Medical Immunology Commons^™

Sars‑Cov‑2 Entry Into And Evolution Within A Skilled Nursing Facility, Nicole R. Sexton, Parker Parker Cline, Emily N. Gallichotte, Emily Fitzmeyer, Michael C. Young, Ashley J. Janich, Kristy L. Pabilonia, Nicole Ehrhart, Gregory D. Ebel

Nebraska Center for Virology: Faculty Publications

SARS-CoV-2 belongs to the family Coronaviridae which includes multiple human pathogens that have an outsized impact on aging populations. As a novel human pathogen, SARS-CoV-2 is undergoing continuous adaptation to this new host species and there is evidence of this throughout the scientific and public literature. However, most investigations of SARS-CoV-2 evolution have focused on largescale collections of data across diverse populations and/or living environments. Here we investigate SARS-CoV-2 evolution in epidemiologically linked individuals within a single outbreak at a skilled nursing facility beginning with initial introduction of the pathogen. The data demonstrate that SARSCoV- 2 was introduced to the …

Performance Of A Modified Fracture Risk Assessment Tool For Fragility Fracture Prediction Among Older Veterans Living With Hiv, Julie A Womack, Terrence E Murphy, Linda Leo-Summers, Farah Kidwai-Khan, Melissa Skanderson, Thomas M Gill, Barbara Gulanski, Maria C Rodriguez-Barradas, Phyllis C Tien, Michael T Yin, Evelyn Hsieh

Faculty, Staff and Students Publications

OBJECTIVE: Fragility fractures (fractures) are a critical outcome for persons aging with HIV (PAH). Research suggests that the fracture risk assessment tool (FRAX) only modestly estimates fracture risk among PAH. We provide an updated evaluation of how well a 'modified FRAX' identifies PAH at risk for fractures in a contemporary HIV cohort.

DESIGN: Cohort study.

METHODS: We used data from the Veterans Aging Cohort Study to evaluate veterans living with HIV, aged 50+ years, for the occurrence of fractures from 1 January 2010 through 31 December 2019. Data from 2009 were used to evaluate the eight FRAX predictors available to …

Structural Insights Into Rna Bridging Between Hiv-1 Vif And Antiviral Factor Apobec3g, Takahide Kouno, Satoshi Shibata, Megumi Shigematsu, Jaekyung Hyun, Tae Gyun Kim, Hiroshi Matsuo, Matthias Wolf

Computational Medicine Center Faculty Papers

Great effort has been devoted to discovering the basis of A3G-Vif interaction, the key event of HIV's counteraction mechanism to evade antiviral innate immune response. Here we show reconstitution of the A3G-Vif complex and subsequent A3G ubiquitination in vitro and report the cryo-EM structure of the A3G-Vif complex at 2.8 Å resolution using solubility-enhanced variants of A3G and Vif. We present an atomic model of the A3G-Vif interface, which assembles via known amino acid determinants. This assembly is not achieved by protein-protein interaction alone, but also involves RNA. The cryo-EM structure and in vitro ubiquitination assays identify an adenine/guanine base …

Adjuvanted Fusion Protein Vaccine Induces Durable Immunity To Onchocerca Volvulus In Mice And Non-Human Primates, Nathan M. Ryan, Jessica A. Hess, Erica J. Robertson, Nancy Tricoche, Cheri Turner, Jenn Davis, Nikolai Petrovsky, Melissa Ferguson, William J. Rinaldi, Valerie M. Wong, Ayako Shimada, Bin Zhan, Maria Elena Bottazzi, Benjamin L. Makepece, Sean A. Gray, Darrick Carter, Sara Lustigman, David Abraham

Department of Microbiology and Immunology Faculty Papers

Onchocerciasis remains a debilitating neglected tropical disease. Due to the many challenges of current control methods, an effective vaccine against the causative agent Onchocerca volvulus is urgently needed. Mice and cynomolgus macaque non-human primates (NHPs) were immunized with a vaccine consisting of a fusion of two O. volvulus protein antigens, Ov-103 and Ov-RAL-2 (Ov-FUS-1), and three different adjuvants: Advax-CpG, alum, and AlT4. All vaccine formulations induced high antigen-specific IgG titers in both mice and NHPs. Challenging mice with O. volvulus L3 contained within subcutaneous diffusion chambers demonstrated that Ov-FUS-1/Advax-CpG-immunized animals developed protective immunity, durable for at least 11 weeks. Passive …

