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Coronavirus Biology and Pathogenesis
Molecular Biology of Coronaviruses
Coronavirus Pathogenesis
Coronavirus Transmission and Persistence
Technology in SARS Discovery
Panel 1 Discussion
On the Front Lines
Approaches to Vaccines and Drug Development
Future Perspectives on Emerging Infections
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SARS in the Context of Emerging Infectious Threats SARS in the Context of Emerging Infectious Threats
Coronavirus Biology and Pathogenesis
Coronavirus Pathogenesis

Kathryn V. Holmes, Department of Microbiology, University of Colorado Health Sciences Center, Denver
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Highlights

Specificity of Coronavirus Infection
• Each coronavirus infects a particular host, and much of the specificity depends on receptor interactions.
• The serogroups of coronavirus have been stable over long periods; human coronaviruses have no animal models for study.
• Spike protein and sometimes hemagglutinin protein (in Group II coronaviruses) determine the restriction of host cells.

S protein Features
• Tip of S protein determines receptor-binding specificity.
• S2 membrane-bound domain determines membrane fusion and cell-to-cell fusion.
• Protease cleavage site between S1 and S2 is essential for infectivity and cell fusion.
• Deletions in S1 do not change receptor specificity but can change tissue tropism.
• Conformational change in S can be induced at pH 8; some regions of small intestine are alkaline.
• Antibodies to S1 and S2 are neutralizing, so these are targets for vaccine development.

Coronavirus-Cell Interaction
• S (or sometimes hemmaglutinin esterase) interacts or maybe docks with a sugary host molecule.
• Virus then interacts with a protein-containing receptor; at 37 degrees this causes a conformational change in S that might allow interaction with a co-receptor.
• Changes in receptor lead to fusion of envelope with cell membrane and delivery of nucleocapsid into the cell.
• Coronavirus fusion domain, like gp41 and HA2, has two heptad repeats and undergoes conformational change.

Host Cell Receptors
• Viruses in Group I share the same receptor, aminopeptidase N, but use it in different ways; it is 150 kDa and on the surface of the enteric and respiratory tracts.
• A single glycan prevents human coronavirus from binding pig aminopeptidase N.
• All group I coronaviruses can use feline aminopeptidase N, so it may be the original receptor for all these viruses before specialization.
• Only known receptors for Group II viruses are CEACAM1 and 9-O acetylated sialic acid in mouse.
• CEACAM1A is an immunoglobulin superfamily member with a projecting region that is available on the surface of the intestine and respiratory tract; it is also a receptor for H. influenza and Neisseria.

Jumping Hosts
• Beginning to look at how many mutations would allow a spike protein to jump hosts using targeted RNA recombination.
• Three regions conserved among all S proteins apparently are for structure, not binding.
• Looking at whether SARS virus can infect both an animal and human host, in which case there would be an animal reservoir for SARS, or whether a mutation caused the virus to jump from an animal to human host.

Human Coronavirus Infection
• 229E has been innocuous and stable for a long time.
• Intranasal infections with 229E caused disruptions in nasal epithelium in all cases and symptoms in some.
• The same person can get the same virus repeatedly.

Vaccine and Drug Targets
• S raises neutralizing antibody and is a good target.
• Inhibitors that block conformational change in S are good targets.
• Monoclonal antibodies that block infection may serve as a receptor blockade.
• Protease inhibitors that prevent polyprotein processing.
• Inhibiting budding, exocytosis, or secretion.

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