Abstract
Respiratory viruses, including coronaviruses (CoVs) and influenza A viruses (IAVs), represent a persistent and significant threat to global health. Understanding the mechanisms that govern virus–host interactions and the resulting immune responses is essential for the development of effective vaccines and therapeutics. However, progress has been limited by the lack of availability of animal models that accurately recapitulate human respiratory anatomy, viral pathogenesis, and immune responses. The overall aim of this thesis is to evaluate the domestic pig as a translational large-animal model for characterising respiratory virus–host interactions and to assess its relevance for understanding human immunity to respiratory viral infections.
To address this aim, three complementary studies were undertaken. The first compared two porcine respiratory coronavirus (PRCV) strains of differing pathogenicity (PRCV 135 and ISU1) to investigate how strain-specific viral properties influence lung pathology and immune responses. The second compared PRCV and pandemic H1N1 2009 influenza A virus (pH1N1) infection in pigs, enabling identification of conserved and virus-specific immune signatures within the same host species. The third focused on the maintenance of lung T cell immunity, using in vivo deuterium labelling to characterise the turnover and persistence of tissue-resident memory T cells (TRM) in the porcine respiratory tract.
PRCV 135 infection resulted in higher viral loads, more extensive lung pathology, and stronger inflammatory and adaptive immune responses compared with ISU-1, demonstrating the ability of the pig model to capture heterogeneity in disease severity analogous to that observed in human coronavirus infections. Comparative analysis of PRCV and pH1N1 infection revealed prolonged viral shedding and increased lung pathology following PRCV infection, alongside distinct innate and adaptive immune trajectories, paralleling key differences between coronavirus and influenza virus infections in humans.
Detailed immunological analyses demonstrated robust compartmentalised immune responses within the lung and bronchoalveolar lavage, including antigen-specific CD4 and CD8 T cell responses and distinct humoral immune kinetics. For the first time, single-cell RNA sequencing was applied to porcine lung tissue and bronchoalveolar lavage, revealing conserved early interferon-driven antiviral programmes across infections, followed by virus-specific transcriptional divergence at later stages. We also demonstrated that porcine lung TRM populations are dynamically maintained through ongoing turnover rather than long-term quiescence, aligning more closely with emerging human data than with findings from small animal models.
In conclusion, this thesis demonstrates that the pig is a highly suitable and informative model for studying respiratory virus and host immune interactions, offering significant translational relevance to human immunity. While practical and species-specific limitations remain, the pig provides a critical bridge between mechanistic studies in small animals and humans. Importantly, the use of the pig aligns with a One Health approach, recognising the interdependence of human and animal health in the context of shared respiratory pathogens.