A recent study posted to the bioRxiv* preprint server observed that the replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron variant was restricted in human lung tissues.
Clinical and epidemiological observations indicated that the recently emerged SARS-CoV-2 Omicron variant leads to milder coronavirus disease 2019 (COVID-19) than previous variants of concern (VOCs). This might be partly attributed to pre-existing immunity besides the intrinsic viral factors. Studies observed inefficient Omicron replication in alveolar organoids and lung tissues of humans infected ex vivo. It has been suggested that SARS-CoV-2 Omicron uses a different cell entry route and might not spread as fast and efficiently by cell fusion, a key mechanism for viral transmission. Despite the preliminary reports, a comprehensive understanding of the reduced pathogenicity of the Omicron variant is required.
The study and findings
The present study investigated the local-mucosal susceptibility of native human nasal and lung tissues to ex vivo SARS-CoV-2 Omicron infection.
Viable nasal and lung tissues were established as organ cultures and infected with SARS-CoV-2 Delta and Omicron variants in parallel. The subgenomic (sg) ribonucleic acid (RNA) of virus and infectious progeny were quantitated. The researchers observed similar viral kinetics in nasal tissues for the two variants; however, Omicron replication in the lungs was restricted while the Delta variant exhibited productive replication. The restricted replication was most evident during the later phase of infection, and confocal microscopic examination revealed the near-absence of Omicron-infected cells in the lung tissues. The kinetics of Delta variant replication in the lung tissues was comparable to previous D614G, Alpha, and Beta variants.
The virus-induced innate immune responses were compared by examining the expression profiles of interferons (IFNs) and antiviral IFN-stimulated genes (ISGs) in lung tissues infected with the two variants in parallel. ISGs included MX dynamin-like GTPase 1 (MX1), IFN-α inducible protein 6 (IFI6), ISG15 ubiquitin-like modifier (ISG15), and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1). These ISGs were selected based on the prior observations of antiviral activities inhibiting viral replication. The authors employed quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assays and observed robust innate immune responses in the lung tissues upon Omicron infection, with a substantial expression of IFN-λ and ISGs.
Upregulation of IFN-α and IFN-β was not observed. The strong IFN responses to the Omicron variant in lung tissues contrasted with the low ISG responses to the Delta variant. The restricted lung tissue responses (observed against the Delta variant) were similarly noted against other variants, while the same tissues elicited a robust response to the influenza virus. Moreover, Omicron infection also enhanced IFN responses in infected nasal tissues to some extent compared to Delta infection. Hence, innate immune responses were remarkable and enhanced in the lung tissues against the Omicron variant, while others exhibited largely restricted responses.
The authors compared ISG induction in lung tissues exposed to infectious or ultraviolet radiation (UV)-inactivated Omicron and Delta virions. ISGs were significantly induced in lung tissues exposed to the UV-inactivated Omicron virions despite the lack of de novo gene expression. This was not evident with inactivated Delta virions. These observations indicated that immune responses were enhanced against the Omicron variant, partly triggered by its structural components after host cell attachment or entry before the viral gene expression.
The study findings demonstrated the restricted replicative competence of the SARS-CoV-2 Omicron variant in the lung tissues compared to other variants, including the Delta VOC. Omicron replication remained relatively unaltered in the nasal tissues. The research team posits that the susceptibility of nasal tissues to Omicron could lead to human-to-human transmission, and the restricted replication might contribute to the milder COVID-19 outcome.
Significantly elevated antiviral IFN responses against Omicron were more apparent in the lung tissues than other tested variants, which exhibited blunted responses. Previously, innate immunity has been regarded as crucial to controlling SARS-CoV-2 infection, and as such, these enhanced responses could limit Omicron’s pathogenicity. The observation that the initial viral entry triggered IFN responses implied a causative association between enhanced early antiviral responses and restricted transmission of Omicron in lung tissues.
The restricted spread could be attributed to the endocytic pathway of cell entry used by the SARS-CoV-2 Omicron variant, activating the endosomal toll-like receptors (TLRs). Notably, since the study was based on native organ cultures that are short-lived, the later stages of viral transmission could not be evaluated. Taken together, Omicron infection enhanced IFN responses in lung tissues more than any other tested variant, implying that the early ISG induction might be involved in restricting replication and pathology of Omicron in the lung tissues.
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.