Pathogenesis, immunity, and control of coronaviruses in a large natural host animal, the pig

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Coronaviruses have caused three epidemics of severe respiratory disease in humans since 2003, the last being the present COVID-19 pandemic. In each case the virus came from an animal species but was able to infect humans. In the first two epidemics, SARS and MERS, although the virus passed from an animal to humans, it did not pass readily from one human to another, limiting the size of the epidemic. SARS-CoV-2 on the other hand is readily transmitted between humans. Because the virus can mutate (change its genetic material), over time it can escape from the immune response, so that as in the case of influenza, repeated vaccination may be required to prevent severe disease, although so far the vaccines have failed to prevent virus transmission.Humans are in increasingly close contact with many animal species and the risk of further epidemics is therefore high. Pigs are one such species and can be infected with many coronaviruses including porcine respiratory coronavirus (PRCV), which causes a pneumonia similar to COVID-19. Like SARS-CoV-2 porcine coronaviruses can mutate, and recently more virulent viruses have emerged that cause economically important disease in pig herds. Pig coronaviruses have also been detected in some humans although as yet they do not appear to transmit between people. Because of the emergence of PRCV strains that cause economically important disease in pigs and because pig coronaviruses might jump to humans and cause another coronavirus epidemic, we wish to understand better how the virus infects cells in the respiratory tract, how the immune system reacts to the virus early in infection and how later on it either causes lung damage or protects against further infection. This information will be important for designing new ways to prevent or treat the disease both in pigs and humans. We will also test a novel vaccine platform which has the potential to induce very strong immune responses and possibly immune responses that could protect against widely different coronavirus.We have discovered PRCV strains that cause either severe lung disease (pneumonia) or very mild lung inflammation. We have also shown that those that cause severe disease multiply in the cells of the nose, windpipe and lungs, while those that cause mild inflammation multiply well only in the nose. Comparing the structure of these strains and making new strains by genetic manipulation will allow us to identify the parts of the virus that are important for virus entry into different cells in the respiratory tract. Part of these studies will be performed on cultured lung and tracheal (windpipe) tissues, minimising the use of live animals. To discover how the immune system responds to the virulent and innocuous viruses we will take tissues from animals infected with the two virus strains and analyse what genes are turned on one day and fourteen days after infection. This will tell us how the two virus strains programme the immune response and what sort of immune response develops after the early interaction of the viruses with the immune system.We will use a novel vaccine platform which allows the part of the virus that binds to cells (the receptor binding domain or RBD) to be displayed on a particle and internal proteins of the virus to be produced in the pig to ask several questions. First whether this vaccine induces strong and protective antibodies, second whether it can also induce protective T cells (the second protective arm of the immune response) and thirdly whether if both antibodies and T cells together are more protective than either alone. Finally using this system, we shall test whether displaying many different RBD in the vaccine induces antibodies that can protect against many different virus strains