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Bias Of The Immune Response To Pneumocystis Murina Does Not Alter The Ability Of Neonatal Mice To Clear The Infection, Cathryn J. Kurkjian, Melissa L. Hollifield, David J. Feola, Beth A. Garvy 2021 University of Kentucky

Bias Of The Immune Response To Pneumocystis Murina Does Not Alter The Ability Of Neonatal Mice To Clear The Infection, Cathryn J. Kurkjian, Melissa L. Hollifield, David J. Feola, Beth A. Garvy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Newborn mice are unable to clear Pneumocystis (PC) infection with the same efficiency as adults due, in part, to their inability to develop a robust immune response to infection until three weeks of age. It is known that infants tend develop a Th2 skewed response to antigen so we sought to determine whether a biased cytokine response altered the clearance of PC infection in neonatal mice. P. murina infection in neonatal mice resulted in increased IL-4 expression by CD4 T cells and myeloid cells, augmented IL-13 secretion within the airways and increased arginase activity in the airways, indicative of Th2-type ...


Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness, Pratyusha Mandal, Lynsey Nagrani, Liliana Hernandez, Anita Louise McCormick, Christopher Dillon, Heather Koehler, Linda Roback, Emad S Alnemri, Douglas Green, Edward Mocarski 2021 Emory University School of Medicine

Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness, Pratyusha Mandal, Lynsey Nagrani, Liliana Hernandez, Anita Louise Mccormick, Christopher Dillon, Heather Koehler, Linda Roback, Emad S Alnemri, Douglas Green, Edward Mocarski

Department of Biochemistry and Molecular Biology Faculty Papers

Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochon-drial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages ...


Apobec Mutagenesis Is Concordant Between Tumor And Viral Genomes In Hpv-Positive Head And Neck Squamous Cell Carcinoma, Daniel L. Faden, Krystle A. Lang Kuhs, Maoxuan Lin, Adam Langenbucher, Maisa Pinheiro, Meredith Yeager, Michael Cullen, Joseph F. Boland, Mia Steinberg, Sara Bass, James S. Lewis, Michael S. Lawrence, Robert L. Ferris, Lisa Mirabello 2021 Massachusetts Eye and Ear

Apobec Mutagenesis Is Concordant Between Tumor And Viral Genomes In Hpv-Positive Head And Neck Squamous Cell Carcinoma, Daniel L. Faden, Krystle A. Lang Kuhs, Maoxuan Lin, Adam Langenbucher, Maisa Pinheiro, Meredith Yeager, Michael Cullen, Joseph F. Boland, Mia Steinberg, Sara Bass, James S. Lewis, Michael S. Lawrence, Robert L. Ferris, Lisa Mirabello

Epidemiology Faculty Publications

APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0–29) mutations per genome ...


Investigation Of Ifnγ-Induced Control Of Intracellular Pathogens, Michael Mcallaster 2021 Washington University in St. Louis

Investigation Of Ifnγ-Induced Control Of Intracellular Pathogens, Michael Mcallaster

Arts & Sciences Electronic Theses and Dissertations

Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct cellular processes with significant physiologic importance. One of the first-described of these ATG gene-dependent processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of norovirus and Toxoplasma gondii replication. In this dissertation we identified novel components that are required for or that negatively regulate this immune mechanism. Enzymes involved in the conjugation of UFM1 to target proteins including UFC1 and UBA5, negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. We identified and confirmed that IFNγ-induced inhibition ...


Regulation Of Host-Microbe Interactions In Autoimmunity And Antiviral Immunity By Cytosolic Nucleic Acid Sensing And Interferon Signaling, Derek Jerome Platt 2021 Washington University in St. Louis

Regulation Of Host-Microbe Interactions In Autoimmunity And Antiviral Immunity By Cytosolic Nucleic Acid Sensing And Interferon Signaling, Derek Jerome Platt

Arts & Sciences Electronic Theses and Dissertations

Cytosolic nucleic acid sensing and interferon (IFN) signaling are central to the host immune response to microbial pathogens. However, dysregulation of immunological pathways such as these can result in devastating autoimmune disease. In order to provide a robust immune response to pathogen without causing harm to self, the host immune system must engage in a delicate balancing act, interacting with microbes and determining whether they are commensal or pathogenic. The cGAS-STING pathway is a key regulator of host-microbe interactions by cytosolic nucleic sensing and IFN signaling. Loss of function in the cGAS-STING pathway leads to increased susceptibility to pathogenic threats ...