Yes-Associated Protein-1 Overexpression In Ocular Surface Squamous Neoplasia; A Potential Diagnostic Marker And Therapeutic Target, Peter Julius, Stepfanie N. Siyumbwa, Fred Maate, Phyllis Moonga, Guobin Kang, Trevor Kaile, John T. T., Charles Wood

Nebraska Center for Virology: Faculty Publications

Yes-associated protein-1 (YAP-1) is a Hippo system transcription factor, which serves as an oncogene in squamous cell carcinoma, and several solid tumors when the Hippo pathway is dysregulated. Yet, the activity of YAP-1 in ocular surface squamous neoplasia (OSSN) has not been determined. Here, we investigate the relationship between YAP-1 overexpression and OSSN. Using a cross-sectional study design, we recruited 227 OSSN patients from the University Teaching Hospitals in Lusaka, Zambia. Immunohistochemistry was used to assess YAP-1 protein overexpression in tumor tissue relative to surrounding benign squamous epithelium. OSSN patient samples (preinvasive, n = 62, 27% and invasive, n = …

Pediatric Vitamin D: Pseudo-Hypervitaminosis, Lily Olayinka, Izmarie Poventud-Fuentes, Emily Garnett, Sridevi Devaraj

Faculty, Staff and Students Publications

BACKGROUND: Vitamin D toxicity is rare in pediatric population. Falsely elevated levels of 25-hydroxyvitamin D have been reported as a major challenge with immunoassay methods for quantifying vitamin D metabolites.

CASE PRESENTATION AND METHOD: Here, we present two pediatric cases of falsely elevated 25-hydroxyvitamin D that resulted in unnecessary further testing. We also report significant same-day variation in the measurement of 25-hydroxyvitamin D using the Abbott i2000SR immunoassay. Samples were spun twice and their values were confirmed with the gold standard liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for confirmation.

CONCLUSION: The addition of a centrifugation step prior to sample testing …

Barriers To A Successful Healthcare Transition For Individuals With Urea Cycle Disorders, Farah A Ladha, Cynthia Le Mons, William J Craigen, Pilar L Magoulas, Ronit Marom, Andrea M Lewis

Faculty, Staff and Students Publications

The pediatric to adult healthcare transition (HCT) is a process for individuals with chronic health conditions to gradually shift from a pediatric to an adult-oriented care system. Autonomy and self-management skills required for an individual's HCT readiness can be evaluated through the transition readiness assessment questionnaire (TRAQ). Despite general HCT preparation guidelines, little is known about the HCT experience of individuals with a urea cycle disorder (UCD). This is the first study to report the parent or guardian perception of the HCT process in children with a UCD by investigating the stages of transition readiness and transition outcome. We identify …

