutics.

Methods:

An in vitro technique was developed to simultaneously study surfactant delivery and ...


Cell-Free Dna Release During Programmed Cell Death In Ischemia Reperfusion Injury, Alexander Dionne, Anthony M. Jevnikar, Zhu-Xu Zhang Jun 2019

Cell-Free Dna Release During Programmed Cell Death In Ischemia Reperfusion Injury, Alexander Dionne, Anthony M. Jevnikar, Zhu-Xu Zhang

Western Research Forum

Transplantation is invariably associated with acute allograft injury caused by ischemia reperfusion injury (IRI). This injury causes cells of the allograft to undergo various forms of programmed cell death including apoptosis and necroptosis. During programmed cell death, immunogenic molecules are released from cells, one of which is cell-free DNA (cfDNA). We hypothesize that cfDNA is released by microvascular endothelial cells (MVECs) during programmed cell death of IRI and that cfDNA acts as both a biomarker for cellular injury as well as a biologically active molecule capable of amplifying inflammation and organ injury.

Our results indicate that cfDNA is released by ...


Inhibition Of Crispr-Cas9 Ribonucleoprotein Complex Assembly By Anti-Crispr Acriic2, Annoj Thavalingam, Erik J. Sontheimer, Yanli Wang, Karen L. Maxwell Jun 2019

Inhibition Of Crispr-Cas9 Ribonucleoprotein Complex Assembly By Anti-Crispr Acriic2, Annoj Thavalingam, Erik J. Sontheimer, Yanli Wang, Karen L. Maxwell

Open Access Articles

CRISPR-Cas adaptive immune systems function to protect bacteria from invasion by foreign genetic elements. The CRISPR-Cas9 system has been widely adopted as a powerful genome-editing tool, and phage-encoded inhibitors, known as anti-CRISPRs, offer a means of regulating its activity. Here, we report the crystal structures of anti-CRISPR protein AcrIIC2Nme alone and in complex with Nme1Cas9. We demonstrate that AcrIIC2Nme inhibits Cas9 through interactions with the positively charged bridge helix, thereby preventing sgRNA loading. In vivo phage plaque assays and in vitro DNA cleavage assays show that AcrIIC2Nme mediates its activity through a large electronegative surface. This work shows that anti-CRISPR ...


Identification Of Small Molecule Enzyme Inhibitors As Broad-Spectrum Anthelmintics, Rahul Tyagi, Elfawal A. Mostafa, Scott A. Wildman, Jon Helander, Christina A. Bulman, Judy Sakanari, Bruce A. Rosa, Paul J. Brindley, James W. Janetka, Raffi V. Aroian, Makedonka Mitreva Jun 2019

Identification Of Small Molecule Enzyme Inhibitors As Broad-Spectrum Anthelmintics, Rahul Tyagi, Elfawal A. Mostafa, Scott A. Wildman, Jon Helander, Christina A. Bulman, Judy Sakanari, Bruce A. Rosa, Paul J. Brindley, James W. Janetka, Raffi V. Aroian, Makedonka Mitreva

Open Access Articles

Targeting chokepoint enzymes in metabolic pathways has led to new drugs for cancers, autoimmune disorders and infectious diseases. This is also a cornerstone approach for discovery and development of anthelmintics against nematode and flatworm parasites. Here, we performed omics-driven knowledge-based identification of chokepoint enzymes as anthelmintic targets. We prioritized 10 of 186 phylogenetically conserved chokepoint enzymes and undertook a target class repurposing approach to test and identify new small molecules with broad spectrum anthelmintic activity. First, we identified and tested 94 commercially available compounds using an in vitro phenotypic assay, and discovered 11 hits that inhibited nematode motility. Based on ...


Open Textbook Project [Poster], Sue Ann Gardner Jun 2019

Open Textbook Project [Poster], Sue Ann Gardner

Library Conference Presentations and Speeches

Details of a porject undertaken to collaboratively write and produce an open access parasitology textbook for undergraduate and graduate students. The book will be published by Zea Books at the University of Nebraska-Lincoln in 2020 and be available in English and Spanish both online and print-on-demand through lulu.com.

Co-Executive Editors: Sue Ann Gardner and Scott L. Gardner, University of nebraska-Lincoln. Copyeditor: Linnea Fredrickson, University of Nebraska-Lincoln. Spanish Translator: Yoanna Esquivel Greenwood, University of Nebraska-Lincoln. Project Coordinator: Sue Ann Gardner.

Project website: https://digitalcommons.unl.edu/parasittext/.


