Medical Immunology Commons^™

Rabies-Based Vaccine Induces Potent Immune Responses Against Nipah Virus., Rohan Keshwara, Thomas Shiels, Elena Postnikova, Drishya Kurup, Christoph Wirblich, Reed F. Johnson, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

Nipah Virus (NiV) is a re-emerging zoonotic pathogen in the genus Henipavirus of the Paramyxoviridae family of viruses. NiV is endemic to Bangladesh and Malaysia and is highly fatal to both livestock and humans (human case fatality rate = 74.5%). Currently, there is no approved vaccine against NiV on the market. The goal of this study was to use a recombinant RABV vector expressing NiV glycoprotein (NiV G) to develop a bivalent candidate vaccine against NiV disease and rabies virus (RABV) disease, which is also a significant health burden in the regions where NiV is endemic. The rabies vector is …

The Promise Of Anti-Idiotype Revisited, Heinz Köhler, Anastas Pashov, Thomas Kieber-Emmons

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The promise of idiotype-based therapeutics has been disappointing forcing a new look at the concept and its potential to generate an effective approach for immunotherapy. Here, the idiotype network theory is revisited with regard to the development of efficacious anti-idiotype vaccines. The experience of polyclonal anti-Idiotype reagents in animal models as well as an understanding of the immune response in humans lends to the proposition that polyclonal anti-Idiotype vaccines will be more effective compared to monoclonal-based anti-Idiotype vaccines. This novel strategy can be adapted in Biotech-standard production of therapeutic antibodies.

Dual Therapy Treatment Of Pediatric Acute Lymphoblastic Leukemia With Blinotumomab And A Standard Chemotherapy Regimen, Tori I. Scheffler

Selected Honors Theses

Leukemia is the number one cancer affecting children in the nation, with acute lymphoblastic leukemia being the most prevalent classification.1 While new and innovative treatment protocols have greatly increased the success rate of primary cancer patients, those who face relapse receive a much more dismal prognosis. Recent studies have shown that patients who relapse quite frequently have developed drug-resistant clones of the original cancer cells, leading to a need for various secondary treatment options. The drug-resistance is due to clonal mutations that take place within the cancer cell, most often because of an outside pressure or stress within the environment …

Enhancing Natural Killer And Cd8 + T Cell-Mediated Anticancer Cytotoxicity And Proliferation Of Cd8 + T Cells With Hla-E Monospecific Monoclonal Antibodies, Mepur H. Ravindranath, Edward J. Filippone, Asokan Devarajan, Shahab Asgharzadeh

Department of Medicine Faculty Papers

Cytotoxic NK/CD8+ T cells interact with MHC-I ligands on tumor cells through either activating or inhibiting receptors. One of the inhibitory receptors is CD94/NKG2A. The NK/CD8+ T cell cytotoxic capability is lost when tumor-associated human leukocyte antigen, HLA-E, binds the CD94/NKG2A receptor, resulting in tumor progression and reduced survival. Failure of cancer patients to respond to natural killer (NK) cell therapies could be due to HLA-E overexpression in tumor tissues. Preventing the inhibitory receptor-ligand interaction by either receptor- or ligand-specific monoclonal antibodies (mAbs) is an innovative passive immunotherapeutic strategy for cancer. Since receptors and ligands can be monomeric or homo- …

A Human Papillomavirus-Independent Cervical Cancer Animal Model Reveals Unconventional Mechanisms Of Cervical Carcinogenesis, Chunbo He, Xiangmin Lv, Cong Huang, Peter C. Angeletti, Guohua Hua, Jixin Dong, Jin Zhou, Zhengfeng Wang, Bowen Ma, Xingcheng Chen, Paul F. Lambert, Bo R. Rueda, John S. Davis, Cheng Wang

Nebraska Center for Virology: Faculty Publications

HPV infections are common in healthy women and only rarely cause cervical cancer, suggesting that individual genetic susceptibility may play a critical role in the establishment of persistent HPV infection and the development of cervical cancer. Here, we provide convincing in vitro and in vivo evidence showing that differential expression and activation of YAP1 oncogene determine individual susceptibility to HPV infection and cervical carcinogenesis. We found that hyperactivation of YAP1 in mouse cervical epithelium was sufficient to induce invasive cervical cancer. Cervical epithelial cell-specific HPV16 E6/E7 and YAP1 double-knockin mouse model demonstrated that high-risk HPV synergized with hyperactivated YAP1 to …

