Digital Commons Network^™

Replicative Acinetobacter Baumannii Strains Interfere With Phagosomal Maturation By Modulating The Vacuolar Ph, Jesus S. Distel, Gisela Di Venanzio, Joseph J. Mackel, David A. Rosen, Mario F. Feldman

2020-Current year OA Pubs

Bacterial pneumonia is a common infection of the lower respiratory tract that can afflict patients of all ages. Multidrug-resistant strains of Acinetobacter baumannii are increasingly responsible for causing nosocomial pneumonias, thus posing an urgent threat. Alveolar macrophages play a critical role in overcoming respiratory infections caused by this pathogen. Recently, we and others have shown that new clinical isolates of A. baumannii, but not the common lab strain ATCC 19606 (19606), can persist and replicate in macrophages within spacious vacuoles that we called Acinetobacter Containing Vacuoles (ACV). In this work, we demonstrate that the modern A. baumannii clinical isolate 398, …

Interleukin-18 Signaling Promotes Activation Of Hepatic Stellate Cells In Mouse Liver Fibrosis, Jana Knorr, Joel D. Schilling, Et Al.

2020-Current year OA Pubs

BACKGROUND AND AIMS: Nucleotide-binding oligomerization domain-like receptor-family pyrin domain-containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL-18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis.

APPROACH AND RESULTS: We observed significantly increased serum levels of IL-18 (128.4 pg/ml vs. 74.9 pg/ml) and IL-18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1 . …

Multi-Omic Assessment Shows Dysregulation Of Pulmonary And Systemic Immunity To E-Cigarette Exposure, David P. Scieszka, Devon Garland, Russell Hunter, Guy Herbert, Selita Lucas, Yan Jin, Haiwei Gu, Matthew J. Campen, Judy L. Cannon

Pathology Research and Scholarship

Electronic cigarette (Ecig) use has become more common, gaining increasing acceptance as a safer alternative to tobacco smoking. However, the 2019 outbreak of Ecig and Vaping-Associated Lung Injury (EVALI) alerted the community to the potential for incorporation of deleterious ingredients such as vitamin E acetate into products without adequate safety testing. Understanding Ecig induced molecular changes in the lung and systemically can provide a path to safety assessment and protect consumers from unsafe formulations. While vitamin E acetate has been largely removed from commercial and illicit products, many Ecig products contain additives that remain largely uncharacterized. In this study, we …

Beclin-1-Dependent Autophagy, But Not Apoptosis, Is Critical For Stem-Cell-Mediated Endometrial Programming And The Establishment Of Pregnancy, Pooja Popli, Suni Tang, Sangappa B Chadchan, Chandni Talwar, Edmund B Rucker, Xiaoming Guan, Diana Monsivais, John P Lydon, Christina L Stallings, Kelle H Moley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5+/Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin …

An Ocular Th1 Immune Response Promotes Corneal Nerve Damage Independently Of The Development Of Corneal Epitheliopathy, Alexia Vereertbrugghen, Manuela Pizzano, Florencia Sabbione, Irene Angelica Keitelman, Carolina Maiumi Shiromizu, Douglas Vera Aguilar, Federico Fuentes, Cintia S De Paiva, Mirta Giordano, Analía Trevani, Jeremías G Galletti

Faculty, Staff and Students Publications

Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured …

Infection Of Neonatal Mice With The Murine Norovirus Strain Wu23 Is A Robust Model To Study Norovirus Pathogenesis, Amy M Peiper, Emily W Helm, Quyen Nguyen, Matthew Phillips, Caroline G Williams, Dhairya Shah, Sarah Tatum, Neha Iyer, Marco Grodzki, Laura B Eurell, Aqsa Nasir, Megan T Baldridge, Stephanie M Karst

2020-Current year OA Pubs

Noroviruses are the leading cause of severe childhood diarrhea and foodborne disease worldwide. While they are a major cause of disease in all age groups, infections in the very young can be quite severe, with annual estimates of 50,000-200,000 fatalities in children under 5 years old. In spite of the remarkable disease burden associated with norovirus infections, very little is known about the pathogenic mechanisms underlying norovirus diarrhea, principally because of the lack of tractable small animal models. The development of the murine norovirus (MNV) model nearly two decades ago has facilitated progress in understanding host-norovirus interactions and norovirus strain …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and …

Updated Analysis To Reject The Laboratory-Engineering Hypothesis Of Sars-Cov-2, Fuqing Wu

Faculty, Staff and Student Publications

A clear understanding of the origin of SARS-CoV-2 is important for future pandemic preparedness. Here, I provided an updated analysis of the type IIS endonuclease maps in genomes of alphacoronavirus, betacoronavirus, and SARS-CoV-2. Scenarios to engineer SARS-CoV-2 in the laboratory and the associated workload was also discussed. The analysis clearly shows that the endonuclease fingerprint does not indicate a synthetic origin of SARS-CoV-2 and engineering a SARS-CoV-2 virus in the laboratory is extremely challenging both scientifically and financially. On the contrary, current scientific evidence does support the animal origin of SARS-CoV-2.

Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Kyung Soo Park, Andrew Kennedy, Xingwu Zhou, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the …

Adad2 Functions In Spermiogenesis And Pirna Biogenesis In Mice, Yonggang Lu, Ippei Nagamori, Hisato Kobayashi, Kanako Kojima-Kita, Kenjiro Shirane, Hsin-Yi Chang, Toru Nishimura, Takayuki Koyano, Zhifeng Yu, Julio M Castañeda, Makoto Matsuyama, Satomi Kuramochi-Miyagawa, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

BACKGROUND: Adenosine deaminase domain containing 2 (ADAD2) is a testis-specific protein composed of a double-stranded RNA binding domain and a non-catalytic adenosine deaminase domain. A recent study showed that ADAD2 is indispensable for the male reproduction in mice. However, the detailed functions of ADAD2 remain elusive.

OBJECTIVES: This study aimed to investigate the cause of male sterility in Adad2 mutant mice and to understand the molecular functions of ADAD2.

MATERIALS AND METHODS: Adad2 homozygous mutant mouse lines, Adad2

RESULTS: Adad2–/– and Adad2Δ/Δ mice exhibit male-specific sterility due to abnormal spermiogenesis. ADAD2 interacts with multiple RNA-binding proteins involved in …

Endogenous Interleukin-10 Contributes To Wound Healing And Regulates Tissue Repair, Walker D Short, Meredith Rae, Thomas Lu, Benjamin Padon, Tanuj J Prajapati, Fayiz Faruk, Oluyinka O Olutoye, Ling Yu, Paul Bollyky, Sundeep G Keswani, Swathi Balaji

Faculty, Staff and Students Publications

INTRODUCTION: Interleukin-10 (IL-10) is essential in fetal regenerative wound healing and likewise promotes a regenerative phenotype in adult dermal wounds. However, the role of endogenous IL-10 in postnatal dermal wound healing is not well-established. We sought to determine the function of endogenous IL-10 in murine full thickness excisional wounds that are splinted to prevent contracture and mimic human patterns of wound closure.

METHODS: Full-thickness excisional wounds were made in wildtype (WT) and IL-10

RESULTS: We observed no difference in wound healing rate between WT and IL-10

CONCLUSIONS: These data suggest that endogenous IL-10 expression does not alter closure of full …

Capsular Polysaccharide Inhibits Vaccine-Induced O-Antigen Antibody Binding And Function Across Both Classical And Hypervirulent K2:O1 Strains Of Klebsiella Pneumoniae, Paeton L. Wantuch, Cory J. Knoot, Lloyd S. Robinson, Evgeny Vinogradov, Nichollas E. Scott, Christian M. Harding, David A. Rosen

2020-Current year OA Pubs

Klebsiella pneumoniae presents as two circulating pathotypes: classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp). Classical isolates are considered urgent threats due to their antibiotic resistance profiles, while hvKp isolates have historically been antibiotic susceptible. Recently, however, increased rates of antibiotic resistance have been observed in both hvKp and cKp, further underscoring the need for preventive and effective immunotherapies. Two distinct surface polysaccharides have gained traction as vaccine candidates against K. pneumoniae: capsular polysaccharide and the O-antigen of lipopolysaccharide. While both targets have practical advantages and disadvantages, it remains unclear which of these antigens included in a vaccine would …

Microbubble Cavitation Restores Staphylococcus Aureus Antibiotic Susceptibility In Vitro And In A Septic Arthritis Model, Neil Zhao, Dylan Curry, Rachel E Evans, Selin Isguven, Theresa A. Freeman, John R. Eisenbrey, Flemming Forsberg, Jessica M Gilbertie, Sophie Boorman, Rachel Hilliard, Sana S. Dastgheyb, Priscilla Machado, Maria Stanczak, Marc I. Harwood, Antonia F Chen, Javad Parvizi, Irving Shapiro, Noreen J. Hickok, Thomas P Schaer

