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Principal Investigator: COSIMO COMMISSO
Organization: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
Fiscal Year: 2020
Award: $195,000
Funding agency: National Cancer Institute
PROJECT SUMMARY
The world has been shocked by the recent COVID-19 pandemic. Macropinocytosis is a form of endocytosis that
viruses use to gain entry into cells or to facilitate infection. Our laboratory has the most extensive experience in
investigating macropinocytosis in the context of cancer, where it functions as a nutrient acquisition pathway2-12.
Macropinocytosis is unique among other endocytic pathways because it is preceded by plasma membrane
activity in the form of ruffling. When ruffles fuse with each other they form a macropinosome that encapsulates
the surrounding fluid and associated particles. Viruses can use macropinocytosis for cellular internalization or
they can hijack macropinocytosis for other aspects of infection. Severe acute respiratory syndrome
coronaviruses (SARS-CoVs) induce macropinocytosis late in infection that is continuous, independent from cell
entry, and associated with increased infection in vitro. These viruses use their Spike protein to signal through
the epidermal growth factor receptor (EGFR) to stimulate macropinocytosis, and inhibitors of macropinocytosis
or EGFR lead to a reduction in viral spread. While CoVs do not seem to utilize macropinocytosis for entry into
the cell, they do use later steps in the macropinosome maturation pathway to augment infection. The maturation
of the macropinosome is not very well characterized, but there are some indications that specific signaling
pathways are involved. We have extensively studied EGFR-driven macropinocytosis in cancer cells and we can
use this expertise to determine strategies for blocking macropinosome maturation and SARS-CoV-2 infection.
Our hypothesis is that SARS-CoV-2 uses mature macropinosomes as a way to spread to surrounding cells,
either by inducing `macropinosome bursting' as occurs in a process called methuosis, or by traveling
extracellularly via recycling macropinosomes. In this proposal, we will explore this hypothesis by 1) taking a
candidate approache to blocking macropinosome maturation and 2) determine the mechanism of SARS-CoV-2
viral escape that involves macropinocytosis. This project will be of great significance and impact because, by
and large, a detailed picture of what controls macropinosome maturation in the context of EGFR signaling and
SARS-CoV-2 is lacking. Moreover, it will constitute the first evaluation of the impact that candidate inhibitors
have on macropinosome maturation. Understanding the regulators of macropinosome maturation will shed light
on a critical aspect of CoV biology and could lead to new approaches for the treatment of COVID-19.
Terms: <2019 novel coronavirus><2019-nCoV><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adenoviridae><Adenoviruses><Assay><Bioassay><Biologic Assays><Biological Assay><Biology><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Cancers><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell membrane><Cells><Circulatory Collapse><Cytoplasmic Membrane><Cytosol><Data><Dose><EGF Receptor><EGFR><ERBB Protein><Echo Viruses><Echovirus><Encapsulated><Endocytosis><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Exocytosis><HER1><HIV><HSV><Herpes Simplex Virus><Herpes labialis Virus><Human Immunodeficiency Viruses><Impact evaluation><In Vitro><Infection><Intracellular Communication and Signaling><LAV-HTLV-III><Laboratories><Lead><Life Cycle><Life Cycle Stages><Light><Liquid substance><Lung><Lung Respiratory System><Lymphadenopathy-Associated Virus><Lysosomes><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Modeling><Nutrient><Pancreas Ductal Adenocarcinoma><Pancreatic Ductal Adenocarcinoma><Pathway interactions><Patients><Pb element><Penetration><Phase><Photoradiation><Plasma Membrane><Poxvirus officinale><Process><Property><Proteins><Receptor Signaling><Recycling><Regulation><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Shock><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Simplexvirus><Stress><System><TGF-alpha Receptor><Testing><Therapeutic><Transforming Growth Factor alpha Receptor><Travel><Urogastrone Receptor><Vaccinia virus><Viral><Viral Diseases><Virus><Virus Diseases><Virus-HIV><Wuhan coronavirus><biological signal transduction><c-erbB-1><c-erbB-1 Protein><cancer cell><circulatory shock><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><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><experience><extracellular><fluid><heavy metal Pb><heavy metal lead><inhibitor><inhibitor/antagonist><life course><liquid><lung basal segment><lung base><malignancy><membrane activity><mutant><necrocytosis><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><pancreatic cancer cells><pancreatic tumor cells><pandemic><pandemic disease><particle><pathway><plasmalemma><proto-oncogene protein c-erbB-1><pulmonary><recombinant vaccinia virus><severe acute respiratory syndrome-CoV><trafficking><uptake><viral infection><virus infection><virus-induced disease>