Ripk1 Can Mediate Apoptosis In Addition To Necroptosis During Embryonic Development., Xuhua Zhang, John P. Dowling, Jianke Zhang

Department of Microbiology and Immunology Faculty Papers

RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. …

Yap1-Lats2 Feedback Loop Dictates Senescent Or Malignant Cell Fate To Maintain Tissue Homeostasis, Chunbo He, Xiangmin Lv, Cong Huang, Guohua Hua, Bowen Ma, Xingcheng Chen, Peter C. Angeletti, Jixin Dong, Jin Zhou, Zhengfeng Wang, Bo R. Rueda, John S. Davis, Cheng Wang

Nebraska Center for Virology: Faculty Publications

Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 …

Tradd Regulates Perinatal Development And Adulthood Survival In Mice Lacking Ripk1 And Ripk3., John P. Dowling, Mohamed Alsabbagh, Christina Del Casale, Zheng-Gang Liu, Jianke Zhang

Department of Microbiology and Immunology Faculty Papers

TRADD is an adaptor for TNFR1-induced apoptosis and NFκB activation. However, TRADD-deficient mice undergo normal development and contain normal lymphoid populations, which contrasts with an embryonic defect in mice lacking FADD, the shared adaptor mediating apoptosis. Recent studies indicate FADD suppresses embryonic necroptosis mediated by RIPK1. TRADD was suggested to also mediate necroptosis. Here we report that targeting TRADD fails to rescue Fadd ^−/− embryos from necroptosis, and ablation of TRADD rescues Ripk1 ^−/− mice from perinatal lethality when RIPK3-mediated necroptosis is disabled. The resulting Ripk1 ^−/− Ripk3 ^−/− Tradd ^−/− mice survive until early adulthood, but die thereafter. A …

Efficacy Of Combination Of Immunotherapies In A Murine In A Murine Squamous Cell Carcinoma Model, E. Correia, C. Portocarrero, U. Rodeck

Phase 1

Introduction: Head and neck squamous cell carcinomas (HNSCCs) are a type of neoplasm found in the epithelium of the oral cavity, oropharynx, nasopharynx, larynx, or hypopharynx. Recent evidence has demonstrated that 70-90% of HNSCC are associated with Human Papillomavirus (HPV), particularly strain 16 producing oncogenic proteins E6/E7. Currently, HNSCCs are treated with surgery, chemotherapy, and radiation, however immunotherapy with immune checkpoint (PD-1) blocking agents promises to improve outcomes in HNSCC.

Objective: This study examined the therapeutic effects of dual and triple combination immunotherapies in a mouse model of HPV-associated HNSCC.

Methods: Treatment modalities included a tumor vaccine (attenuated Listeria monocytogenes …

The Underdeveloped Innate Immunity In Embryonic Stem Cells: The Molecular Basis And Biological Perspectives From Early Embryogenesis, Yan-Lin Guo

Faculty Publications

Embryonic stem cells (ESCs) have been intensively studied as a promising cell source for regenerative medicine. The rapid advancements in the field have not only proven the feasibility of ESC‐based cell therapy, but also led to a better understanding of pluripotent stem cells (PSCs) as a unique cell population at an early stage of embryogenesis. Recent studies have revealed that both human and mouse ESCs have attenuated innate immune responses to infectious agents and inflammatory cytokines. These findings raise interesting questions about the rationale for ESCs, the PSCs experimentally derived from preimplantation stage embryos, to not have an innate defense …

Quantitative Clinical And Autoimmune Assessments In Stiff Person Syndrome: Evidence For A Progressive Disorder., Goran Rakocevic, Harry Alexopoulos, Marinos C. Dalakas

Department of Neurology Faculty Papers

BACKGROUND: Stiff Person Syndrome (SPS) is an under-diagnosed disorder that affects mobility and the quality of life of affected patients. The aim of the study is to describe the natural history of SPS, the extent of accumulated disability and the associated clinical and immunological features in patients followed for up to 8 years in a single center.

METHODS: Our collective cohort included 57 SPS patients. Additionally, 32 of these patients were examined every 6 months for a two-year period in a longitudinal study protocol, to assess disease progression using quantitative measures of stiffness and heightened sensitivity.