Genome-Wide Association Analyses Define Pathogenic Signaling Pathways And Prioritize Drug Targets For Iga Nephropathy, Krzysztof Kiryluk, Elena Sanchez-Rodriguez, Xu-Jie Zhou, Francesca Zanoni, Lili Liu, Nikol Mladkova, Atlas Khan, Maddalena Marasa, Jun Y Zhang, Olivia Balderes, Simone Sanna-Cherchi, Andrew S Bomback, Pietro A Canetta, Gerald B Appel, Jai Radhakrishnan, Hernan Trimarchi, Ben Sprangers, Daniel C Cattran, Heather Reich, York Pei, Pietro Ravani, Kresimir Galesic, Dita Maixnerova, Vladimir Tesar, Benedicte Stengel, Marie Metzger, Guillaume Canaud, Nicolas Maillard, Francois Berthoux, Laureline Berthelot, Evangeline Pillebout, Renato Monteiro, Raoul Nelson, Robert J Wyatt, William Smoyer, John Mahan, Al-Akash Samhar, Guillermo Hidalgo, Alejandro Quiroga, Patricia Weng, Raji Sreedharan, David Selewski, Keefe Davis, Mahmoud Kallash, Tetyana L Vasylyeva, Michelle Rheault, Aftab Chishti, Daniel Ranch, Scott E Wenderfer, Dmitry Samsonov, Donna J Claes, Oleh Akchurin, Dimitrios Goumenos, Maria Stangou, Judit Nagy, Tibor Kovacs, Enrico Fiaccadori, Antonio Amoroso, Cristina Barlassina, Daniele Cusi, Lucia Del Vecchio, Giovanni Giorgio Battaglia, Monica Bodria, Emanuela Boer, Luisa Bono, Giuliano Boscutti, Gianluca Caridi, Francesca Lugani, Gianmarco Ghiggeri, Rosanna Coppo, Licia Peruzzi, Vittoria Esposito, Ciro Esposito, Sandro Feriozzi, Rosaria Polci, Giovanni Frasca, Marco Galliani, Maurizio Garozzo, Adele Mitrotti, Loreto Gesualdo, Simona Granata, Gianluigi Zaza, Francesco Londrino, Riccardo Magistroni, Isabella Pisani, Andrea Magnano, Carmelita Marcantoni, Piergiorgio Messa, Renzo Mignani, Antonello Pani, Claudio Ponticelli, Dario Roccatello, Maurizio Salvadori, Erica Salvi, Domenico Santoro, Guido Gembillo, Silvana Savoldi, Donatella Spotti, Pasquale Zamboli, Claudia Izzi, Federico Alberici, Elisa Delbarba, Michał Florczak, Natalia Krata, Krzysztof Mucha, Leszek Pączek, Stanisław Niemczyk, Barbara Moszczuk, Malgorzata Pańczyk-Tomaszewska, Malgorzata Mizerska-Wasiak, Agnieszka Perkowska-Ptasińska, Teresa Bączkowska, Magdalena Durlik, Krzysztof Pawlaczyk, Przemyslaw Sikora, Marcin Zaniew, Dorota Kaminska, Magdalena Krajewska, Izabella Kuzmiuk-Glembin, Zbigniew Heleniak, Barbara Bullo-Piontecka, Tomasz Liberek, Alicja Dębska-Slizien, Tomasz Hryszko, Anna Materna-Kiryluk, Monika Miklaszewska, Maria Szczepańska, Katarzyna Dyga, Edyta Machura, Katarzyna Siniewicz-Luzeńczyk, Monika Pawlak-Bratkowska, Marcin Tkaczyk, Dariusz Runowski, Norbert Kwella, Dorota Drożdż, Ireneusz Habura, Florian Kronenberg, Larisa Prikhodina, David Van Heel, Bertrand Fontaine, Chris Cotsapas, Cisca Wijmenga, Andre Franke, Vito Annese, Peter K Gregersen, Sreeja Parameswaran, Matthew Weirauch, Leah Kottyan, John B Harley, Hitoshi Suzuki, Ichiei Narita, Shin Goto, Hajeong Lee, Dong Ki Kim, Yon Su Kim, Jin-Ho Park, Belong Cho, Murim Choi, Ans Van Wijk, Ana Huerta, Elisabet Ars, Jose Ballarin, Sigrid Lundberg, Bruno Vogt, Laila-Yasmin Mani, Yasar Caliskan, Jonathan Barratt, Thilini Abeygunaratne, Philip A Kalra, Daniel P Gale, Ulf Panzer, Thomas Rauen, Jürgen Floege, Pascal Schlosser, Arif B Ekici, Kai-Uwe Eckardt, Nan Chen, Jingyuan Xie, Richard P Lifton, Ruth J F Loos, Eimear E Kenny, Iuliana Ionita-Laza, Anna Köttgen, Bruce A Julian, Jan Novak, Francesco Scolari, Hong Zhang, Ali G Gharavi

Faculty, Staff and Students Publications

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum …

First-In-Human Study Of Oleclumab, A Potent, Selective Anti-Cd73 Monoclonal Antibody, Alone Or In Combination With Durvalumab In Patients With Advanced Solid Tumors, Johanna Bendell, Patricia Lorusso, Michael Overman, Anne M Noonan, Dong-Wan Kim, John H Strickler, Sang-We Kim, Stephen Clarke, Thomas J George, Peter S Grimison, Minal Barve, Manik Amin, Jayesh Desai, Trisha Wise-Draper, Steven Eck, Yu Jiang, Anis A Khan, Yuling Wu, Philip Martin, Zachary A Cooper, Nairouz Elgeioushi, Nancy Mueller, Rakesh Kumar, Sandip Pravin Patel

Faculty, Staff and Student Publications

BACKGROUND: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC).

METHODS: Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W.

