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Principal Investigator: PETER CRESSWELL
Organization: YALE UNIVERSITY
Fiscal Year: 2023
Award: $209,375
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
COVID-19 is a dangerous pandemic disease caused by the highly infectious coronavirus
SARS-CoV-2, which arose by zoonotic transfer from bats. CD8-positive T cells contribute to
viral elimination by killing infected cells, preventing viral expansion in an infected individual and
limiting the exposure of others to infection. CD8-positive T cells kill virally infected cells by
recognizing Major Histocompatibility Complex class I (MHC-I) molecules on their surface that
are associated with peptides derived from viral proteins. Like many viruses, SARS-CoV-2
encodes specific proteins that affect surface expression of MHC-I-peptide complexes, resulting
in resistance to T cell-mediated killing. We hypothesize that, since SARS-CoV-2 transferred
from bats to humans, its MHC-I inhibitory properties evolved in bats. We further hypothesize
that, because evolutionary pressure on the virus was mediated by natural selection in the face
of chronic exposure to the bat immune system, inhibition of MHC-I function will be more efficient
in bats than in humans. Investigating these hypotheses is limited by the lack of appropriate
reagents. This proposal seeks to remedy the situation by developing antibodies in mice and
rabbits and nanobodies in yeast that identify bat MHC-I proteins as well as the bat equivalents
of the additional human gene products that facilitate the generation and surface expression of
MHC-I molecules containing bound antigenic peptides, namely TAP1 and TAP2, tapasin,
calreticulin and the thiol oxidoreductase ERp57 (PDIA3). As we produce these reagents we will
use them to characterize MHC-I-restricted antigen processing in bats and determine how
SARS-CoV-2 infection affects it. We have identified four SARS-CoV-2 proteins that
independently cause MHC-I down-regulation in humans, and we suggest that these proteins
acting in combination are responsible for the reduction in MHC-I surface expression in infected
cells. Our goal is to determine whether these gene products, and potentially others, affect the
same process in bat cells and how well they do it. Understanding MHC-I function and adaptive
immunity in bats will help us to uncover why they are a such potent reservoir for coronaviruses.
Determining how bats survive infection by such viruses may suggest targeted therapeutic
approaches to improve the ability of humans to resist them and enhance our ability to control
and defeat future coronavirus pandemics.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><55-kDa High-Affinity Calcium Binding Protein><ABC Transporter, MHC, 2><ABC17><ABCB2><ABCB3><APT2><ATP-Binding Cassette, Sub-Family B, Member 3><Adaptive Immune System><Affect><Affinity><Antibodies><Antigen Peptide Transporter 2><Avian Infectious Bronchitis Virus><Bats><Binding><Binding Proteins><CAB-63><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Calcium-Binding Protein-3><Calregulin><Cell Body><Cell Line><Cell surface><CellLine><Cells><Cessation of life><Chiroptera><Chronic><Class I Genes><Clinical Treatment Moab><CoV pandemic><CoV-2><CoV2><Complex><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><D6S114E><Dangerousness><Death><Dehydrogenases><Dendritic Cells><Disease><Disorder><Domestic Rabbit><Down-Regulation><ERp57><ERp60><Endoplasmic Reticulum><Ergastoplasm><Exposure to><Future><Generations><Globulins><Glycoproteins><Goals><Golgi><Golgi Apparatus><Golgi Complex><HACBP><Histocompatibility Complex><Histocompatibility Complices><Homologous Protein><Human><IFN><Immune system><Immunity><Individual><Infection><Infectious bronchitis virus><Innate Immune System><Interferons><Ion Channel><Ionic Channels><LYT3><Ligand Binding Protein><Ligand Binding Protein Gene><MHC Class I><MHC Class I 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pandemic><Severe acute respiratory syndrome related corona virus 2><Source><Strains Cell Lines><Sulfhydryl Compounds><Surface><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TAP-A protein><TAP1><TAP1 gene><TAP2><TAP2 gene><Testing><Thiols><Time><Translations><Transporter, ATP-Binding Cassette, Major Histocompatibility Complex, 2><Veiled Cells><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Writing><Wuhan coronavirus><Yeasts><Zoonoses><Zoonotic><Zoonotic Infection><acquired immune system><adaptive immunity><antigen processing><bound protein><cC1qR Protein><calreticulin><cell killing><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><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 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