Document text
Principal Investigator: Arjun Rustagi
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $175,510
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
COVID-19 remains an ongoing global health crisis, in part due to emerging variants. Fundamental questions
remain about the mechanisms by which SARS-CoV-2 infection drives inflammation in the lower lung, in part
due to the lack of in vitro infection models. Better understanding of variant biology and the immune pathways
involved in early SARS-CoV-2 infection could offer insights for the development of novel therapeutic strategies.
The antiviral cytokines type I interferons and their downstream effects have been implicated in COVID-19.
SARS-CoV-2 may inhibit or promote interferon effects in some cell types in the lung, and this may differ
between viral variants. My preliminary work shows that organoids and lung slice cultures can be used to study
these early events in SARS-CoV-2 infection and identifies macrophages as a cell type that activates the
interferon pathway in infected cultures. Thus, I propose using quantitative PCR, single-cell RNA sequencing,
and flow cytometry to study viral variants and to deeply profile the changes to viral and host gene and protein
expression during infection. I will study highly relevant cell types that can interact with each other in a similar
fashion to the in vivo lung. I will study the interferon stimulated gene response and identify the cell types in
which it is being modulated or would be good targets for therapeutic intervention. This knowledge will be critical
to our efforts to combat the COVID-19 pandemic.
I am currently a fellow in Dr. Catherine Blish’s lab in the Division of Infectious Diseases at Stanford University
and I am in the process of being promoted to a full time Instructor position. Stanford University offers an
outstanding scientific environment, where all the resources necessary to the success of this project are made
available to me. My long-term goal is to become an independent physician-scientist, with a research focus in
respiratory viral pathogenesis. I aim to establish a research program focused on modeling established and
emerging infections in primary lung tissue with a goal of developing new treatments.
To achieve this goal, I have designed a tailored career development plan that comprises both formal and
informal training. This training will enhance my expertise in lung biology, immunology, and sequencing
analysis. Informal training in these topics will be provided by my mentor, Dr. Catherine Blish, and by the rest of
my advisory committee, Dr. Calvin Kuo, Dr. Mark Krasnow, Dr. Susan Holmes, and Dr. Ben Pinsky. With their
guidance, I will complete the proposed project, submit research manuscripts, obtain further funding, and obtain
an independent research position.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><3-D><3-Dimensional><3D><Acute><Acute respiratory infection><Advisory Committees><Air><Alveolar Cell><Alveolar Macrophages><Animals><Autoantibodies><Automobile Driving><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Basal Cell><Biology><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 pathogenesis><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 infection><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cachectin><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Line><Cell Signaling><Cell-to-Cell Interaction><CellLine><Cells><Cessation of life><CoV-2><CoV2><Communicable Diseases><Coronavirus Infectious Disease 2019><Data><Death><Dependence><Development><Development Plans><Disease><Disorder><Emerging infection><Environment><Epithelial Cells><Epithelium><Event><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><GS-5734><Gene Expression><Genes><Genetic Alteration><Genetic Change><Genetic defect><Goals><HPGF><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN><IFN-Gamma-Inducing Factor Gene><IFN-beta 2><IFN-gamma-Inducing Factor><IFNB2><IGIF><IGIF Gene><IL-1 Gamma><IL-1 Gamma Gene><IL-18><IL-18 Gene><IL-1g><IL-1g Gene><IL-6><IL18><IL18 Protein><IL18 gene><IL1F4><IL1F4 Gene><IL6 Protein><Immune><Immune Cell Activation><Immune infiltrates><Immune response><Immunes><Immunity><Immunological response><Immunology><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><Innate Immune Response><Interferon Type I><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interferons><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><Interleukin-6><Intracellular Communication and Signaling><Knowledge><Liquid substance><Lung><Lung Diseases><Lung Parenchyma><Lung Respiratory System><Lung Tissue><MGC12320><MGC12320 Gene><MGI-2><Macrophage><Macrophage Activation><Macrophage-Derived TNF><Manuscripts><Maps><Mentors><Microscopy><Modeling><Modern Man><Monocyte-Derived TNF><Mucosa><Mucosal Tissue><Mucous Membrane><Mutation><Myeloid Differentiation-Inducing Protein><Mφ><Organoids><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Physicians><Plasmacytoma Growth Factor><Play><Position><Positioning Attribute><Process><Productivity><Progenitor Cells><Protein Analysis><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Macrophages><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA amplification><Research><Research Resources><Resources><Rest><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 pathogenesis><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><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><Scientist><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 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Stimulus><Strains Cell Lines><Structure of parenchyma of lung><Supporting Cell><System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Task Forces><Techniques><Testing><Therapeutic Intervention><Training><Transcript><Tropism><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Universities><Variant><Variation><Veklury><Viral><Viral Gene Products><Viral Gene Proteins><Viral Pathogenesis><Viral Proteins><Virus><Virus Replication><Work><Wuhan coronavirus><acute infection><advisory team><autoimmune antibody><autoreactive antibody><biological signal transduction><career><career development><cell type><combat><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><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 pandemic><coronavirus disease-19 pathogenesis><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cultured cell line><cytokine><deliver vaccines><design><designing><developmental><disease of the lung><disorder of the lung><driving><emergent infection><flow cytophotometry><fluid><genome mutation><global health><hCoV19><hesitant to vaccination><high risk><host response><immune activation><immune cell infiltrate><immune system response><immunoresponse><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innate immune pathways><insight><instructor><interferon beta 2><intervention therapy><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><liquid><lung disorder><nCoV2><nasopharyngeal swab><new diagnostics><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation diagnostics><next generation therapeutics><novel><novel diagnostics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pandemic><pandemic disease><pathway><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><programs><protein expression><pulmonary><qRTPCR><remdesivir><respiratory><respiratory pathogen><respiratory virus><response><scRNA-seq><self reactive antibody><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 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 pathogenesis><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><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><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><statistics><stem cells><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><three dimensional><tool><vaccination hesitancy><vaccine delivery><vaccine hesitancy><vaccine hesitant><variant of interest><variants of concern><viral multiplication><viral replication><virus multiplication><virus pathogenesis><virus protein>