RESULTS: The most frequent …

Intranasal Peptide-Based Fpva-Klh Conjugate Vaccine Protects Mice From Pseudomonas Aeruginosa Acute Murine Pneumonia, Emel Sen-Kilic, Catherine B. Blackwood, Dylan T. Boehm, Wiliam T. Witt, Aaron C. Malkowski, Justin R. Bevere, Ting Y. Wong, Jesse M. Hall, Shelby D. Bradford, Melinda E. Varney, Fredrick Heath Damron, Mariette Barbier

Faculty & Staff Scholarship

Pseudomonas aeruginosa is an opportunistic pathogen causing acute and chronic respiratory infections associated with morbidity and mortality, especially in patients with cystic fibrosis. Vaccination against P. aeruginosa before colonization may be a solution against these infections and improve the quality of life of at-risk patients. To develop a vaccine against P. aeruginosa, we formulated a novel peptide-based P. aeruginosa subunit vaccine based on the extracellular regions of one of its major siderophore receptors, FpvA. We evaluated the effectiveness and immunogenicity of the FpvA peptides conjugated to keyhole limpet hemocyanin (KLH) with the adjuvant curdlan in a murine vaccination and challenge …

Janus Kinase 1 Is Required For Transcriptional Reprograming Of Murine Astrocytes In Response To Endoplasmic Reticulum Stress, Savannah G. Sims, Gordon P. Meares

Faculty & Staff Scholarship

Neurodegenerative diseases are associated with the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. To adapt, cells initiate the unfolded protein response (UPR). However, severe or unresolved UPR activation leads to cell death and inflammation. The UPR is initiated, in part, by the transER membrane kinase PKR-like ER kinase (PERK). Recent evidence indicates ER stress and inflammation are linked, and we have shown that this involves PERKdependent signaling via Janus Kinase (JAK) 1. This signaling provokes the production of soluble inflammatory mediators such as interleukin-6 (IL-6) and chemokine C-C motif ligand 2 (CCL2). We, therefore, …

Endoplasmic Reticulum Stress Differentially Modulates The Il-6 Family Of Cytokines In Murine Astrocytes And Macrophages, Cristina L. Sanchez, Savnnah G. Sims, John D. Nowery, Gordon P. Meares

Faculty & Staff Scholarship

In many diseases, misfolded proteins accumulate within the endoplasmic reticulum (ER), leading to ER stress. In response, the cell initiates the unfolded protein response (UPR) to reestablish homeostasis. Additionally, in response to ER stress, various cell types mount an inflammatory response involving interleukin (IL)-6. While IL-6 has been widely studied, the impact of ER stress on other members of the IL-6 cytokine family, including oncostatin (OSM), IL-11, ciliary neurotrophic factor (CNTF), and leukemia inhibitor factor (LIF) remains to be elucidated. Here, we have examined the expression of the IL-6 family cytokines in response to pharmacologically-induced ER stress in astrocytes and …

Intranasal Acellular Pertussis Vaccine Provides Mucosal Immunity And Protects Mice From Bordetella Pertussis, Dylan T. Boehm, M. Allison Wolf, Jesse M. Hall, Ting Y. Wong, Emel Sen-Kilic, Hayden D. Basinger, Sebastian A. Dziadowicz, Maria De La Paz Gutierrez, Catherine B. Blackwood, Shelby D. Bradford, Katherine A. Begley, William T. Witt, Melinda E. Varney, Mariette Barbier, F. Heath Damron

Faculty & Staff Scholarship

Current acellular pertussis vaccines fall short of optimal protection against the human respiratory pathogen Bordetella pertussis resulting in increased incidence of a previously controlled vaccine- preventable disease. Natural infection is known to induce a protective mucosal immunity. Therefore, in this study, we aimed to use acellular pertussis vaccines to recapitulate these mucosal immune responses. We utilized a murine immunization and challenge model to characterize the efficacy of intranasal immunization (IN) with DTaP vaccine or DTaP vaccine supplemented with curdlan, a known Th1/Th17 promoting adjuvant. Protection from IN delivered DTaP was compared to protection mediated by intraperitoneal injection of DTaP and …

Bordetella Pertussis Can Be Motile And Express Flagellum-Like Structures, Cassandra L. Hoffman, Laura A. Gonyar, Federico Zacca, Federico Sisti, Julieta Fernandez, Ting Wong, F. Heath Damron, Erik L. Hewlett

Faculty & Staff Scholarship

ABSTRACT Bordetella bronchiseptica encodes and expresses a flagellar apparatus. In contrast, Bordetella pertussis, the causative agent of whooping cough, has historically been described as a nonmotile and nonflagellated organism. The previous statements that B. pertussis was a nonmotile organism were consistent with a stop codon located in the flagellar biosynthesis gene, flhA, discovered when the B. pertussis Tohama I genome was sequenced and analyzed by Parkhill et al. in 2003 (J. Parkhill, M. Sebaihia, A. Preston, L. D. Murphy, et al., Nat Genet, 35:32– 40, 2003, https://doi.org/10 .1038/ng1227). The stop codon has subsequently been found in all annotated genomes. Parkhill …

