A recent study conducted by researchers from University College London, Imperial College London, and the UKMRC-University of Glasgow Centre for Virus Research has revealed new insights into the evolutionary mechanisms of the Omicron subvariants of the SARS-CoV-2 virus. Published in Nature Microbiology, the study focused on the enhanced innate immune suppression exhibited by newer subvariants, particularly BA.4 and BA.5, compared to earlier subvariants such as BA.1 and BA.2.
The researchers compared the replication and host responses of various Omicron subvariants with the previously dominant Delta variant. Using human airway epithelial cells and primary airway cultures, they accurately measured viral replication and host responses. The results showed that BA.4 and BA.5 demonstrated improved suppression of innate immunity compared to earlier subvariants, indicating a convergent evolution of enhanced innate immune antagonist expression.
To better understand the phenotypic differences between Omicron subvariants, the study emphasized the importance of equalizing the input dose of each variant. Even when replication rates were similar, BA.4 and BA.5 triggered less innate immune activation than BA.1 and BA.2, suggesting a potential adaptation to reduce innate immune activation as Omicron subvariants evolve.
The researchers extended their analysis to primary human airway epithelial (HAE) cultures to gain a better understanding of the host response. Despite replicating similarly to BA.2 in HAEs, BA.5 exhibited reduced innate immune activation. This indicates a potential adaptation to evade innate immune activation as Omicron subvariants evolve.
The impact of lower temperatures on Omicron subvariant replication was also explored. The results showed that BA.1 to BA.5 replicated less efficiently at 32°C. Interestingly, BA.4 and BA.5 continued to exhibit lower innate immune activation despite reduced replication, suggesting a temperature-independent mechanism of enhanced innate immune evasion.
The study delved into the molecular mechanisms behind the observed differences in innate immune activation and identified increased expression of viral proteins Orf6 and N in BA.4 and BA.5 as a potential explanation. Blocking IFN signaling rescued viral replication, indicating the crucial role of Orf6 in antagonizing innate immune responses.
As new Omicron subvariants continue to emerge, the research expanded its analysis to include BA.2.75, XBB.1, XBB.1.5, and BQ.1.1. The results consistently showed enhanced innate immune evasion across these subvariants, characterized by increased Orf6 expression. This suggests that evolving innate immune escape mechanisms may be a central feature of Omicron lineage adaptation.
Overall, this study provides detailed insights into the enhanced innate immune suppression exhibited by newer Omicron subvariants. The research highlights the role of Orf6 in innate immune antagonism and proposes a model where early interactions with host innate immune responses influence viral transmission. Further research efforts are crucial to unravel the intricacies of viral adaptation and inform effective strategies for prevention and treatment as the COVID-19 pandemic unfolds.