Medicine and Health Sciences Commons^™

Ido2 In Immunomodulation And Autoimmune Disease., George C Prendergast, Richard Metz, Alexander J Muller, Lauren M F Merlo, Laura Mandik-Nayak

Department of Microbiology and Immunology Faculty Papers

IDO2 is a relative of IDO1 implicated in tryptophan catabolism and immune modulation but its specific contributions to normal physiology and pathophysiology are not known. Evolutionary genetic studies suggest that IDO2 has a unique function ancestral to IDO1. In mice, IDO2 gene deletion does not appreciably affect embryonic development or hematopoiesis, but it leads to defects in allergic or autoimmune responses and in the ability of IDO1 to influence the generation of T regulatory cells. Gene expression studies indicate that IDO2 is a basally and more narrowly expressed gene than IDO1 and that IDO2 is uniquely regulated by AhR, which …

Vaccination With A Genetically Modified Brugia Malayi Cysteine Protease Inhibitor-2 Reduces Adult Parasite Numbers And Affects The Fertility Of Female Worms Following A Subcutaneous Challenge Of Mongolian Gerbils (Meriones Unguiculatus) With B. Malayi Infective Larvae., Sridhar Arumugam, Junfei Wei, Danielle Ward, David Abraham, Sara Lustigman, Bin Zhan, Thomas R. Klei

Department of Microbiology and Immunology Faculty Papers

Vaccination of Mongolian gerbils with Brugia malayi cysteine protease inhibitor-2 in which the amino acid Asn66 was mutated to Lys66 (Bm-CPI-2M) resulted in reduced parasite numbers of 48.6% and 48.0% at 42 and 90 days p.i. with B. malayi L3s. Fertility of female worms was also affected at 90 days p.i. In vitro killing of L3s observed in the presence of gerbil peritoneal exudate cells and anti-Bm-CPI-2M sera suggests antibody-dependent cell-mediated cytotoxicity as a putative protective mechanism. These observations suggest that Bm-CPI-2M is a promising prophylactic and anti-fecundity vaccine candidate.

Vaccines To Combat River Blindness: Expression, Selection And Formulation Of Vaccines Against Infection With Onchocerca Volvulus In A Mouse Model., Jessica A. Hess, Bin Zhan, Sandra Bonne-Annee, Jessica M. Deckman, Maria Elena Bottazzi, Peter J. Hotez, Thomas R R. Klei, Sara Lustigman, David Abraham

Department of Microbiology and Immunology Faculty Papers

Human onchocerciasis is a neglected tropical disease caused by Onchocerca volvulus and an important cause of blindness and chronic disability in the developing world. Although mass drug administration of ivermectin has had a profound effect on control of the disease, additional tools are critically needed including the need for a vaccine against onchocerciasis. The objectives of the present study were to: (i) select antigens with known vaccine pedigrees as components of a vaccine; (ii) produce the selected vaccine antigens under controlled conditions, using two expression systems and in one laboratory and (iii) evaluate their vaccine efficacy using a single immunisation …

Systemic Hematogenous Maintenance Of Memory Inflation By Mcmv Infection., Corinne J Smith, Holly Turula, Christopher M. Snyder

Department of Microbiology and Immunology Faculty Papers

Several low-grade persistent viral infections induce and sustain very large numbers of virus-specific effector T cells. This was first described as a response to cytomegalovirus (CMV), a herpesvirus that establishes a life-long persistent/latent infection, and sustains the largest known effector T cell populations in healthy people. These T cells remain functional and traffic systemically, which has led to the recent exploration of CMV as a persistent vaccine vector. However, the maintenance of this remarkable response is not understood. Current models propose that reservoirs of viral antigen and/or latently infected cells in lymph nodes stimulate T cell proliferation and effector differentiation, …

Small-Molecule Probes Targeting The Viral Ppxy-Host Nedd4 Interface Block Egress Of A Broad Range Of Rna Viruses., Ziying Han, Jianhong Lu, Yuliang Liu, Benjamin Davis, Michael S Lee, Mark A Olson, Gordon Ruthel, Bruce D Freedman, Matthias J. Schnell, Jay E Wrobel, Allen B Reitz, Ronald N Harty

Department of Microbiology and Immunology Faculty Papers

Budding of filoviruses, arenaviruses, and rhabdoviruses is facilitated by subversion of host proteins, such as Nedd4 E3 ubiquitin ligase, by viral PPxY late (L) budding domains expressed within the matrix proteins of these RNA viruses. As L domains are important for budding and are highly conserved in a wide array of RNA viruses, they represent potential broad-spectrum targets for the development of antiviral drugs. To identify potential competitive blockers, we used the known Nedd4 WW domain-PPxY interaction interface as the basis of an in silico screen. Using PPxY-dependent budding of Marburg (MARV) VP40 virus-like particles (VLPs) as our model system, …

Extracellular Traps Are Associated With Human And Mouse Neutrophil And Macrophage Mediated Killing Of Larval Strongyloides Stercoralis., Sandra Bonne-Annee, Laura A. Kerepesi, Jessica A. Hess, Jordan Wesolowski, Fabienne Paumet, James B. Lok, Thomas J. Nolan, David Abraham