Complement Alone Drives Efficacy Of A Chimeric Antigonococcal Monoclonal Antibody, Sunita Gulati, Frank J. Beurskens, Bo Zheng, Rosane B. Deoliveira, Jutamas Shaughnessy, Nancy Nowak, Peter A. Rice, Sanjay Ram Jun 2019

Complement Alone Drives Efficacy Of A Chimeric Antigonococcal Monoclonal Antibody, Sunita Gulati, Frank J. Beurskens, Bo Zheng, Rosane B. Deoliveira, Jutamas Shaughnessy, Nancy Nowak, Peter A. Rice, Sanjay Ram

Open Access Articles

Multidrug-resistant Neisseria gonorrhoeae is a global health problem. Monoclonal antibody (mAb) 2C7 recognizes a gonococcal lipooligosaccharide epitope that is expressed by > 95% of clinical isolates and hastens gonococcal vaginal clearance in mice. Chimeric mAb 2C7 (human immunoglobulin G1 [IgG1]) with an E430G Fc modification that enhances Fc:Fc interactions and hexamerization following surface-target binding and increases complement activation (HexaBody technology) showed significantly greater C1q engagement and C4 and C3 deposition compared to mAb 2C7 with wild-type Fc. Greater complement activation by 2C7-E430G Fc translated to increased bactericidal activity in vitro and, consequently, enhanced efficacy in mice, compared with "Fc-unmodified" chimeric ...


A Meningococcal Outer Membrane Vesicle Vaccine With Overexpressed Mutant Fhbp Elicits Higher Protective Antibody Responses In Infant Rhesus Macaques Than A Licensed Serogroup B Vaccine, Peter T. Beernink, Vianca Vianzon, Lisa A. Lewis, Gregory R. Moe, Dan M. Granoff Jun 2019

A Meningococcal Outer Membrane Vesicle Vaccine With Overexpressed Mutant Fhbp Elicits Higher Protective Antibody Responses In Infant Rhesus Macaques Than A Licensed Serogroup B Vaccine, Peter T. Beernink, Vianca Vianzon, Lisa A. Lewis, Gregory R. Moe, Dan M. Granoff

Open Access Articles

MenB-4C (Bexsero; GlaxoSmithKline Biologicals) is a licensed meningococcal vaccine for capsular B strains. The vaccine contains detergent-extracted outer membrane vesicles (dOMV) and three recombinant proteins, of which one is factor H binding protein (FHbp). In previous studies, overexpression of FHbp in native OMV (NOMV) with genetically attenuated endotoxin (LpxL1) and/or by the use of mutant FHbp antigens with low factor H (FH) binding increased serum bactericidal antibody (SBA) responses. In this study, we immunized 13 infant macaques with 2 doses of NOMV with overexpressed mutant (R41S) FHbp with low binding to macaque FH (NOMV-FHbp). Control macaques received MenB-4C (n ...


The Fatty Acid Oleate Is Required For Innate Immune Activation And Pathogen Defense In Caenorhabditis Elegans, Sarah M. Anderson, Hilary K. Cheesman, Nicholas D. Peterson, Elisabeth B. Salisbury, Alexander A. Soukas, Read Pukkila-Worley Jun 2019

The Fatty Acid Oleate Is Required For Innate Immune Activation And Pathogen Defense In Caenorhabditis Elegans, Sarah M. Anderson, Hilary K. Cheesman, Nicholas D. Peterson, Elisabeth B. Salisbury, Alexander A. Soukas, Read Pukkila-Worley

Open Access Articles

Fatty acids affect a number of physiological processes, in addition to forming the building blocks of membranes and body fat stores. In this study, we uncover a role for the monounsaturated fatty acid oleate in the innate immune response of the nematode Caenorhabditis elegans. From an RNAi screen for regulators of innate immune defense genes, we identified the two stearoyl-coenzyme A desaturases that synthesize oleate in C. elegans. We show that the synthesis of oleate is necessary for the pathogen-mediated induction of immune defense genes. Accordingly, C. elegans deficient in oleate production are hypersusceptible to infection with diverse human pathogens ...


