Document text
Principal Investigator: Anice C Lowen
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $189,353
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
The central role of the interferon (IFN) cytokines in innate antiviral responses has been recognized for decades
and many of the mechanisms underlying their induction and the responses they trigger have been worked out in
molecular detail. Much less well-understood, however, is the impact of IFN on the genetic structure of viral
populations within and between hosts. We hypothesize that the restriction of viral propagation imposed by IFNs
reduces the effective size of viral populations within infected hosts and contributes to tight bottlenecks during
transmission to new hosts. Owing to their different properties, we furthermore expect differing effects of type I
IFN and type III IFN (IFN-λ). We anticipate that both will restrict diversity within an infected host, but may do so
with differing kinetics. In addition, due to its localized action within the epithelium, we expect that IFN-λ
contributes to a further reduction in effective population size during transmission between hosts. To test these
hypotheses we will leverage two valuable experimental tools. The first constitutes the application of CRISPR
Cas-9 editing to generate guinea pigs that lack either IFNAR1 or IFNLR1, the receptors for type I IFN and IFN-
λ, respectively. Guinea pigs are naturally susceptible to a wide range of influenza A viruses (IAVs) and an
excellent model for following the longitudinal dynamics of infection within a host as well as transmission to new
hosts. The second tool is an IAV population carrying a highly diverse and fitness-neutral genetic barcode.
Monitoring barcode diversity through deep sequencing will allow us to determine the impact on viral dynamics of
disrupting IFN signaling. With this combination of host and viral genetics, we are well-positioned to uncover the
effects of type I IFN and IFN-λ, the lynch-pins of mammalian innate defenses, on viral genetic diversity and
evolutionary potential.
Terms: <(IFN) α><(IFN)-α><(IFN)α><Ablation><Address><Aerosols><Affect><Alferon><Alpha-Beta-Omega Interferon Receptor-1><Anti-viral Response><Antiviral Protein Alpha Type><Bar Codes><Biological><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><Cas nuclease technology><Cavia><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><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><Endogenous Interferon Beta><Environmental Factor><Environmental Risk Factor><Epithelium><Evolution><Fibroblast Interferon><Flu epidemic><Genetic><Genetic Differentiation><Genetic Divergence><Genetic Diversity><Genetic Drift><Genetic Structures><Genetic Variation><Genome><Guinea Pigs><Guinea Pigs Mammals><H3N2><H3N2 Virus><Health><Host Factor><Host Factor Protein><HuIFN-Alpha-Rec><IFN><IFN Alpha><IFN α><IFN-Beta><IFN-α><IFN-β><IFNAR><IFNAR1><IFNAR1 gene><IFNBR><IFNa><IFNb><IFNα><IFRC><Individual><Infection><Influenza A><Influenza A Virus, H3N2 Subtype><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Integration Host Factors><Interferon Alfa-n3><Interferon Alpha-Beta Receptor Alpha Chain><Interferon Type I><Interferon alpha><Interferon-beta><Interferon-α><Interferon-β><Interferons><Intracellular Communication and Signaling><Kinetics><Knock-out><Knockout><Lead><Leukocyte Interferon><Lymphoblast Interferon><Lymphoblastoid Interferon><Mice><Mice Mammals><Modeling><Molecular><Monitor><Murine><Mus><Natural Interferon Beta><Natural Selections><Natural human interferon beta><Orthomyxovirus Type A><Panama><Pb element><Population><Population Dynamics><Population Genetics><Population Sizes><Position><Positioning Attribute><Predisposition><Process><Property><Proteins><Public Health><RNA Viruses><Receptor Protein><Research><Respiratory Epithelium><Role><Route><Seasons><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Site><Spatial Distribution><Structure of respiratory epithelium><Susceptibility><Testing><Transmission><Type A Influenza><Variant><Variation><Viral><Viral Burden><Viral Genetics><Viral Load><Viral Load result><Virus><Work><airway epithelium><barcode><biologic><biological signal transduction><cytokine><deep sequencing><design><designing><economic impact><environmental risk><fitness><flu serotype><flu strain><flu subtype><flu transmission><flu viral strain><flu virus strain><heavy metal Pb><heavy metal lead><ifnar1 gene product><influenza epidemic><influenza serotype><influenza strain><influenza subtype><influenza transmission><influenza viral strain><influenza virus strain><influenzavirus><pandemic><pandemic disease><particle><receptor><respiratory tract epithelium><response><reverse genetics><seasonal flu><seasonal influenza><social role><tool><transmission of the flu virus><transmission process><type I IFN receptor><type I interferon receptor><viral transmission><virus genetics><virus transmission>