Department of Microbiology and Immunology Faculty Papers

Neutrophils are multifaceted cells that are often the immune system's first line of defense. Human and murine cells release extracellular DNA traps (ETs) in response to several pathogens and diseases. Neutrophil extracellular trap (NET) formation is crucial to trapping and killing extracellular pathogens. Aside from neutrophils, macrophages and eosinophils also release ETs. We hypothesized that ETs serve as a mechanism of ensnaring the large and highly motile helminth parasite Strongyloides stercoralis thereby providing a static target for the immune response. We demonstrated that S. stercoralis larvae trigger the release of ETs by human neutrophils and macrophages. Analysis of NETs revealed …

Cd27high/Klrg1low Cd8+ T Cells That Persist Throughout Mcmv Infection Are Highly Expansive And Have The Ability To Reestablish Mcmv Immunity, Michael Quinn, Holly Turula, Christopher M. Snyder

Department of Microbiology and Immunology Faculty Papers

Abstract

Cytomegalovirus (CMV) is a herpesvirus that establishes life-long latency in 60-80% of Americans. Constant immune surveillance is necessary to prevent viral reactivation from latency and results in the accumulation of functional CMV-specific CD8+ T cells (CD8s) over time, a process termed memory inflation. As such, CMV reactivations remain a clinical concern for immunosuppressed patients and reconstituting CMV immunity is critical for the long-term prevention of CMV disease. Understanding the maintenance of memory inflation may reveal novel approaches to restore CMV immunity.

Previous work has shown that the majority of inflationary CD8s express a terminally-differentiated “effector” (T_EFF) phenotype, …

Limited Brain Metabolism Changes Differentiate Between The Progression And Clearance Of Rabies Virus., Keith Schutsky, Carla Portocarrero, D Craig Hooper, Bernhard Dietzschold, Milosz Faber

Department of Microbiology and Immunology Faculty Papers

Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of …

Resolving The Titer Of Murine Cytomegalovirus By Plaque Assay Using The M2-10b4 Cell Line And A Low Viscosity Overlay., Katherine A Zurbach, Toktam Moghbeli, Christopher M Snyder

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Murine cytomegalovirus (MCMV) is increasingly used as an infectious model to investigate host-pathogen interactions in mice. Detailed methods have been published for using primary murine embryonic fibroblasts (MEFs) for preparing stocks and determining viral titers of MCMV. For determining the titer of MCMV by plaque assay, these methods rely on a high viscosity media that restricts viral spreading through the supernatant of the culture, but is also usually too viscous to pipet. Moreover, MEFs must be repeatedly generated and can vary widely from batch-to-batch in purity, proliferation rates, and the development of senescence. In contrast, the M2-10B4 bone marrow …

Interleukin-7-Dependent B Lymphocytes Are Required For The Anti-Pneumococcal Polysaccharide Response And Protective Immunity To Streptococcus Pneumoniae, Gregory S. Dickinson, Phd, Raja Vuyyuru, Timothy L. Manser, Phd, John F. Kerney, Kishore Alugupalli, Phd

Department of Microbiology and Immunology Faculty Papers

Unlike human adults or adult mice, young children or young mice respond poorly to pneumococcal polysaccharides (PPS). In mice, B1b lymphocytes are the major responders to a variety of bacterial polysaccharides including PPS. Despite having B1b cells, young mice are severely impaired in responding to PPS, suggesting that B cells in the young are distinct from those in adults. Since B lymphopoeisis early in life is largely Interleukin-7 (IL-7)-independent, while in adults it is IL-7-dependent, we hypothesize that B cells developed in the presence of IL-7 are required for generating anti-PPS antibody responses. In support of this, we found that …

Myd88-Dependent Immunity To A Natural Model Of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2., Michael L Davies, Janet J Sei, Nicholas A Siciliano, Ren-Huan Xu, Felicia Roscoe, Luis J Sigal, Laurence C. Eisenlohr, Christopher C Norbury

Department of Microbiology and Immunology Faculty Papers

UNLABELLED: Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for …

Efficient B Cell Responses To Borrelia Hermsii Infection Depend On Baff And Baffr But Not Taci., Gregory S. Dickinson, Phd, Guizhi Sun, Richard J Bram, Kishore Alugupalli

Department of Microbiology and Immunology Faculty Papers

T cell-independent antibody responses develop rapidly, within 3 to 4 days, and are critical for preventing blood-borne pathogens from evolving into life-threatening infections. The interaction of BAFF, also known as BLyS, with its receptors BAFFR and TACI on B cells is critical for B cell homeostasis and function. Using a synthetic polysaccharide antigen, it has previously been shown that TACI is critical for T cell-independent antibody responses. To examine the role of BAFFR and TACI in T cell-independent antibody responses to an active infection, we utilized the Borrelia hermsii infection system. In this infection system, T cell-independent responses mediated by …