Schoeman, Dewald2025-11-212025-11-212024N/Ahttps://hdl.handle.net/10566/21451Human coronaviruses (HCoVs) have garnered intense interest due to the large outbreaks caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which have resulted in severe respiratory disease and significant global morbidity and mortality. In contrast, four other HCoVs—HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1—are associated with milder, more frequent, and seasonal respiratory tract infections. Of the four canonical coronavirus structural proteins, the envelope (E) protein remains the least well-characterised, despite its critical functions in viral assembly and release, as well as its role as a major contributor to viral pathogenesis. Its contribution to viral pathogenesis has been strongly linked to a C-terminal PDZ-binding motif (PBM) that interacts with host post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and zonula occludens-1 protein (ZO-1) (PDZ) domain-containing proteins, facilitating immune dysregulation and hyperinflammation. Early work on SARS-CoV-1 revealed that the PBM of its E protein serves as a pathogenic determinant, which was later supported by SARS-CoV-2 studies that demonstrated similar immunopathological outcomes. This raised a central question: if all HCoVs possess an E protein containing a PBM, why do some induce severe disease while others cause only mild infections?enHuman coronavirusHCoV-NL63Envelope proteinPALS1PDZ-binding motifThesis