A Novel Phox/Cd38/Mcoln1/Tfeb Axis Important For Macrophage Activation During Bacterial Phagocytosis, Mehran Najibi, Joseph A. Moreau, Havisha H. Honwad, Javier E. Irazoqui Jun 2019

A Novel Phox/Cd38/Mcoln1/Tfeb Axis Important For Macrophage Activation During Bacterial Phagocytosis, Mehran Najibi, Joseph A. Moreau, Havisha H. Honwad, Javier E. Irazoqui

University of Massachusetts Medical School Faculty Publications

Macrophages are a key and heterogenous class of phagocytic cells of the innate immune system, which act as sentinels in peripheral tissues and are mobilized during infection. Macrophage activation in the presence of bacterial cells and molecules entails specific and complex programs of gene expression. How such triggers elicit the gene expression programs is incompletely understood. We previously discovered that transcription factor TFEB is a key contributor to macrophage activation during bacterial phagocytosis. However, the mechanism linking phagocytosis of bacterial cells to TFEB activation remained unknown. In this article, we describe a previously unknown pathway that links phagocytosis with the ...


Structure-Based Design Of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses To A Conserved Epitope, Brian G. Pierce, Elisabeth N. Boucher, Kurt H. Piepenbrink, Ejemel Monir, Chelsea A. Rapp, William D. Thomas Jr., Eric J. Sundberg, Zhiping Weng, Yan Wang Jun 2019

Structure-Based Design Of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses To A Conserved Epitope, Brian G. Pierce, Elisabeth N. Boucher, Kurt H. Piepenbrink, Ejemel Monir, Chelsea A. Rapp, William D. Thomas Jr., Eric J. Sundberg, Zhiping Weng, Yan Wang

Kurt Piepenbrink

Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, as ...


Failure Of Oxysterols Such As Lanosterol To Restore Lens Clarity From Cataracts, Damian M. Daszynski, Puttur Santhoshkumar, Ashutosh S. Phadte, K. Krishna Sharma, Haizhen A. Zhong, Marjorie F. Lou, Peter F. Kador Jun 2019

Failure Of Oxysterols Such As Lanosterol To Restore Lens Clarity From Cataracts, Damian M. Daszynski, Puttur Santhoshkumar, Ashutosh S. Phadte, K. Krishna Sharma, Haizhen A. Zhong, Marjorie F. Lou, Peter F. Kador

Papers in Veterinary and Biomedical Science

The paradigm that cataracts are irreversible and that vision from cataracts can only be restored through surgery has recently been challenged by reports that oxysterols such as lanosterol and 25-hydroxycholesterol can restore vision by binding to αB-crystallin chaperone protein to dissolve or disaggregate lenticular opacities. To confirm this premise, in vitro rat lens studies along with human lens protein solubilization studies were conducted. Cataracts were induced in viable rat lenses cultured for 48 hours in TC-199 bicarbonate media through physical trauma, 10 mM ouabain as Na+/K+ ATPase ion transport inhibitor, or 1 mM of an experimental compound that induces ...


Trim5alpha Restricts Flavivirus Replication By Targeting The Viral Protease For Proteasomal Degradation, Abhilash I. Chiramel, Nicholas R. Meyerson, Kristin L. Mcnally, Rebecca M. Broeckel, Vanessa R. Montoya, Omayra Mendez-Solis, Shelly J. Robertson, Gail L. Sturdevant, Kirk J. Lubick, Vinod Nair, Brian H. Youseff, Robin M. Ireland, Catharine M. Bosio, Kyusik Kim, Jeremy Luban, Vanessa M. Hirsch, R. Travis Taylor, Fadila Bouamr, Sara L. Sawyer, Sonja M. Best Jun 2019

Trim5alpha Restricts Flavivirus Replication By Targeting The Viral Protease For Proteasomal Degradation, Abhilash I. Chiramel, Nicholas R. Meyerson, Kristin L. Mcnally, Rebecca M. Broeckel, Vanessa R. Montoya, Omayra Mendez-Solis, Shelly J. Robertson, Gail L. Sturdevant, Kirk J. Lubick, Vinod Nair, Brian H. Youseff, Robin M. Ireland, Catharine M. Bosio, Kyusik Kim, Jeremy Luban, Vanessa M. Hirsch, R. Travis Taylor, Fadila Bouamr, Sara L. Sawyer, Sonja M. Best

Program in Molecular Medicine Publications and Presentations

Tripartite motif-containing protein 5alpha (TRIM5alpha) is a cellular antiviral restriction factor that prevents early events in retrovirus replication. The activity of TRIM5alpha is thought to be limited to retroviruses as a result of highly specific interactions with capsid lattices. In contrast to this current understanding, we show that both human and rhesus macaque TRIM5alpha suppress replication of specific flaviviruses. Multiple viruses in the tick-borne encephalitis complex are sensitive to TRIM5alpha-dependent restriction, but mosquito-borne flaviviruses, including yellow fever, dengue, and Zika viruses, are resistant. TRIM5alpha suppresses replication by binding to the viral protease NS2B/3 to promote its K48-linked ubiquitination and ...