The Immunoregulation Of Autoimmune Diabetes, Hao Hu 2021 Washington University in St. Louis

The Immunoregulation Of Autoimmune Diabetes, Hao Hu

Arts & Sciences Electronic Theses and Dissertations

How autoimmune diseases are regulated is a long-term research topic in the autoimmunity field. We use autoimmune diabetes as a model to study this. Autoimmune diabetes is a T cell-dependent autoimmune syndrome. The functions of T cells are regulated during their development and activation. Developmentally, T cells will undergo a stringent thymic selection: a process that self-reactive T cells are tolerized to become thymic derived Tregs or can be deleted by apoptosis based on binding affinity and avidity between the TCRs and self-peptide:MHC complexes. After T cells mature, they can also be tolerized in the periphery in many other ...


Peripheral Nerve Macrophages And Their Implications In Neuroimmunity, Peter Leon Wang 2021 Washington University in St. Louis

Peripheral Nerve Macrophages And Their Implications In Neuroimmunity, Peter Leon Wang

Arts & Sciences Electronic Theses and Dissertations

Macrophages are innate immune cells that protect against pathogens and maintain tissue integrity. In vertebrates, macrophages reside in every tissue where they perform specific functions from early development through adulthood. While macrophages provide important functions across all tissues, a major focus in recent years has been the role of resident brain macrophages, known as microglia, in neurodegeneration. As microglia have been shown to affect brain development, homeostasis, and disease, they demonstrate how immune cells critically mediate neurological health and point to the broader significance of neuroimmune interactions, or the coordinated actions of the nervous and immune systems for maintaining tissue ...


Modulation Of Glucose Homeostasis By Nucleotide P2y2 Receptor And Biological Sex, Hailee Anne Marino 2021 Missouri State University

Modulation Of Glucose Homeostasis By Nucleotide P2y2 Receptor And Biological Sex, Hailee Anne Marino

MSU Graduate Theses

Recent insights into the pathological role of Nucleotide P2Y2 receptor suggest P2Y2R involvement in high fat diet-induced obesity and potentiates insulin resistance. However, these recent insights do not demonstrate how P2Y2R modulates glucose homeostasis under physiological conditions. Further, it remains unknown how sex biological factors influence P2Y2R receptor signaling in the regulation of glucose homeostasis. The research objective for the present study is to elucidate the novel roles of P2Y2 in fasting blood glucose and glucose tolerance (basal insulin sensitivity) under resting conditions in males and females. We expected that under physiological ...


Effect Of Lactoferrin To Increase Drug Permeability Of Primary Pulmonary Mycobacterial Granulomas, Thao Nguyen, Thao KT Nguyen 2021 The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences

Effect Of Lactoferrin To Increase Drug Permeability Of Primary Pulmonary Mycobacterial Granulomas, Thao Nguyen, Thao Kt Nguyen

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Despite extensive research and worldwide eradication efforts, Mycobacterium tuberculosis (Mtb) remains a major infectious pathogen to the human population with about 10 million cases of infection per year globally. The host-pathogen interaction, pulmonary granuloma formation, and Mtb adaptions result in increased complexity of the disease. Granulomas are formed by active immune responses generated during Mtb infection, and serve to contain and limit bacterial dissemination. The major mycobacterial surface mycolic acid, trehalose 6,6'-dimycolate (TDM), functions in multiple ways to enhance immune cell recruitment of sites of infection, to induce inflammation and granulomatous responses, and to initiate survival strategies for ...


Targeting Human Langerin Promotes Hiv-1 Specific Humoral Immune Responses., Jérôme Kervevan, Aurélie Bouteau, Juliane S Lanza, Adele Hammoudi, Sandra Zurawski, Mathieu Surenaud, Lydie Dieudonné, Marion Bonnet, Cécile Lefebvre, Hakim Hocini, Romain Marlin, Aurélie Guguin, Barbara Hersant, Oana Hermeziu, Elisabeth Menu, Christine Lacabaratz, Jean-Daniel Lelièvre, Gerard Zurawski, Véronique Godot, Sandrine Henri, Botond Z. Igyártó, Yves Levy, Sylvain Cardinaud 2021 Vaccine Research Institute, Créteil, France, Inserm U955, Équipe 16, Créteil, France

