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.
• 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.
• 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.