Parasitic Dinoflagellate Hematodinium Perezi Prevalence In Larval And Juvenile Blue Crabs Callinectes Sapidus From Coastal Bays Of Virginia, Hj Small, Jp Huchin-Mian, Ks Reece, Km Pagenkopp Lohan, Mj Butler Iv, Jd Shields Jun 2019

Parasitic Dinoflagellate Hematodinium Perezi Prevalence In Larval And Juvenile Blue Crabs Callinectes Sapidus From Coastal Bays Of Virginia, Hj Small, Jp Huchin-Mian, Ks Reece, Km Pagenkopp Lohan, Mj Butler Iv, Jd Shields

VIMS Articles

The parasitic dinoflagellate Hematodinium perezi infects the American blue crab Callinectes sapidus and other decapods along the Eastern seaboard and Gulf of Mexico coast of the USA. Large juvenile and adult blue crabs experience high mortality during seasonal outbreaks of H. perezi, but less is known about its presence in the early life history stages of this host. We determined the prevalence of H. perezi in megalopae and early benthic juvenile crabs from multiple locations along the Virginia portion of the Delmarva Peninsula. The DNA of H. perezi was not detected in any megalopae collected from several locations within the ...


Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman Jun 2019

Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman

Neal Silverman

Fruit flies elicit effective defense responses against numerous microbes. The responses against Gram-negative bacteria are mediated by the Imd pathway, an evolutionarily conserved NF-kappaB pathway recognizing meso-diaminopimelic acid (DAP)-type peptidoglycan from bacterial cell walls. Several reviews already provide a detailed view of ligand recognition and signal transduction during Imd signaling, but the formation and regulation of the signaling complex immediately downstream of the peptidoglycan-sensing receptors is still elusive. In this review, we focus on the formation of the Imd amyloidal signaling center and post-translational modifications in the assembly and disassembly of the Imd signaling complex.


Trav1-2(+) Cd8(+) T-Cells Including Oligoconal Expansions Of Mait Cells Are Enriched In The Airways In Human Tuberculosis, Emily B. Wong, Samuel M. Behar, David M. Lewinsohn Jun 2019

Trav1-2(+) Cd8(+) T-Cells Including Oligoconal Expansions Of Mait Cells Are Enriched In The Airways In Human Tuberculosis, Emily B. Wong, Samuel M. Behar, David M. Lewinsohn

Open Access Articles

Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2(+) semi-invariant TCRalpha that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT cells are associated with immune control of bacterial and mycobacterial infections in murine models. Here, we report that a population of pro-inflammatory TRAV1-2(+) CD8(+) T cells are present in the airways and lungs of healthy individuals and are enriched in bronchoalveolar fluid of patients with active pulmonary tuberculosis (TB). High-throughput T cell receptor analysis reveals oligoclonal expansions of canonical and donor-unique TRAV1-2(+) MAIT-consistent TCRalpha sequences within this population. Some of these cells demonstrate MR1-restricted mycobacterial ...


The Molecular Basis Of Human Igg-Mediated Enhancement Of C4b-Binding Protein Recruitment To Group A Streptococcus, David Ermert, Maisem Laabei, Antonin Weckel, Matthias Morgelin, Martin Lundqvist, Lars Bjorck, Sanjay Ram, Sara Linse, Anna M. Blom Jun 2019

The Molecular Basis Of Human Igg-Mediated Enhancement Of C4b-Binding Protein Recruitment To Group A Streptococcus, David Ermert, Maisem Laabei, Antonin Weckel, Matthias Morgelin, Martin Lundqvist, Lars Bjorck, Sanjay Ram, Sara Linse, Anna M. Blom

Open Access Articles

Streptococcus pyogenes infects over 700 million people worldwide annually. Immune evasion strategies employed by the bacteria include binding of the complement inhibitors, C4b-binding protein (C4BP) and Factor H in a human-specific manner. We recently showed that human IgG increased C4BP binding to the bacterial surface, which promoted streptococcal immune evasion and increased mortality in mice. We sought to identify how IgG promotes C4BP binding to Protein H, a member of the M protein family. Dimerization of Protein H is pivotal for enhanced binding to human C4BP. First, we illustrated that Protein H, IgG, and C4BP formed a tripartite complex. Second ...