RESULTS: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy …

Time Is Ticking For Cervical Cancer, Vijay Kumar, Caitlin Bauer, John H. Stewart

School of Medicine Faculty Publications

Cervical cancer (CC) is a major health problem among reproductive-age females and comprises a leading cause of cancer-related deaths. Human papillomavirus (HPV) is the major risk factor associated with CC incidence. However, lifestyle is also a critical factor in CC pathogenesis. Despite HPV vaccination introduction, the incidence of CC is increasing worldwide. Therefore, it becomes critical to understand the CC tumor immune microenvironment (TIME) to develop immune cell-based vaccination and immunotherapeutic approaches. The current article discusses the immune environment in the normal cervix of adult females and its role in HPV infection. The subsequent sections discuss the alteration of different …

Equine Polyclonal Antibodies Prevent Acute Chikungunya Virus Infection In Mice, Douglas Barker, Xiaobing Han, Eryu Wang, Ashley Dagley, Deborah M. Anderson, Aruni Jha, Scott C. Weaver, Justin Julander, Cory Nykiforuk, Shantha Kodihalli

Office of Research Faculty and Staff Publications

Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen that causes chikungunya disease (CHIK); the disease is characterized by fever, muscle ache, rash, and arthralgia. This arthralgia can be debilitating and long-lasting, seriously impacting quality of life for years. Currently, there is no specific therapy available for CHIKV infection. We have developed a despeciated equine polyclonal antibody (CHIKV-EIG) treatment against CHIKV and evaluated its protective efficacy in mouse models of CHIKV infection. In immunocompromised (IFNAR^−/−) mice infected with CHIKV, daily treatment for five consecutive days with CHIKV-EIG administered at 100 mg/kg starting on the day of infection prevented mortality, reduced …

The Utility Of Fecal Calprotectin In The Diagnosis And Management Of Microscopic Colitis, Busara Songtanin, Abbie Evans, Kenneth Nugent, Vanessa Costilla

Journal of Community Hospital Internal Medicine Perspectives

Background: The incidence of microscopic colitis has increased over time. To date, there is no specific biomarker for microscopic colitis, and the diagnosis relies on histopathological tissue obtained during colonoscopy which is an invasive and costly procedure. Unlike Crohn’s disease and ulcerative colitis, the utility of fecal calprotectin in diagnosing or monitoring microscopic colitis has not been established, and studies on the role of fecal calprotectin in microscopic colitis are limited. In this retrospective study, we analyzed the utility of this biomarker in the diagnosis of microscopic colitis. Methods: The medical records of patients who have been diagnosed with collagenous …

Il-11 Induces Nlrp3 Inflammasome Activation In Monocytes And Inflammatory Cell Migration To The Central Nervous System, Maryamsadat Seyedsadr, Yan Wang, Manal Elzoheiry, Sowmya Shree Gopal, Soohwa Jang, Gayel Duran, Inna Chervoneva, Ezgi Kasimoglu, John A. Wrobel, Daniel Hwang, James Garifallou, Xin Zhang, Tabish H. Khan, Ulrike Lorenz, Maureen Su, Jenny P. Ting, Bieke Broux, A M Rostami, Dhanashri Miskin, Silva Markovic-Plese

Department of Neurology Faculty Papers

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes, and IL-11R+ neutrophils in comparison to matched healthy controls. IL-11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of …

Cutting Edge: Il-21 And Tissue-Specific Signals Instruct Tbet+Cd11c+ B Cell Development Following Viral Infection, Wenzhi Song, Gina M Sanchez, Daniel P Mayer, Holly N Blackburn, Irene Chernova, Richard A Flavell, Jason S Weinstein, Joe Craft

Faculty, Staff and Student Publications

Tbet+CD11c+ B cells, also known as age-associated B cells (ABCs), are pivotal contributors to humoral immunity following infection and in autoimmunity, yet their in vivo generation is incompletely understood. We used a mouse model of systemic acute lymphocytic choriomeningitis virus infection to examine the developmental requirements of ABCs that emerged in the spleen and liver. IL-21 signaling through STAT3 was indispensable for ABC development. In contrast, IFN-γ signaling through STAT1 was required for B cell activation and proliferation. Mice that underwent splenectomy or were deficient in lymphotoxin α generated hepatic ABCs despite the lack of secondary lymphoid organ contributions, suggesting …

Relative And Quantitative Characterization Of The Bovine Bacterial Ocular Surface Microbiome In The Context Of Suspected Ocular Squamous Cell Carcinoma, Hannah B. Gafen, Chin-Chi Liu, Nikole E. Ineck, Clare M. Scully, Melanie A. Mironovich, Lauren Guarneri, Christopher M. Taylor, Meng Luo, Marina L. Leis, Erin M. Scott, Renee T. Carter, Andrew C. Lewin

