Document text
Principal Investigator: Eric M. Poeschla
Organization: VA EASTERN COLORADO HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
SARS-CoV-2 emerged in late 2019, with much evidence tracing the initial human spillover to a market with
extensive human-animal contact. As the coronavirus spread in its new host species, multiple variants of
concern representing distinct genetic lineages appeared and propagated globally. Ongoing viral evolution has
increased transmission, and also evasion of neutralizing antibodies (adaptive arm of the immune system).
Hence, many important studies have deservedly focused on dissecting consequences of Spike protein
mutations in different emerged variants. However, mutations have also been detected in viral genes other than
Spike, and several of these genes are linked to antagonism of innate immune responses. We provide detailed
evidence that compared to ancestral or early SARS-CoV-2 isolates, the five major variants of concern so far
(alpha, beta, gamma, delta and omicron) have become more resistant to multiple human interferons that
included the 12 IFNα subtypes, IFNβ, IFNω and 3 IFNλ subtypes1. The underlying mechanisms for these IFN
resistance phenotypes are unclear and, paralleling the four decades it has taken to understand innate immune
evasions mediated by the proteins encoded by the nine genes of HIV-1, a full picture for SARS-CoV-2 will
require sustained investigation over time. However, in both the short and long terms, the scientific and medical
impacts of characterizing resistance of this newly emerged coronavirus mechanistically can be highly
significant, for not only the current pandemic but potentially also for future sarbecovirus spillover events. We
thus propose to build on our ample published1 and unpublished preliminary data and accumulated experience
to track the evolution of SARS-CoV-2 IFN resistance during the course of the COVID-19 pandemic and to
determine virus mutations and effector mechanisms involved. As interferon responses can regulate virus
levels during the critical acute phase of infection, these studies will have implications for understanding
SARS-CoV-2 transmission and pathogenesis that may inform therapeutic strategies not only against SARS-
CoV-2 but also future emerging viruses.
Terms: <(IFN) α><(IFN)-α><(IFN)α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><A549><Active Follow-up><Acute><Adrenal Cortex Hormones><Alferon><Alveolar><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Drug Resistance><Anti-viral Drug Resistant><Antibodies><Attention><Automobile Driving><B.1.1.529><B.1.1.7><B.1.351><B.1.617.2><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 crisis><COVID-19 death><COVID-19 epidemic><COVID-19 era><COVID-19 fatality><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 mortality><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 transmission><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus transmission><COVID-19 years><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Cessation of life><Chronic><Clinical Trials><CoV emergence><CoV-2><CoV2><Collaborations><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Corticoids><Corticosteroids><Data><Death><Delta variant><Development><Early treatment><Employee><Epidemiology><Epithelial Cells><Evolution><Family><Funding><Future><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Grant><HIV infection in mucosa><HIV mucosal challenge><HIV-1><HIV-1 infection in mucosa><HIV-1 mucosal challenge><HIV-I><HIV1><Hospital Admission><Hospitalization><Human><Human Genome><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><IFN><IFN Alpha><IFN α><IFN-Gamma><IFN-g><IFN-α><IFN-γ><IFNAR><IFNAR1><IFNAR1 gene><IFNG><IFNa><IFNα><IFNγ><Immune><Immune Evasion><Immune Interferon><Immune system><Immunes><Immunity><In Vitro><Infection><Inflammation><Innate Immune Response><Innate Immunity><Interferon Alfa-n3><Interferon Gamma><Interferon Type I><Interferon Type II><Interferon alpha><Interferon-α><Interferons><Intracellular Communication and Signaling><Investigation><Investigators><Laboratories><Leukocyte Interferon><Link><Long term disability><Lower respiratory tract structure><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lymphoblast Interferon><Lymphoblastoid Interferon><Marketing><Mediating><Medical><Modeling><Modern Man><Mucosa><Mucosal Tissue><Mucous Membrane><Mutation><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Nucleocapsid><Omicron variant><Pathogenesis><Persons><Phase><Phenotype><Physiologic><Physiological><Probability><Process><Proteins><Publishing><Receptor Protein><Records><Research Personnel><Researchers><Resistance><Resistance development><Resistant development><Risk><Role><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.1.529><SARS-CoV-2 B.1.1.7><SARS-CoV-2 B.1.351><SARS-CoV-2 B.1.617.2><SARS-CoV-2 alpha><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 beta><SARS-CoV-2 death><SARS-CoV-2 delta><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 inhibitor><SARS-CoV-2 mortality><SARS-CoV-2 omicron><SARS-CoV-2 omicron variant><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 transmission><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Sarbecovirus><Science><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><South Africa strain><South Africa variant><South African strain><South African variant><Strains Cell Lines><Structure of parenchyma of lung><System><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Testing><Therapeutic><Therapeutic Agents><Time><Transmission><U.K. variant><UK strain><UK variant><United Kingdom variant><Upper respiratory tract><Vaccinee><Vaccines><Variant><Variation><Veterans><Viral><Viral Activity><Viral Burden><Viral Drug Resistance><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Genes><Viral Load><Viral Load result><Viral Physiology><Viral Proteins><Virus><Virus Replication><Work><Writing><Wuhan coronavirus><active followup><acute COVID-19><acute SARS-CoV-2 infection><acute phase of COVID-19><acute phase of SARS-CoV-2 infection><adaptive immune response><antagonism><antagonist><arm><biological signal transduction><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><breakthrough infection><cellular targeting><comparative><corona virus><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 crisis><coronavirus disease 2019 death><coronavirus disease 2019 epidemic><coronavirus disease 2019 fatality><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 mortality><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 transmission><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease 2019 virus transmission><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 mortality><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus patient><cultured cell line><current pandemic><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><design><designing><develop therapy><developing resistance><developmental><driving><early therapy><emergent CoV><emergent corona virus><emergent coronavirus><emergent virus><emerging CoV><emerging corona virus><emerging coronavirus><emerging virus><epidemiologic><epidemiological><experience><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><follow up><follow-up><followed up><followup><genome mutation><global gene expression><global transcription profile><hCoV19><human whole genome><immune evasive><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><insight><intervention development><lFN-Gamma><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lower respiratory tract><model of animal><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mucosal HIV infection><mucosal HIV-1 infection><nCoV><nCoV2><neutralizing antibody><new CoV><new corona virus><new coronavirus><novel><novel CoV><novel corona virus><novel coronavirus><omicron variant of COVID-19><omicron variant of SARS-CoV-2><overexpress><overexpression><pandemic><pandemic concern><pandemic disease><pandemic potential><pandemic risk><pandemic threat><pandemic virus><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><present pandemic><protein function><pulmonary><receptor><resistance mechanism><resistance to anti-viral><resistant><resistant mechanism><resistant to anti-viral><response><reverse genetics><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 B.1.1.529><severe acute respiratory syndrome coronavirus 2 B.1.1.7><severe acute respiratory syndrome coronavirus 2 B.1.351><severe acute respiratory syndrome coronavirus 2 B.1.617.2><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 transmission><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><spillover event><therapy development><thymus derived lymphocyte><tissue culture><transcriptome><transmission process><transmitted COVID-19><transmitted SARS-CoV-2><transmitted coronavirus disease 2019><transmitted severe acute respiratory syndrome coronavirus 2><treatment development><upper airway tract><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><variants of concern><viral emergence><viral multiplication><viral replication><virus host interaction><virus multiplication><virus protein>