Impact of intra-host immune adaptations on the evolution of SARS-CoV-2 S protein among individuals with SARS-CoV-2 infections in South Africa, 2020 to 2022 (preprint)

Background: Intra-host diversity studies are used to characterise mutational heterogeneity of SARS-CoV-2 infections to understand the impact of virus-host adaptations. This study investigated the frequency and diversity of the spike (S) protein mutations within SARS-CoV-2 infected South African individuals. Methods Single nucleotide polymorphism (SNP) assays and whole genome sequencing were performed on SARS-CoV-2 positive samples. Allele frequency (AF) was determined using TaqMan Genotyper software for SNP analysis and galaxy.eu for analysis of FASTQ reads. Results The SNP assays identified 5.3% (50/948) Delta cases with heterogeneity at delY144 (4%; 2/50), E484Q (6%; 3/50), N501Y (2%; 1/50) and P681H (88%; 44/50). Sequencing identified 9% (210/2381) cases with Beta, Delta, Omicron BA.1, BA.2.15, and BA.4 lineages with heterogeneity in the S protein. Heterogeneity was primarily identified at positions 19 (1.4%) with T19IR (AF 0.2-0.7), 371 (92.3%) with S371FP (AF 0.1-1.0), and 484 (1.9%) with E484AK (0.2-0.7), E484AQ (AF 0.4-0.5) and E484KQ (AF 0.1-0.4). Conclusion Mutations at heterozygous amino acid positions 19, 371 and 484 reduce recognition of neutralising antibodies, however the impact of the multiple substitutions at the same position is unknown. Therefore, we hypothesise that intra-host SARS-CoV-2 quasispecies with heterogeneity in the S protein facilitate competitive advantage of variants that can completely/partially evade host’s natural and vaccine-induced immune responses.

Comparative studies of the seven human coronavirus envelope proteins using topology prediction and molecular modelling to understand their pathogenicity (preprint)

Human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 are less virulent and cause mild, self-limiting respiratory tract infections, while SARS-CoV, MERS-CoV, and SARS-CoV-2, are more virulent and have caused severe outbreaks. The CoV envelope (E) protein, an important contributor to the pathogenesis of severe hCoVs infections, may provide insight into this disparate severity of the disease. Topology prediction programs and 3D modelling software was used to predict and visualize structural aspects of the hCoV E protein related to its functions. All seven hCoV E proteins largely adopted different topologies, with some distinction between the more virulent and less virulent ones. The 3D models refined this distinction, showing the PDZ-binding motif (PBM) of SARS-CoV, MERS-CoV, and SARS-CoV-2 to be more flexible than the PBM of hCoVs 229E, NL63, OC43, and HKU1. We speculate that the increased flexibility of the PBM may provide the more virulent hCoVs with a greater degree of freedom, which can allow them to bind to different host proteins and can contribute to a more severe form of the disease. This is the first paper to predict the topologies and model 3D structures of all seven hCoVs E proteins, providing novel insights for possible drug and/or vaccine development.