School of Medicine Faculty Publications

The ocular surface microbiome is altered in certain disease states. The aim of this study was to characterize the bovine bacterial ocular surface microbiome (BBOSM) in the context of ocular squamous cell carcinoma (OSCC). The conjunctiva of normal (n = 28) and OSCC (n = 10) eyes of cows aged 2 to 13 years from two farms in Louisiana and Wyoming were sampled using individual sterile swabs. DNA extraction followed by 16S ribosomal ribonucleic acid (rRNA) gene sequencing and real-time polymerase chain reaction (RT-PCR) were performed to, respectively, assess the relative and absolute BBOSM. Discriminant analysis (DA) was performed using …

Assessment Of The First Presentations Of Common Variable Immunodeficiency In A Large Cohort Of Patients, Hossein Esmaeilzadeh, Armita Jokar-Derisi, Amir Hossein Hassani, Reza Yazdani, Samaneh Delavari, Hassan Abolhassani, Negar Mortazavi, Aida Askarisarvestani

Department of Neurology Faculty Papers

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations.

METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated.

RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) …

Effects Of Interleukin-22 (Il-22) On Necroptosis, Inflammatory Responses, And Metabolism Of Mycobacterium Tuberculosis Stimulated Type 2 Diabetes Mellitus Mouse Macrophages, Bismark Owusu-Afriyie

Biotechnology Theses

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and causes nearly 1.3 million deaths per year. Limited information is available about the immune responses during Mtb infection in type 2 diabetic hosts. Our laboratory developed an experimentally induced type 2 diabetes (T2DM) model in wild-type C57BL/6 mice and found that IL-22 and type 3 innate lymphoid cells (ILC3s) reduce inflammation and mortality of Mtb-infected T2DM mice. Our laboratory also found that Mtb-infected alveolar macrophages (AMs) from T2DM mice undergo necroptosis compared to Mtb-infected AMs of non-T2DM mice. In the current study, we determined whether …

Viral Dna Accumulation Regulates Replication Efficiency Of Chlorovirus Osy-Ne5 In Two Closely Related Chlorella Variabilis Strains, Ahmed Esmael, Irina V. Agarkova, David D. Dunigan, You Zhou, James L. Van Etten

Nebraska Center for Virology: Faculty Publications

Many chloroviruses replicate in Chlorella variabilis algal strains that are ex-endosymbionts isolated from the protozoan Paramecium bursaria, including the NC64A and Syngen 2-3 strains. We noticed that indigenous water samples produced a higher number of plaque-forming viruses on C. variabilis Syngen 2-3 lawns than on C. variabilis NC64A lawns. These observed differences led to the discovery of viruses that replicate exclusively in Syngen 2-3 cells, named Only Syngen (OSy) viruses. Here, we demonstrate that OSy viruses initiate infection in the restricted host NC64A by synthesizing some early virus gene products and that approximately 20% of the cells produce a …

Interleukin-1 Signaling And Alcohol-Induced Cortical Dysfunction, Florence Varodayan, Amanda Pahng, Tony Davis, T. Nadav, I. Polis, C.C. Cates-Gatto, Michal Bajo, Michael D. Burkart, Scott Edwards, Amanda J. Roberts, Marisa Roberto

School of Medicine Faculty Publications

Alcoholism and Stress: A Framework for Future Treatment Strategies; Volterra, Italy; May 16-19, 2023

The Role Of Limch1 Alternative Splicing In Skeletal Muscle Function, Matthew S Penna, Rong-Chi Hu, George G Rodney, Thomas A Cooper

Faculty, Staff and Students Publications

Postnatal skeletal muscle development is a highly dynamic period associated with widespread alternative splicing changes required to adapt tissues to adult function. These splicing events have significant implications because the reversion of adult mRNA isoforms to fetal isoforms is observed in forms of muscular dystrophy. LIMCH1 is a stress fiber–associated protein that is alternatively spliced to generate uLIMCH1, a ubiquitously expressed isoform, and mLIMCH1, a skeletal muscle–specific isoform containing six additional exons simultaneously included after birth in the mouse. CRISPR/Cas9 was used to delete the six alternatively spliced exons of LIMCH1 in mice, thereby forcing the constitutive expression of the …