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Principal Investigator: Nicola Decaro
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2023
Award: $205,587
Funding agency: National Institute of Allergy and Infectious Diseases
1 Project Summary
2 There is growing evidence that canine coronaviruses (CCoVs) can infect humans and be associated with
3 clinical (mostly acute respiratory) illness in children and adults. Human infections with CCoVs with recombinant
4 canine-feline-porcine spike proteins (hCFPL-CoVs) have been confirmed in several countries including Haiti
5 (2017), Malaysia (2018), the USA (2014) and Thailand (2003). The high sequence identity (SI, 99.4%) observed
6 between hCFPL-CoVs from geographically distant Malaysia (CCoV-HuPn-2018) and Haiti (HuCCoV-Z19)
7 suggests that they may be capable of human-to-human transmission or represents temporal clustering. CCoVs
8 have not been recognized previously as human pathogens, and the threat they pose to public health is unknown
9 and may be underappreciated. While complete genome sequencing demonstrated hCFPL-CoVs are canine-
10 feline recombinant alphacoronaviruses, it failed to identify potential ancestral strains likely due to scarcity of
11 CCoV genomic data (only 17 complete genome sequences are available in the GenBank). To address that, we
12 will conduct complete genomic sequencing of up to 200 new CCoVs (from Dr. Decaro) and additional hCFPL-
13 CoVs (if identified in Dr. Gray’s ongoing study).
14 A unique 36 nt (12-aa) deletion identified in the N protein in the SR-rich domain (ΔSR-N) of CCoV-HuPn-
15 2018 may be associated with a recent zoonotic transmission of CCoV-HuPn-2018 and certain biological
16 functions acquired or lost by the virus. While such deletions in the SR-rich region of the N-protein were not
17 previously found in CCoVs, presence of a similar deletion was demonstrated in severe acute respiratory
18 syndrome coronavirus (SARS-CoV) strains early following their emergence into human population but not in
19 SARS-CoV-like bat strains. This deletion was shown to be associated with the altered cellular localization of the
20 N-protein and increased pathogenicity of the SARS-CoV strains bearing them. Because SARS-CoV N-protein
21 plays an important role in inhibition of type I interferon (IFN) production, deletions in it may alter innate immune
22 responses against SARS-CoV as well as other CoVs including CCoV-HuPn-2018. Using reverse genetics, we
23 will evaluate the biological function of this mutation. We propose the following Specific Aims to study the
24 genomics, evolution and human emergence mechanisms of hCFPL-CoVs. Aim 1. Conduct genome-wide
25 analysis of historic and current CCoV strains a) to determine the evolutionary relationship between hCFPL-CoVs
26 and their potentially ancestral strains and b) to identify genetic features associated with CCoV-HuPn-2018
27 infectivity or pathogenicity to human host. Aim 2. To generate and use CCoV-HuPn-2018 infectious clone to
28 investigate the effect of the identified N- deletion (ΔSR-N) on CCoV-HuPn-2018 cellular localization, replication
29 dynamics and the host transcriptome response. These studies will identify the genomic features associated with
30 hCFPL-CoV/CCoV infectivity to humans and generate essential fundamental knowledge regarding the common
31 mechanisms regulating zoonotic transmission of CoVs.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Acute><Address><Adult><Adult Human><Affect><Bats><Biological><Biological Function><Biological Process><COVID-19 virus><COVID19 virus><Canine Species><Canis familiaris><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Child><Child Youth><Children (0-21)><Chiroptera><Clinical><CoV-2><CoV2><Collaborations><Collection><Coronaviridae><Coronavirus><Coronavirus N protein><Coronavirus nucleocapsid protein><Country><DNA Molecular Biology><Disease><Disorder><Dogs><Dogs Mammals><Evolution><Family Felidae><Family suidae><Federation of Malaya><Felidae><Felids><Genbank><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Markers><Genetic defect><Genome><Genomics><Genotype><Haiti><Human><IFN><Immune><Immune response><Immunes><Immunological response><Infant><Infection><Innate Immune Response><Interferon Type I><Interferons><Intracellular Communication and Signaling><Knowledge><Malay Federation><Malaya><Malaysia><Modeling><Modern Man><Molecular><Molecular Biology><Mutation><N protein, Severe acute respiratory syndrome virus><NGS Method><NGS system><Pathogenicity><Patients><Phenotype><Phosphorylation><Phylogenetic Analysis><Phylogenetics><Pigs><Play><Pneumonia><Population><Production><Protein Phosphorylation><Proteins><Public Health><RNA Binding><RNA bound><Recombinants><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS virus N protein><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV N protein><SARS-CoV-1><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Suidae><Swine><Syndrome><Thailand><Transmission><Virion><Virus><Virus Particle><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><adulthood><biologic><biological signal transduction><canine><comparative><corona virus><coronavirus disease 2019 virus><coronavirus disease-19 virus><domestic dog><feline><genetic biomarker><genome mutation><genome scale><genome sequencing><genome wide analysis><genome wide studies><genome-wide><genome-wide analysis><genome-wide identification><genomewide><genomic RNA><genomic data><genomic data-set><genomic dataset><geographically distant><global gene expression><global transcription profile><hCoV19><high risk><host response><human pathogen><immune system response><immunoresponse><kids><molecular clock><nCoV2><next gen sequencing><next generation sequencing><nextgen sequencing><novel><porcine><respiratory><response><reverse genetics><severe acute respiratory syndrome-CoV><social role><suid><trait><transcriptome><transcriptomics><transmission process><youngster>