Targeting Human Langerin Promotes Hiv-1 Specific Humoral Immune Responses., Jérôme Kervevan, Aurélie Bouteau, Juliane S Lanza, Adele Hammoudi, Sandra Zurawski, Mathieu Surenaud, Lydie Dieudonné, Marion Bonnet, Cécile Lefebvre, Hakim Hocini, Romain Marlin, Aurélie Guguin, Barbara Hersant, Oana Hermeziu, Elisabeth Menu, Christine Lacabaratz, Jean-Daniel Lelièvre, Gerard Zurawski, Véronique Godot, Sandrine Henri, Botond Z. Igyártó, Yves Levy, Sylvain Cardinaud

Department of Microbiology and Immunology Faculty Papers

The main avenue for the development of an HIV-1 vaccine remains the induction of protective antibodies. A rationale approach is to target antigen to specific receptors on dendritic cells (DC) via fused monoclonal antibodies (mAb). In mouse and non-human primate models, targeting of skin Langerhans cells (LC) with anti-Langerin mAbs fused with HIV-1 Gag antigen drives antigen-specific humoral responses. The development of these immunization strategies in humans requires a better understanding of early immune events driven by human LC. We therefore produced anti-Langerin mAbs fused with the HIV-1 gp140z Envelope (αLC.Env). First, we show that primary skin human LC ...


Targeted Oral Delivery Of Paclitaxel Using Colostrum-Derived Exosomes, Raghuram Kandimalla, Farrukh Aqil, Sara S. Alhakeem, Jeyaprakash Jeyabalan, Neha Tyagi, Ashish Agrawal, Jun Yan, Wendy Spencer, Subbarao Bondada, Ramesh C. Gupta 2021 University of Louisville

Targeted Oral Delivery Of Paclitaxel Using Colostrum-Derived Exosomes, Raghuram Kandimalla, Farrukh Aqil, Sara S. Alhakeem, Jeyaprakash Jeyabalan, Neha Tyagi, Ashish Agrawal, Jun Yan, Wendy Spencer, Subbarao Bondada, Ramesh C. Gupta

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) is the most common type accounting for 84% of all lung cancers. Paclitaxel (PAC) is a widely used drug in the treatment of a broad spectrum of human cancers, including lung. While efficacious, PAC generally is not well tolerated and its limitations include low aqueous solubility, and significant toxicity. To overcome the dose-related toxicity of solvent-based PAC, we utilized bovine colostrum-derived exosomes as a delivery vehicle for PAC for the treatment of lung cancer. Colostrum provided higher yield of exosomes and could be loaded with higher ...


Inhibitory Molecules Pd-1, Cd73 And Cd39 Are Expressed By Cd8+ T Cells In A Tissue-Dependent Manner And Can Inhibit T Cell Responses To Stimulation, Corinne J. Smith, Christopher M. Snyder 2021 Thomas Jefferson University

Inhibitory Molecules Pd-1, Cd73 And Cd39 Are Expressed By Cd8+ T Cells In A Tissue-Dependent Manner And Can Inhibit T Cell Responses To Stimulation, Corinne J. Smith, Christopher M. Snyder

Department of Microbiology and Immunology Faculty Papers

The salivary gland is an important tissue for persistence and transmission of multiple viruses. Previous work showed that salivary gland tissue-resident CD8+ T cells elicited by viruses were poorly functional ex vivo. Using a model of persistent murine cytomegalovirus (MCMV) infection, we now show that CD8+ T cells in the salivary gland and other non-lymphoid tissues of mice express multiple molecules associated with T cell exhaustion including PD-1, CD73 and CD39. Strikingly however, these molecules were expressed independently of virus or antigen. Rather, PD-1-expressing T cells remained PD-1+ after migration into tissues regardless of infection, while CD73 was activated on ...


Novel Scalable And Simplified System To Generate Microglia-Containing Cerebral Organoids From Human Induced Pluripotent Stem Cells, Brittany Bodnar, Yongang Zhang, Jinbiao Liu, Yuan Lin, Peng Wang, Zhengyu Wei, Sami Saribas, Yuanjun Zhu, Fang Li, Xu Wang, Wenli Yang, Qingsheng Li, Wen-Zhe Ho, Wenhui Hu 2021 Temple University Lewis Katz School of Medicine

