Document text
Principal Investigator: Maria Kalamvoki
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2020
Award: $420,750
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
COronaVIrus Disease 2019 (COVID-19) is caused by a human coronavirus, SARS-CoV-2. This virus
caused a large outbreak in China that was associated with a high human-to-human transmission rate and mortality
and subsequently led to a pandemic in the human population. SARS-CoV-2 is member of the â-coronaviruses and
is highly related to SARS-CoV. In an ongoing evolutionary arms race, viruses have evolved factors that facilitate
their replication while the host cell has evolved signaling networks to detect and eradicate invading viruses. The
innate immune system is a conserved defense strategy critical for the initial detection and restriction of pathogens
and later activation of the adaptive immune response. Activation of innate immunity relies on the recognition of
pathogen-associated molecular patterns (PAMP) by pattern recognition receptors (PRRs) such as Toll-like
receptors, RNA and DNA sensors. Upon activation by PAMPs, PRRs recruit adaptor proteins that initiate signaling
pathways involving modifying enzymes such as kinases, phosphatases, E3 ubiquitin ligases that ultimately lead
to the activation of crucial transcription factors including IRF3 and NF-êB. Synergistically, these factors promote
the production of antiviral type I interferons (IFN-I), inflammatory cytokines, NK cell immunity, apoptosis, and
autophagy. Thus, the pathogenicity and spread of a virus in the host is in part determined by the ability of the virus
to evade host cell innate responses. The SARS-CoV-2 virion has three transmembrane proteins [envelope (E),
membrane (M), and spike (S)] that are necessary for viral assembly and infectivity. They also have important
immunomodulatory functions as they trigger or antagonize innate immune responses within infected cells. The
E proteins from other coronaviruses have been shown to form an oligomeric structure with ion channel activity that
can alter calcium homeostasis with implications on viral pathogenesis. The M protein of other coronaviruses was
shown to have a range of immunomodulatory effects through TLR-dependent and independent mechanisms and
the S protein can exert its effects by modulating surface signaling responses. It also causes the degradation of
BST-2 (tetherin), which functions to prevent release of progeny virus. We hypothesize that the
immunomodulatory properties of SARS-CoV-2 membrane proteins will determine the outcome of the
infection and viral mediated pathogenesis. To test this, in Aim 1, we propose to examine E, M, and S proteins
from SARS-CoV-2 and compare their impact in modulating innate immunity, proinflammatory responses,
autophagy, and apoptosis with the same proteins from SARS-CoV, MERS-CoV, and HCoV-OC43. In Aim 2, we
will determine the immunomodulatory effects of virus-like particles (VLPs) formed by the membrane proteins of
the four viruses. We will also determine the immunoevasion capabilities of of SARS-CoV-2 and compare them
with SARS-CoV, MERS and HCoV-OC43. Overall, the results of these studies will further our knowledge of
immunoevasion strategies of human coronaviruses and guide in the development of efficacious vaccines.
Terms: <2019 novel coronavirus><2019-nCoV><Acute Nasopharyngitis><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Affect><Antiviral Agents><Antiviral Drugs><Antivirals><Apoptosis><Apoptosis Pathway><Assay><Autophagocytosis><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biologic Assays><Biological Assay><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Calcium><Cell Body><Cell Communication and Signaling><Cell Components><Cell Function><Cell Process><Cell Signaling><Cell Structure><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Structures><China><Common Cold><Coronaviridae><Coronavirus><Custom><Cytotoxic cell><DNA><Deoxyribonucleic Acid><Detection><Development><Disease Outbreaks><E3 Ligase><E3 Ubiquitin Ligase><Endothelial Cells><Envelope Protein><Enzyme Gene><Enzymes><Epithelial Cells><Fibroblasts><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><HCoV><Homeostasis><Human><Human Activities><IFN><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune response><Immunity><Immunological response><Immunomodulation><Infection><Inflammation><Inflammatory><Innate Immune Response><Innate Immune System><Innate Immunity><Integral Membrane Protein><Interferon Regulatory Factor 3><Interferon Type I><Interferons><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Invaded><Ion Channel><Ionic Channels><K lymphocyte><Kinases><Knowledge><Lead><Link><Lung><Lung Respiratory System><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Mainland China><Mediating><Membrane><Membrane Channels><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modern Man><Modification><Molecular><Monitor><Morbidity><Morbidity - disease rate><Morphogenesis><NK Cells><Native Immunity><Natural Immunity><Natural Killer Cells><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Nucleotides><Outbreaks><Outcome><Pathogenesis><Pathogenicity><Pathway interactions><Pattern><Pattern recognition receptor><Pb element><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphotransferase Gene><Phosphotransferases><Physiological Homeostasis><Population><Production><Programmed Cell Death><Property><Proteins><RNA><RNA Gene Products><Race><Racial Group><Racial Stocks><Reporting><Ribonucleic Acid><Role><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Structural Protein><Structure><Subcellular Process><Surface><Surface Proteins><TLR protein><Testing><Toll-Like Receptor Family Gene><Toll-like receptors><Transcription Factor Proto-Oncogene><Transcription factor genes><Transmembrane Protein><Transmembrane Protein Gene><Transmission><Transphosphorylases><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Vaccines><Viral><Viral Gene Products><Viral Gene Proteins><Viral Pathogenesis><Viral Proteins><Virion><Virus><Virus Assembly><Virus Particle><Virus-like particle><Wuhan coronavirus><adapter protein><adaptive immune response><airway epithelium><anti-viral agents><anti-viral drugs><anti-virals><arm><autophagy><biological adaptation to stress><biological signal transduction><cell type><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><cytokine><develop a vaccine><development of a vaccine><developmental><env Antigens><env Gene Products><env Polyproteins><env Protein><gene function><heavy metal Pb><heavy metal lead><host response><human CoV><human corona virus><human coronavirus><immune modulation><immune regulation><immune regulator><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><insight><macrophage><member><membrane structure><morphogenetic process><mortality><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pandemic><pandemic disease><particle><particle exposure><pathogen><pathogenic virus><pathway><prevent><preventing><pulmonary><reaction; crisis><recruit><response><sensor><severe acute respiratory syndrome-CoV><social role><stem><stress response><stress; reaction><transcription factor><transmission process><ubiquitin-protein ligase><vaccine development><vaccine formulation><viral assembly><viral pathogen><virus pathogenesis><virus protein><virus-like nanoparticles><viruslike particle>