Study suggests BA.5 evolved to induce enhanced inflammation when compared to prior Omicron subvariants
In a recent study posted to the bioRxiv* preprint server, researchers evaluated the comparative pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sub-variants BA.1, BA.2, and BA.5, in vitro and in vivo.
Omicron subvariant BA.5 recently emerged from South Africa in parallel with BA.4 and subsequently has been detected in several countries worldwide. By August 2022, it outcompeted BA.2 to become the dominant Omicron sub-variant in the world. Though BA.5 and BA.4 appear to be the descendants of Omiron sub-variant BA.2 in genome sequencing and evolutionary analyses, they seem to be acquiring enhanced pathogenicity, transmission ability, and potential of escaping neutralizing antibodies induced by vaccination or infection.
Additionally, BA.5 contains some unique mutations in its spike (S) protein, including L542R, which confers enhanced fusogenicity and resistance to the immunity induced by prior infection with early variants. The emergence of BA.5 raises concerns that SARS-CoV-2 is continuously evolving to acquire mutations that would increase its pathogenicity; thus, there is an urgent need to characterize BA.5 to intervene early and mitigate its spread.
About the study
In the present study, researchers characterized virological characteristics of Omicron sub-variant BA.5 in vitro and in vivo in parallel with its predecessors BA.1 and BA.2; they used an early pandemic B.1.1 isolate containing D614G mutation as the control. For characterizing in vitro growth kinetics of Omicron sub-variants, they used three cell lines viz., VeroE6/ transmembrane protease, serine 2 (TMPRSS2), Calu-3, and induced pluripotent stem (iPS) cell-derived alveolar epithelial cells.
Electron microscopic analysis revealed that VeroE6/TMPRSS2 cells infected with SARS-CoV-2 showed several membranous structures or annulate lamellae (AL) gathered within electron-dense areas near the nucleus. The researchers utilized the airway-on-a-chip method to study the observed AL in the microscopic cell sections.
Furthermore, they analyzed the pulmonary function of infected hamsters for an in vivo evaluation of the pathogenicity of Omicron sub-variants. They assessed three surrogate markers for airway obstruction: i) subcutaneous oxygen saturation (SpO2), ii) enhanced pause (Penh), and iii) the ratio of peak expiratory time to the total expiratory time (Rpef).
Lastly, to investigate the ability of Omicron sub-variants to cause inflammation in animal lungs, the researchers performed histopathological scoring. The method evaluated bronchitis, hemorrhage, alveolar damage with epithelial apoptosis, macrophage infiltration, and hyperplasia of type II pneumocytes. They also examined inflammatory response upon infection with Omicron sub-variants in vivo.
The key study finding was that while BA.5 was less pathogenic than the ancestral Omicron strain B.1.1, yet, it had evolved to induce a stronger inflammatory response than other Omicron sub-variants, including BA.1 and BA.2. Despite similar in vitro growth kinetics as other Omicron sub-variants, BA.5 was more fusogenic than BA.1 and BA.2. Inside VeroE6/TMPRSS2 and Calu-3 cell lines, BA.2 and BA.5 showed replication comparable to B.1.1, but BA.1 showed a lower replication rate. Conversely, in the iPS cell-derived alveolar epithelium cells, B.1.1, BA.1, and BA.5 exhibited high replication efficiency than BA.2.
B.1.1 formed larger syncytia than Omicron subvariants, and concomitantly exhibited the highest S cleavage efficiency. However, among all the Omicron sub-variants, BA.5 exhibited the most efficient S cleavage, indicating its evolution towards efficient fusogenicity in VeroE6/TMPRSS2 cells. The airway-on-a-chip method allowed researchers to evaluate SARS-CoV-2’s ability to disrupt the respiratory endothelial and epithelial barriers. Among all Omicron sub-variants, BA.5 possessed the highest barrier disruption capacity.
In a hamster model, the dynamics of weight changes of BA.5-infected animals were significantly different from that of the BA.2-infected and uninfected hamsters. Moreover, in BA.1-, BA.2- and BA.5-infected hamsters, the Penh value was significantly lower, and the Rpef value was substantially higher than those in B.1.1-infected hamsters. Although lower than B.1.1, among Omicrn sub-variants, BA.5 caused the most severe inflammation. Additionally, BA.5 infection caused upregulation of four interferon-stimulated genes (ISGs) viz., CXC-chemokine ligand 10 (CXCL10), interleukin-6 (IL-6), ISG15, and MX Dynamin Like GTPase 1 (MX-1).
The current study comprehensively investigated the in vitro and in vivo characteristics of three clinical isolates of Omicron sub-variants BA.1, BA.2, and BA.5 and highlighted the significance of continuous coronavirus disease 2019 (COVID-19) mitigation measures. Kawaoka et al. showed that the clinical isolate BA.5 exhibited lower pathogenicity than the ancestral Delta in hamster models. Also, they showed that the weight loss dynamics during BA.5 infection were slightly higher than during BA.2 infection.
Consistent with the previous findings, the current study results also showed that though the virulence of the Omicron sub-variants was less than that of the ancestral lineage B.1.1, BA.5 is acquiring enhanced pathogenicity by evolving to improve inflammatory response. Additionally, BA.5 is acquiring higher fusogenicity and more robust barrier disruption capacity than other Omicron sub-variants.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Tamura, T. et al. (2022) "Comparative pathogenicity of SARS-CoV-2 Omicron subvariants including BA.1, BA.2, and BA.5". bioRxiv. doi: 10.1101/2022.08.05.502758. https://www.biorxiv.org/content/10.1101/2022.08.05.502758v1
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