Novel Scalable And Simplified System To Generate Microglia-Containing Cerebral Organoids From Human Induced Pluripotent Stem Cells, Brittany Bodnar, Yongang Zhang, Jinbiao Liu, Yuan Lin, Peng Wang, Zhengyu Wei, Sami Saribas, Yuanjun Zhu, Fang Li, Xu Wang, Wenli Yang, Qingsheng Li, Wen-Zhe Ho, Wenhui Hu

Virology Papers

Human cerebral organoid (CO) is a three-dimensional (3D) cell culture system that recapitulates the developing human brain. While CO has proved an invaluable tool for studying neurological disorders in a more clinically relevant matter, there have still been several shortcomings including CO variability and reproducibility as well as lack of or underrepresentation of certain cell types typically found in the brain. As the technology to generate COs has continued to improve, more efficient and streamlined protocols have addressed some of these issues. Here we present a novel scalable and simplified system to generate microglia-containing CO (MCO). We characterize the cell ...


The Impact Of Nanopulse Treatment On The Tumor Microenvironment In Breast Cancer: Overturning The Treg Immunosuppressive Dominance, Anthony Nanajian 2021 Old Dominion University

The Impact Of Nanopulse Treatment On The Tumor Microenvironment In Breast Cancer: Overturning The Treg Immunosuppressive Dominance, Anthony Nanajian

Biomedical Sciences Theses & Dissertations

Nanopulse treatment (NPT) is a high-power electric engineering modality that has been shown to be an effective local tumor treatment approach in multiple cancer models. Our previous studies on the orthotopic 4T1-luc breast cancer model demonstrated that NPT ablated local tumors. The treatment consequently conferred protection against a second live tumor challenge and minimized spontaneous metastasis. This study aims to understand how NPT mounts a potent immune response in a predominantly immunosuppressive tumor.

NPT changed the local and systemic dynamics of immunosuppressive cells by significantly reducing the numbers of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages ...


Sars-Cov-2 Viral Proteins Nsp1 And Nsp13 Inhibit Interferon Activation Through Distinct Mechanisms, Christine Vazquez, Sydnie E Swanson, Seble G Negatu, Mark Dittmar, Jesse Miller, Holly Ramage, Sara Cherry, Kellie A Jurado 2021 University of Pennsylvania Perelman School of Medicine

Sars-Cov-2 Viral Proteins Nsp1 And Nsp13 Inhibit Interferon Activation Through Distinct Mechanisms, Christine Vazquez, Sydnie E Swanson, Seble G Negatu, Mark Dittmar, Jesse Miller, Holly Ramage, Sara Cherry, Kellie A Jurado

Department of Microbiology and Immunology Faculty Papers

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic, infecting over 43 million people and claiming over 1 million lives, with these numbers increasing daily. Therefore, there is urgent need to understand the molecular mechanisms governing SARS-CoV-2 pathogenesis, immune evasion, and disease progression. Here, we show that SARS-CoV-2 can block IRF3 and NF-κB activation early during virus infection. We also identify that the SARS-CoV-2 viral proteins NSP1 and NSP13 can block interferon activation via distinct mechanisms. NSP1 antagonizes interferon signaling by suppressing host mRNA translation, while NSP13 downregulates interferon and NF-κB promoter signaling by limiting TBK1 ...


Report Of The Pathogenesis And Pathophysiology Of Lyme Disease Subcommittee Of The Hhs Tick Borne Disease Working Group, Sam T. Donta, Leith J. States, Wendy A. Adams, Troy Bankhead, Nicole Baumgarth, Monica E. Embers, Robert B. Lochhead, Brian Stevenson 2021 Falmouth Hospital

Report Of The Pathogenesis And Pathophysiology Of Lyme Disease Subcommittee Of The Hhs Tick Borne Disease Working Group, Sam T. Donta, Leith J. States, Wendy A. Adams, Troy Bankhead, Nicole Baumgarth, Monica E. Embers, Robert B. Lochhead, Brian Stevenson

Microbiology, Immunology, and Molecular Genetics Faculty Publications

An understanding of the pathogenesis and pathophysiology of Lyme disease is key to the ultimate care of patients with Lyme disease. To better understand the various mechanisms underlying the infection caused by Borrelia burgdorferi, the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee was formed to review what is currently known about the pathogenesis and pathophysiology of Lyme disease, from its inception, but also especially about its ability to persist in the host. To that end, the authors of this report were assembled to update our knowledge about the infectious process, identify the gaps that exist in our understanding of the ...