Department of Orthopaedic Surgery Faculty Papers

Treatment failure in joint infections is associated with fibrinous, antibiotic-resistant, floating and tissue-associated Staphylococcus aureus aggregates formed in synovial fluid (SynF). We explore whether antibiotic activity could be increased against Staphylococcus aureus aggregates using ultrasound-triggered microbubble destruction (UTMD), in vitro and in a porcine model of septic arthritis. In vitro, when bacterially laden SynF is diluted, akin to the dilution achieved clinically with lavage and local injection of antibiotics, amikacin and ultrasound application result in increased bacterial metabolism, aggregate permeabilization, and a 4-5 log decrease in colony forming units, independent of microbubble destruction. Without SynF dilution, amikacin + UTMD does …

Development Of A Corticosteroid-Immunosuppressed Mouse Model To Study The Pathogenesis And Therapy Of Influenza-Associated Pulmonary Aspergillosis, Sebastian Wurster, Jezreel Pantaleón García, Nathaniel D Albert, Ying Jiang, Keerthi Bhoda, Vikram V Kulkarni, Yongxing Wang, Thomas J Walsh, Scott Evans, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.

Il-15 Enhances Hiv-1 Infection By Promoting Survival And Proliferation Of Ccr5+Cd4+ T Cells, Yuhao Li, Hongbo Gao, Kolin M. Clark, Liang Shan

2020-Current year OA Pubs

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 was expressed by CD4+ T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL-2/IL-15 receptor common β and γ chains. IL-15, but not IL-7, improved the survival of CCR5+CD4+ T cells, drove their expansion, …

Myeloid Autophagy Genes Protect Mice Against Fatal Tnf- And Lps-Induced Cytokine Storm Syndromes, Ya-Ting Wang, Amy Sansone, Asya Smirnov, Christina L Stallings, Anthony Orvedahl

2020-Current year OA Pubs

ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin …

Genomic Analysis Of Two Phlebotomine Sand Fly Vectors Of Leishmania From The New And Old World, Frédéric Labbé, Maha Abdeladhim, Jenica Abrudan, Alejandra Saori Araki, Ricardo N Araujo, Peter Arensburger, Joshua B Benoit, Reginaldo Pecanha Brazil, Rafaela V Bruno, Gustavo Bueno Da Silva Rivas, Vinicius Carvalho De Abreu, Jason Charamis, Iliano V Coutinho-Abreu, Samara G Da Costa-Latgé, Alistair Darby, Viv M Dillon, Scott J Emrich, Daniela Fernandez-Medina, Nelder Figueiredo Gontijo, Catherine M Flanley, Derek Gatherer, Fernando A Genta, Sandra Gesing, Gloria I Giraldo-Calderón, Bruno Gomes, Eric Roberto Guimaraes Rocha Aguiar, James G C Hamilton, Omar Hamarsheh, Mallory Hawksworth, Jacob M Hendershot, Paul V Hickner, Jean-Luc Imler, Panagiotis Ioannidis, Emily C Jennings, Shaden Kamhawi, Charikleia Karageorgiou, Ryan C Kennedy, Andreas Krueger, José M Latorre-Estivalis, Petros Ligoxygakis, Antonio Carlos A Meireles-Filho, Patrick Minx, Jose Carlos Miranda, Michael J Montague, Ronald J Nowling, Fabiano Oliveira, João Ortigão-Farias, Marcio G Pavan, Marcos Horacio Pereira, Andre Nobrega Pitaluga, Roenick Proveti Olmo, Marcelo Ramalho-Ortigao, José M C Ribeiro, Andrew J Rosendale, Mauricio R V Sant'anna, Steven E Scherer, Nágila F C Secundino, Douglas A Shoue, Caroline Da Silva Moraes, João Silveira Moledo Gesto, Nataly Araujo Souza, Zainulabueddin Syed, Samuel Tadros, Rayane Teles-De-Freitas, Erich L Telleria, Chad Tomlinson, Yara M Traub-Csekö, João Trindade Marques, Zhijian Tu, Maria F Unger, Jesus Valenzuela, Flávia V Ferreira, Karla P V De Oliveira, Felipe M Vigoder, John Vontas, Lihui Wang, Gareth D Weedall, Elyes Zhioua, Stephen Richards, Wesley C Warren, Robert M Waterhouse, Rod J Dillon, Mary Ann Mcdowell

