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Principal Investigator: Raul Andino
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2022
Award: $868,678
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Human enterovirus (HEV) infections primarily affect infant and adolescent populations, causing a
wide range of clinical manifestations that commonly include respiratory illness and
mucocutaneous lesions, or hand, foot and mouth disease. In some cases, the infection is life-
threatening. The clinical manifestations are a function of their tropism. For example, some HEVs,
including EV-A71 and EV-D68, are associated with serious neurological symptoms due to
invasion and damage of central nervous tissues. Others, such CVB3, are implicated in respiratory
symptoms and cardiomyopathy. This proposal aims to take an integrative approach to understand
how tissues, and cells within these tissues, respond to infection by CVB3 and the emerging
pathogens EV-D68 and EV-A71. We will determine the temporal and spatial dynamics of HEV
infection using recent advances in genomics: (i) We will profile single-cell transcriptomes to
quantify viral replication levels and the host response to infection across cells and tissues over
the course of infection. (ii) Given that intra-host adaptation appears to be important in infection,
in parallel, we will map the mutational spectrum of the replicating viruses using a novel ultra-deep
sequencing approach. We will use new innovative technologies, such as ultra-deep virus
population sequencing, deep learning and single-cell analysis to increase our basic understanding
of the pathogenesis of enteroviruses A, B and D. Finally, given that innate immunity is a major
determinant of tissue tropism, we will use mice with deletions of specific type-I IFN subtypes to
determine the significance of interferon diversity in controlling HEV infections. These data will
enable us to determine cell types that HEVs infect, the response that the host mounts against
them in each cell and tissue, and the viral mutants that emerge in different tissues. Understanding
pathogenesis is critically needed for developing effective and broadly-acting countermeasures
and to inform the development of effective and broad-spectrum vaccines and antiviral
compounds.
Terms: <(IFN) α><(IFN)-α><(IFN)α><Acute><Adolescent><Adolescent Youth><Affect><Alferon><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Atlases><Attenuated><Biological><Body Tissues><Brain Inflammation><Brain Stem><Brainstem><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cardiac Diseases><Cardiac Disorders><Cardiomyopathies><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Coxsackie B Viruses><Coxsackieviruses B><Data><Data Set><Dataset><Development><Diabetes Mellitus><Differential Gene Expression><Disease><Disorder><Drugs><Encephalitis><Endogenous Interferon Beta><Enterovirus><Enterovirus Infections><Evolution><Family><Fibroblast Interferon><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Determinism><Genetic Structures><Genetic Transcription><Genetic defect><Genomics><Goals><Hand, Foot and Mouth Disease><Heart Diseases><Hospital Admission><Hospitalization><Human><Human poliovirus><IFN><IFN Alpha><IFN α><IFN-Beta><IFN-α><IFN-β><IFNa><IFNb><IFNα><Immune response><Immunological response><Individual><Infant><Infection><Innate Immune Response><Innate Immunity><Interferon Alfa-n3><Interferon Type I><Interferon-alpha><Interferon-beta><Interferon-α><Interferon-β><Interferons><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Lesion><Leukocyte Interferon><Life><Link><Lymphoblast Interferon><Lymphoblastoid Interferon><Maps><Math Models><Measures><Medical><Medication><Meningitis><Methods><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Myocarditis><Native Immunity><Natural Immunity><Natural Interferon Beta><Natural human interferon beta><Nerve Tissue><Nervous Tissue><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Manifestations><Neurological Signs and Symptoms><Non-Specific Immunity><Nonspecific Immunity><Palsy><Pancreatitis><Paralysed><Pathogenesis><Pathogenicity><Pathway interactions><Pericarditis><Pharmaceutic Preparations><Pharmaceutical Preparations><Phylogenetic Analysis><Phylogenetics><Plegia><Polio Virus><Poliovirus><Population><Population Dynamics><Population Genetics><Primary Infection><Process><RNA Expression><Respiratory Signs and Symptoms><Reverse engineering><Role><Severities><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Source><Specificity><Structure><Testing><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Tissues><Transcription><Tropism><United States><Vaccines><Viral><Viral Diseases><Viral Genetics><Virulence><Virus><Virus Diseases><Virus Replication><airway symptom><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><biologic><biological signal transduction><cardiac inflammation><cell type><deep learning><deep sequencing><develop a vaccine><develop vaccines><development of a vaccine><developmental><diabetes><drug/agent><emerging pathogen><experiment><experimental research><experimental study><genetic determinant><genome mutation><global gene expression><global transcription profile><heart disorder><host response><immune system response><immunoresponse><in vivo><innovative technologies><insight><interventional strategy><juvenile><juvenile human><mathematic model><mathematical model><mathematical modeling><model of animal><model organism><mouse model><murine model><mutant><myocardium disease><myocardium disorder><neonatal sepsis><neural manifestation><new pathogen><novel><novel pathogen><paralysis><paralytic><pathway><poliomyelitis virus><pressure><prevent><preventing><respiratory><respiratory symptom><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spatiotemporal><tissue tropism><transcriptome><transcriptomics><vaccine development><viral infection><viral multiplication><viral replication><virus genetics><virus host interaction><virus infection><virus multiplication><virus-induced disease>