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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 2019 Northwestern University

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 ...


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 2019 University of Massachusetts Medical School

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 2019 Duke University

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 ...


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 2019 PSL Research University

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 2019 University of Western Ontario

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 2019 The University of Western Ontario

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 2019 University of Toronto

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 2019 Washington University in St. Louis

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 2019 University of Nebraska-Lincoln

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 2019 University of Massachusetts Medical School

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 2019 University of California, San Francisco

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 2019 University of Massachusetts Medical School

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 2019 University of Massachusetts Medical School

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 2019 University of Massachusetts Medical School

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 ...


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 2019 National Institute of Allergy and Infectious Diseases

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 2019 Virginia Institute of Marine Science

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 2019 Aarhus University

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 2019 University College London

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 2019 University of Massachusetts Medical School

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 ...


Nf-Κb In Biomphalaria Glabrata: A Genetic Fluke?, Paige Stocker 2019 Lawrence University

Nf-Κb In Biomphalaria Glabrata: A Genetic Fluke?, Paige Stocker

Lawrence University Honors Projects

Biomphalaria glabrata is the intermediate host to the disease causing parasitic worm, Schistosoma mansoni. Previous work has identified homologs of NF-κB, a known immune related transcription factor, in B. glabrata and work has also been done to establish putative κB sites. It has also been observed that the p65 homologous subunit has an extended N-terminal region not present in other homologs. The goal of the present study is twofold: investigate DNA binding affinity of two NF-κB subunits, Bg-p65 and Bg-p50, and characterize the nature of the N-terminal extension of Bg-p65. In the current work, it is shown through the use ...


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