Faculty, Staff and Students Publications

Phlebotomine sand flies are of global significance as important vectors of human disease, transmitting bacterial, viral, and protozoan pathogens, including the kinetoplastid parasites of the genus Leishmania, the causative agents of devastating diseases collectively termed leishmaniasis. More than 40 pathogenic Leishmania species are transmitted to humans by approximately 35 sand fly species in 98 countries with hundreds of millions of people at risk around the world. No approved efficacious vaccine exists for leishmaniasis and available therapeutic drugs are either toxic and/or expensive, or the parasites are becoming resistant to the more recently developed drugs. Therefore, sand fly and/or reservoir control …

A Mast Cell-Thermoregulatory Neuron Circuit Axis Regulates Hypothermia In Anaphylaxis, Chunjing Bao, Ouyang Chen, Huaxin Sheng, Jeffrey Zhang, Yikai Luo, Byron W Hayes, Han Liang, Wolfgang Liedtke, Ru-Rong Ji, Soman N Abraham

Faculty, Staff and Student Publications

IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1+ …

Tsks Localizes To Nuage In Spermatids And Regulates Cytoplasmic Elimination During Spermiation, Keisuke Shimada, Soojin Park, Seiya Oura, Taichi Noda, Akane Morohoshi, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Spermatozoa have a streamlined shape to swim through the oviduct to fertilize oocytes. To become svelte spermatozoa, spermatid cytoplasm must be eliminated in several steps including sperm release, which is part of spermiation. Although this process has been well observed, the molecular mechanisms that underlie it remain unclear. In male germ cells, there are membraneless organelles called nuage, which are observed by electron microscopy in various forms of dense material. Reticulated body (RB) and chromatoid body remnant (CR) are two types of nuage in spermatids, but the functions of both are unknown. Using CRISPR/Cas9 technology, we deleted the entire coding …

Neuronal Sirt3 Deletion Predisposes To Female-Specific Alterations In Cellular Metabolism, Memory, And Network Excitability, Jennifer N Pearson-Smith, Ruth Fulton, Christopher Q Huynh, Anna G Figueroa, Gia B Huynh, Li-Ping Liang, Lindsey B Gano, Cole R Michel, Nichole Reisdorph, Richard Reisdorph, Kristofer S Fritz, Eric Verdin, Manisha Patel

Faculty, Staff and Students Publications

Mitochondrial dysfunction is an early event in the pathogenesis of neurologic disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass spectrometry-based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons …

A Genetic Locus Complements Resistance To Bordetella Pertussis-Induced Histamine Sensitization., Abbas Raza, Sean A Diehl, Dimitry N Krementsov, Laure K Case, Dawei Li, Jason Kost, Robyn L Ball, Elissa J Chesler, Vivek M. Philip, Rui Huang, Yan Chen, Runlin Ma, Anna L Tyler, J Matthew Mahoney, Elizabeth P Blankenhorn, Cory Teuscher

Faculty Research 2023

Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with P

Genetic Mapping Of Microbial And Host Traits Reveals Production Of Immunomodulatory Lipids By Akkermansia Muciniphila In The Murine Gut., Qijun Zhang, Vanessa Linke, Katherine A Overmyer, Lindsay L Traeger, Kazuyuki Kasahara, Ian J Miller, Daniel E Manson, Thomas J Polaske, Robert L Kerby, Julia H Kemis, Edna A Trujillo, Thiru R Reddy, Jason D Russell, Kathryn L Schueler, Donald S Stapleton, Mary E Rabaglia, Marcus Seldin, Daniel M Gatti, Gregory R Keele, Duy T Pham, Joseph P Gerdt, Eugenio I Vivas, Aldons J Lusis, Mark P Keller, Gary Churchill, Helen E Blackwell, Karl W Broman, Alan D Attie, Joshua J Coon, Federico E Rey

Faculty Research 2023

The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in …

A Potent And Broad Neutralization Of Sars-Cov-2 Variants Of Concern By Darpins, Vikas Chonira, Young D Kwon, Jason Gorman, James Brett Case, Zhiqiang Ku, Rudo Simeon, Ryan G Casner, Darcy R Harris, Adam S Olia, Tyler Stephens, Lawrence Shapiro, Michael F Bender, Hannah Boyd, I-Ting Teng, Yaroslav Tsybovsky, Florian Krammer, Ningyan Zhang, Michael S Diamond, Peter D Kwong, Zhiqiang An, Zhilei Chen

Faculty, Staff and Student Publications

We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and FSR22 are trimeric proteins composed of DARPin SR16m or SR22 fused with a T4 foldon. Despite selection by a spike protein from a now historical SARS-CoV-2 strain, FSR16m and FSR22 exhibit broad-spectrum neutralization of SARS-CoV-2 strains, inhibiting authentic B.1.351, B.1.617.2 and BA.1.1 viruses, with respective IC

