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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
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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 Transmission and Persistence

Linda Saif, Professor, Food Animal Health Research Program, Ohio State University, Wooster
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Highlights

Porcine Coronaviruses
• The porcine coronaviruses that cause enteric infections are TGEV (transmissible gastroenteric virus) and PEDV (porcine epidemic diarrhea virus).
• Porcine respiratory coronavirus (PRCV) is thought to be an S-gene deletion mutant of TGEV but they are the same serotype.
• RT-PCR and nested PCR assays can detect and differentiate between PRCV and TGEV.
• TGEV infects small intestinal villous enteric sites, occasionally the upper respiratory tract, and induces villous atrophy and a cytolytic infection, leading to vomiting and diarrhea.
• PRCV infects epithelial cells of upper and lower respiratory tract but not intestinal epithelia, so there may be a co-receptor for TGEV on those cells.
• PRRS infects cells in the lamina propria, causes moderate to subclinical respiratory disease, and replicates to high titers in lung.
• The PRCV S gene retains the immunodominant epitope A, but not the C and D epitopes on TGEV.
• PRCV S gene deletions vary in size, and strains with shorter deletions may be more virulent than those with longer deletions.
• PRCV causes viremia, and virus can replicate in alveolar macrophages.
• Two point mutations in S appear responsible for going from enteric to respiratory tropism.
• For TGE, vaccine strains are intermediate between wild type and attenuated strains.
• Enteric coronavirus can be fatal in young animals, and respiratory coronavirus infections are more often fatal in adults when combined with other factors.

Bovine Coronaviruses
• All bovine coronaviruses belong to a single serotype and are pneumoenteric.
• Viruses infect a range of enteric and respiratory tissues.
• Have identified 42 amino acid changes at 38 sites, with 5–6 clustered changes, but no indication of what this means for phenotype.

Viral Shedding
• Virus is shed in feces when intestinal epithelial cells are infected and sometimes, with PRCV, when few intestinal tract cells are infected, possibly due to large amounts of virus being swallowed.

Animal vs. Human Respiratory Viruses
• Induce similar clinical signs and infect similar tissues to SARS, but PRCV can infect alveolar macrophages.
• Pathology and shedding periods are similar.

Co-Infections with Coronaviruses
• In pigs, concurrent or sequential infections of respiratory exacerbate shedding, fever, respiratory disease, and infiltration of monocytes in lung; co-infection with flu and PRCV produces enhanced respiratory disease. This may have relevance for SARS and flu outbreaks.
• Secondary bacterial infections with PRCV enhanced respiratory disease.
• Animals with lower serum antibody titers were more likely to develop bovine coronavirus infection and disease.
• Stress and commingling of animals from different locations leads to more outbreaks among cattle.
• Concurrent respiratory infections and bacteria in cows act synergistically to produce pneumonia.

Coronavirus Reinfections
• Reinfections with PED are symptomatic but are not with bovine CoVs or PRCV.
• Reinfections are usually mild or subclinical.

Crossing the Species Barrier
• Coronavirus from wild ruminants can experimentally infect young calves, indicating a potential reservoir.
• Turkey poults, but not chicks, can be infected with bovine enteric CoV, so cattle-to-bird transmission is possible.

Animal Coronavirus Vaccines
• The focus in animals is on passive immunity via the mother's milk, exploiting the common mucosal immune system.
• TGE vaccines induce IgA antibodies in milk.
• PRCV infections only produce partial immunity to TGE, suggesting compartmentalization in the common mucosal immune system.
• Repeated immunization at multiple sites may increase IgA titers in mother's milk.
• Attenuated vaccines for pigs, intranasal or oral, replicate poorly in intestines and produce low IgA titers in milk.
• Killed TGE vaccines given intramuscularly only induce IgG in milk and are not protective.
• It is easier to boost mucosal immune response than elicit intestinal immune response.
• Virulent TGE virus stimulates high IgA antibody secreting cell numbers and lymphoproliferative response in intestinal tract but not respiratory tract; animals are protected against diarrhea and nasal and rectal shedding.
• Virulent PRCV elicits few IgA-producing cells in intestine, but mostly IgG and lymphoproliferative response in respiratory tract; animals are partially protected against diarrhea and completely against nasal shedding.
• Systematic S vaccine given subcutaneously with incomplete foynes does not induce protective immunity to TGE, but when combined with other viral proteins, given IP, and with a potent mucosal adjuvant, it induces partial protection against TGE shedding.
• Recombinant N proteins with T-cell epitopes and S proteins may be required for maximal antibody response.
• The only existing commercial respiratory coronavirus vaccine is for infectious bronchitis (IBV) in chickens, using killed or live vaccines; effectiveness is complicated by multiple serotypes of IBV.
• Live attenuated TGE vaccine is stable over 100 passages in culture.
• An appropriate animal model is extremely important to design effective SARS vaccines.

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