In Vivo Gene Essentiality And Metabolism In Bordetella Pertussis, Laura A. Gonyar, Patrick E. Gelbach, Dennis G. Mcduffe, Alexander F. Koeppel, Qing Chen, Gloria Lee, Louise M. Temple, Scott Stibitz, Erik L. Hewlwtt, Jason A. Papin, F. Heath Damron, Joshua C. Eby

Faculty & Staff Scholarship

Bordetella pertussis is the causative agent of whooping cough, a serious respiratory illness affecting children and adults, associated with prolonged cough and potential mortality. Whooping cough has reemerged in recent years, emphasizing a need for increased knowledge of basic mechanisms of B. pertussis growth and pathogenicity. While previous studies have provided insight into in vitro gene essentiality of this organism, very little is known about in vivo gene essentiality, a critical gap in knowledge, since B. pertussis has no previously identified environmental reservoir and is isolated from human respiratory tract samples. We hypothesize that the metabolic capabilities of B. pertussis …

Caspase-11 Mediates Neutrophil Chemotaxis And Extracellular Trap Formation During Acute Gouty Arthritis Through Alteration Of Cofilin Phosphorylation, Kyle Caution, Nicholas Young, Frank Robledo-Avila, Kathrin Krause, Arwa Abu Khweek, Kaitlin Hamilton, Asmaa Badr, Anup Vaidya, Kylene Daily, Hawin Gosu, Midhun N. K. Anne, Mostafa Eltobgy, Duaa Dakhlallah, Sudha Argwal, Shady Estfanous, Xiaoli Zhang, Santiago Partida-Sanchez, Mikhail A. Gavrilin, Wael N. Jarjour, Amal O. Amer

Faculty & Staff Scholarship

Gout is characterized by attacks of arthritis with hyperuricemia and monosodium urate (MSU) crystal-induced inflammation within joints. Innate immune responses are the primary drivers for tissue destruction and inflammation in gout. MSU crystals engage the Nlrp3 inflammasome, leading to the activation of caspase-1 and production of IL-1β and IL-18 within gout-affected joints, promoting the influx of neutrophils and monocytes. Here, we show that caspase-11−/− mice and their derived macrophages produce significantly reduced levels of gout-specific cytokines including IL-1β, TNFα, IL-6, and KC, while others like IFNγ and IL-12p70 are not altered. IL-1β induces the expression of caspase-11 in an IL-1 …

Structural And Functional Determinants Of Rodent And Human Surfactant Protein A: A Synthesis Of Binding And Computational Data, Armen Nalian, Todd M. Umstead, Ching-Hui Yang, Patricia Silveyra, Neal J. Thomas, Joanna Floros, Francis X. Mccormack, Zissis C. Chroneos

Faculty Publications

Surfactant protein A (SP-A) provides surfactant stability, first line host defense, and lung homeostasis by binding surfactant phospholipids, pathogens, alveolar macrophages (AMs), and epithelial cells. Non-primates express one SP-A protein whereas humans express two: SP-A1 and SP-A2 with core intra- and inter-species differences in the collagen-like domain. Here, we used macrophages and solid phase binding assays to discern structural correlates of rat (r) and human (h) SP-A function. Binding assays using recombinant rSP-A expressed in insect cells showed that lack of proline hydroxylation, truncations of amino-terminal oligomerization domains, and site-directed serine (S) or alanine (A) mutagenesis of cysteine 6 (C6S), …

Antibodies In The Diagnosis, Prognosis, And Prediction Of Psychotic Disorders., Thomas A Pollak, Jonathan P Rogers, Robert G Nagele, Mark Peakman, James M Stone, Anthony S David, Philip Mcguire

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Blood-based biomarker discovery for psychotic disorders has yet to impact upon routine clinical practice. In physical disorders antibodies have established roles as diagnostic, prognostic and predictive (theranostic) biomarkers, particularly in disorders thought to have a substantial autoimmune or infective aetiology. Two approaches to antibody biomarker identification are distinguished: a "top-down" approach, in which antibodies to specific antigens are sought based on the known function of the antigen and its putative role in the disorder, and emerging "bottom-up" or "omics" approaches that are agnostic as to the significance of any one antigen, using high-throughput arrays to identify distinctive components of the …