The Microbiome And Its Impact On Allogeneic Hematopoietic Cell Transplantation, Florent Malard, Robert R Jenq

Faculty, Staff and Student Publications

Allogeneic hematopoietic cell transplantation (alloHCT) is a standard curative therapy for a variety of benign and malignant hematological diseases. Previously, patients who underwent alloHCT were at high risk for complications with potentially life-threatening toxicities, including a variety of opportunistic infections as well as acute and chronic manifestations of graft-versus-host disease (GVHD), where the transplanted immune system can produce inflammatory damage to the patient. With recent advances, including newer conditioning regimens, advances in viral and fungal infection prophylaxis, and novel GVHD prophylactic and treatment strategies, improvements in clinical outcomes have steadily improved. One modality with great potential that has yet to …

Apoptosis Of Hematopoietic Stem Cells Contributes To Bone Marrow Suppression Following Chimeric Antigen Receptor T Cell Therapy, Jay A Read, Rayne H Rouce, Feiyan Mo, Maksim Mamonkin, Katherine Y King

Faculty, Staff and Students Publications

Background: CAR-T therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from release of pro-inflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias and those with the most severe CRS also have the greatest delay in full marrow recovery. While an association between CRS and delayed bone marrow recovery has been established, the precise mechanism underlying this phenomenon remains unknown.

Objective: To test our hypothesis that delayed bone marrow recovery following CAR-T …

A Randomized, Controlled Phase 1b Trial Of The Sm-Tsp-2 Vaccine For Intestinal Schistosomiasis In Healthy Brazilian Adults Living In An Endemic Area, David J Diemert, Rodrigo Correa-Oliveira, Carlo Geraldo Fraga, Frederico Talles, Marcella Rezende Silva, Shital M Patel, Shirley Galbiati, Jessie K Kennedy, Jordan S Lundeen, Maria Flavia Gazzinelli, Guangzhao Li, Lara Hoeweler, Gregory A Deye, Maria Elena Bottazzi, Peter J Hotez, Hana M El Sahly, Wendy A Keitel, Jeffrey Bethony, Robert L Atmar

Faculty, Staff and Students Publications

BACKGROUND: Recombinant Schistosoma mansoni Tetraspanin-2 formulated on Alhydrogel (Sm-TSP-2/Alhydrogel) is being developed to prevent intestinal and hepatic disease caused by S. mansoni. The tegumentary Sm-TSP-2 antigen was selected based on its unique recognition by cytophilic antibodies in putatively immune individuals living in areas of ongoing S. mansoni transmission in Brazil, and preclinical studies in which vaccination with Sm-TSP-2 protected mice following infection challenge.

METHODS: A randomized, observer-blind, controlled, Phase 1b clinical trial was conducted in 60 healthy adults living in a region of Brazil with ongoing S. mansoni transmission. In each cohort of 20 participants, 16 were randomized to receive …

Frequent First-Trimester Pregnancy Loss In Rhesus Macaques Infected With African-Lineage Zika Virus, Jenna R. Rosinski, Kevin K. Noguchi, Et Al.

2020-Current year OA Pubs

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV- animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest …

Cmpk2 Is A Host Restriction Factor That Inhibits Infection Of Multiple Coronaviruses In A Cell-Intrinsic Manner, Mingjun Zhu, Jiahuang Lv, Wei Wang, Rongli Guo, Chunyan Zhong, Avan Antia, Qiru Zeng, Jizong Li, Qingtao Liu, Jinzhu Zhou, Xuejiao Zhu, Baochao Fan, Siyuan Ding, Bin Li

2020-Current year OA Pubs

Coronaviruses (CoVs) comprise a group of important human and animal pathogens. Despite extensive research in the past 3 years, the host innate immune defense mechanisms against CoVs remain incompletely understood, limiting the development of effective antivirals and non-antibody-based therapeutics. Here, we performed an integrated transcriptomic analysis of porcine jejunal epithelial cells infected with porcine epidemic diarrhea virus (PEDV) and identified cytidine/uridine monophosphate kinase 2 (CMPK2) as a potential host restriction factor. CMPK2 exhibited modest antiviral activity against PEDV infection in multiple cell types. CMPK2 transcription was regulated by interferon-dependent and interferon regulatory factor 1 (IRF1)-dependent pathways post-PEDV infection. We demonstrated …