An Update On The Hiv Dna Vaccine Strategy, Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Mudit Tyagi 2021 Kampala International University-Western Campus

An Update On The Hiv Dna Vaccine Strategy, Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Mudit Tyagi

Center for Translational Medicine Faculty Papers

In 2020, the global prevalence of human immunodeficiency virus (HIV) infection was estimated to be 38 million, and a total of 690,000 people died from acquired immunodeficiency syndrome (AIDS)–related complications. Notably, around 12.6 million people living with HIIV/AIDS did not have access to life-saving treatment. The advent of the highly active antiretroviral therapy (HAART) in the mid-1990s remarkably enhanced the life expectancy of people living with HIV/AIDS as a result of improved immune functions. However, HAART has several drawbacks, especially when it is not used properly, including a high risk for the development of drug ...


Resistance To Lethal Ectromelia Virus Infection Requires Type I Interferon Receptor In Natural Killer Cells And Monocytes But Not In Adaptive Immune Or Parenchymal Cells., Carolina R Melo-Silva, Pedro Alves-Peixoto, Natasha Heath, Lingjuan Tang, Brian Montoya, Cory J Knudson, Colby Stotesbury, Maria Ferez, Eric B. Wong, Luis J. Sigal 2021 Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, United States

Resistance To Lethal Ectromelia Virus Infection Requires Type I Interferon Receptor In Natural Killer Cells And Monocytes But Not In Adaptive Immune Or Parenchymal Cells., Carolina R Melo-Silva, Pedro Alves-Peixoto, Natasha Heath, Lingjuan Tang, Brian Montoya, Cory J Knudson, Colby Stotesbury, Maria Ferez, Eric B. Wong, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

Type I interferons (IFN-I) are antiviral cytokines that signal through the ubiquitous IFN-I receptor (IFNAR). Following footpad infection with ectromelia virus (ECTV), a mouse-specific pathogen, C57BL/6 (B6) mice survive without disease, while B6 mice broadly deficient in IFNAR succumb rapidly. We now show that for survival to ECTV, only hematopoietic cells require IFNAR expression. Survival to ECTV specifically requires IFNAR in both natural killer (NK) cells and monocytes. However, intrinsic IFNAR signaling is not essential for adaptive immune cell responses or to directly protect non-hematopoietic cells such as hepatocytes, which are principal ECTV targets. Mechanistically, IFNAR-deficient NK cells have ...


Genome Sequence Of A Virulent African Swine Fever Virus Isolated In 2020 From A Domestic Pig In Northern Vietnam, Quang Lam Truong, Thi Lan Nguyen, Thi Hoa Nguyen, Jishu Shi, Hiep Lai Xuan Vu, Thi Lan Huong Lai, Van Giap Nguyen 2021 Vietnam National University of Agriculture

Genome Sequence Of A Virulent African Swine Fever Virus Isolated In 2020 From A Domestic Pig In Northern Vietnam, Quang Lam Truong, Thi Lan Nguyen, Thi Hoa Nguyen, Jishu Shi, Hiep Lai Xuan Vu, Thi Lan Huong Lai, Van Giap Nguyen

Virology Papers

This study reports the genome sequence of an isolated African swine fever (ASF) virus (VNUA-ASFV-05L1/HaNam) obtained at the fourth passage on pulmonary alveolar macrophages. The virus was isolated during a typical acute ASF outbreak in pigs in a northern province of Vietnam in 2020.


Codon Bias Can Determine Sorting Of A Potassium Channel Protein, Anja J. Engel, Marina Kithil, Markus Langhans, Oliver Rauh, Matea Cartolano, James L. Van Etten, Anna Moroni, Gerhard Thiel 2021 Technische Universitat Darmstadt

Codon Bias Can Determine Sorting Of A Potassium Channel Protein, Anja J. Engel, Marina Kithil, Markus Langhans, Oliver Rauh, Matea Cartolano, James L. Van Etten, Anna Moroni, Gerhard Thiel

Virology Papers

Due to the redundancy of the genetic code most amino acids are encoded by multiple synonymous codons. It has been proposed that a biased frequency of synonymous codons can affect the function of proteins by modulating distinct steps in transcription, translation and folding. Here, we use two similar prototype K+ channels as model systems to examine whether codon choice has an impact on protein sorting. By monitoring transient expression of GFP-tagged channels in mammalian cells, we find that one of the two channels is sorted in a codon and cell cycle-dependent manner either to mitochondria or the secretory pathway. The ...


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