Medical Genetics Commons^™

Cns Recruitment Of Cd8+ T Lymphocytes Specific For A Peripheral Virus Infection Triggers Neuropathogenesis During Polymicrobial Challenge., Christine M Matullo, Kevin J O'Regan, Mark Curtis, Glenn F Rall

Department of Microbiology and Immunology Faculty Papers

Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with …

Buffered Memory: A Hypothesis For The Maintenance Of Functional, Virus-Specific Cd8(+) T Cells During Cytomegalovirus Infection., Christopher M Snyder

Department of Microbiology and Immunology Faculty Papers

Chronic infections have been a major topic of investigation in recent years, but the mechanisms that dictate whether or not a pathogen is successfully controlled are incompletely understood. Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent infection in the majority of people in the world. Like other herpesviruses, CMV is well controlled by an effective immune response and induces little, if any, pathology in healthy individuals. However, controlling CMV requires continuous immune surveillance, and thus, CMV is a significant cause of morbidity and death in immune-compromised individuals. T cells in particular play an important role in controlling CMV and …

Epitope Characterization Of Sero-Specific Monoclonal Antibody To Clostridium Botulinum Neurotoxin Type A., Cindi R Corbett, Erin Ballegeer, Kelly A Weedmark, M D Elias, Fetweh H Al-Saleem, Denise M Ancharski, Lance L Simpson, Jody D Berry

Department of Medicine Faculty Papers

Botulinum neurotoxins (BoNTs) are extremely potent toxins that can contaminate foods and are a public health concern. Anti-BoNT antibodies have been described that are capable of detecting BoNTs; however there still exists a need for accurate and sensitive detection capabilities for BoNTs. Herein, we describe the characterization of a panel of eight monoclonal antibodies (MAbs) generated to the non-toxic receptor-binding domain of BoNT/A (H(C)50/A) developed using a high-throughput screening approach. In two independent hybridoma fusions, two groups of four IgG MAbs were developed against recombinant H(C)50/A. Of these eight, only a single MAb, F90G5-3, bound to the whole BoNT/A protein …

The Characteristics Of Borrelia Hermsii Infection In Human Hematopoeitic Stem Cell-Engrafted Mice Mirror Those Of Human Relapsing Fever, Raja Vuyyuru, Hongqi Liu, Tim Manser, Kishore Alugupalli

Department of Microbiology and Immunology Faculty Papers

Rodents are natural reservoirs for a variety of species of Borrelia that cause relapsing fevers in humans. The murine model of this disease recapitulates many of the clinical manifestations of the human disease and has revealed that T cell-independent antibody responses are required to resolve the bacteremic episodes. However, it is not clear whether such protective humoral responses are mounted in humans.

Sustained Cd8+ T Cell Memory Inflation After Infection With A Single-Cycle Cytomegalovirus., Christopher M Snyder, Kathy S Cho, Elizabeth L Bonnett, Jane E Allan, Ann B Hill

Department of Microbiology and Immunology Faculty Papers

Cytomegalovirus (CMV) is a β-herpesvirus that establishes a lifelong latent or persistent infection. A hallmark of chronic CMV infection is the lifelong persistence of large numbers of virus-specific CD8+ effector/effector memory T cells, a phenomenon called "memory inflation". How the virus continuously stimulates these T cells without being eradicated remains an enigma. The prevailing view is that CMV establishes a low grade "smoldering" infection characterized by tiny bursts of productive infection which are rapidly extinguished, leaving no detectable virus but replenishing the latent pool and leaving the immune system in a highly charged state. However, since abortive reactivation with limited …

Rip1-Dependent And Independent Effects Of Necrostatin-1 In Necrosis And T Cell Activation., Youngsik Cho, Thomas Mcquade, Haibing Zhang, Jianke Zhang, Francis Ka-Ming Chan

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Programmed necrosis/necroptosis is an emerging form of cell death that plays important roles in mammalian development and the immune system. The pro-necrotic kinases in the receptor interacting protein (RIP) family are crucial mediators of programmed necrosis. Recent advances in necrosis research have been greatly aided by the identification of chemical inhibitors that block programmed necrosis. Necrostatin-1 (Nec-1) and its derivatives were previously shown to target the pro-necrotic kinase RIP1/RIPK1. The protective effect conferred by Nec-1 and its derivatives in many experimental model systems was often attributed to the inhibition of RIP1 function.

METHODOLOGY/PRINCIPAL FINDINGS: We compared the effect of …

Functional Macroautophagy Induction By Influenza A Virus Without A Contribution To Major Histocompatibility Complex Class Ii-Restricted Presentation., Joseph D Comber, Tara M Robinson, Nicholas A Siciliano, Adam E Snook, Laurence C Eisenlohr

Department of Microbiology and Immunology Faculty Papers

Major histocompatibility complex (MHC) class II-presented peptides can be derived from both exogenous (extracellular) and endogenous (biosynthesized) sources of antigen. Although several endogenous antigen-processing pathways have been reported, little is known about their relative contributions to global CD4(+) T cell responses against complex antigens. Using influenza virus for this purpose, we assessed the role of macroautophagy, a process in which cytosolic proteins are delivered to the lysosome by de novo vesicle formation and membrane fusion. Influenza infection triggered productive macroautophagy, and autophagy-dependent presentation was readily observed with model antigens that naturally traffic to the autophagosome. Furthermore, treatments that enhance or …

Microarray-Based Analysis Of Differential Gene Expression Between Infective And Noninfective Larvae Of Strongyloides Stercoralis., Roshan Ramanathan, Sudhir Varma, José M C Ribeiro, Timothy G Myers, Thomas J Nolan, David Abraham, James B Lok, Thomas B Nutman

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Differences between noninfective first-stage (L1) and infective third-stage (L3i) larvae of parasitic nematode Strongyloides stercoralis at the molecular level are relatively uncharacterized. DNA microarrays were developed and utilized for this purpose.

METHODS AND FINDINGS: Oligonucleotide hybridization probes for the array were designed to bind 3,571 putative mRNA transcripts predicted by analysis of 11,335 expressed sequence tags (ESTs) obtained as part of the Nematode EST project. RNA obtained from S. stercoralis L3i and L1 was co-hybridized to each array after labeling the individual samples with different fluorescent tags. Bioinformatic predictions of gene function were developed using a novel cDNA Annotation …

Comparison Of Human Memory Cd8 T Cell Responses To Adenoviral Early And Late Proteins In Peripheral Blood And Lymphoid Tissue., Amita Joshi, Biwei Zhao, Cara Romanowski, David Rosen, Phyllis Flomenberg

Department of Microbiology and Immunology Faculty Papers

Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs) targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977) and late protein hexon (H-892) were compared in peripheral blood (PB) and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly …

Hydrophobicity As A Driver Of Mhc Class I Antigen Processing., Lan Huang, Matthew C Kuhls, Laurence C. Eisenlohr

Department of Microbiology and Immunology Faculty Papers

The forces that drive conversion of nascent protein to major histocompatibility complex (MHC) class I-restricted peptides remain unknown. We explored the fundamental property of overt hydrophobicity as such a driver. Relocation of a membrane glycoprotein to the cytosol via signal sequence ablation resulted in rapid processing of nascent protein not because of the misfolded luminal domain but because of the unembedded transmembrane (TM) domain, which serves as a dose-dependent degradation motif. Dislocation of the TM domain during the natural process of endoplasmic reticulum-associated degradation (ERAD) similarly accelerated peptide production, but in the context of markedly prolonged processing that included nonnascent …