Unraveling the Innate Immune Evasion Strategies of SARS-CoV-2: Insights from ORF6 and its Variant Polymorphisms


The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a global health crisis despite the development of vaccines and antiviral treatments.

This article delves into the intricate interplay between the virus and the host’s immune response, focusing on the innate immune antagonist, ORF6, and its role in SARS-CoV-2’s evasion strategies. It also explores the impact of variant polymorphisms on the virus’s ability to subvert the host’s defenses.

The Complexity of COVID-19 Clinical Presentations

The clinical manifestations of COVID-19 vary widely, from asymptomatic cases to severe and sometimes fatal disease. These diverse outcomes can be attributed to multiple factors, with an emphasis on the host’s ability to mount an effective antiviral interferon (IFN) response.

An inadequate or delayed IFN response can contribute to viral persistence and tissue damage, intensifying the severity of COVID-19.

Innate Immune Evasion Mechanisms of SARS-CoV-2

Research has identified inborn errors of immunity affecting Toll-like receptor 3 (TLR3) and the IFN pathway, as well as the presence of autoantibodies against type I IFN in some severe COVID-19 patients. Furthermore, various viral proteins have been implicated in inhibiting or suppressing the host’s innate immune responses, underscoring the importance of type I IFN in combating SARS-CoV-2 infection.

Among these proteins, non-structural protein NSP1, accessory protein ORF9B, and ORF6 play pivotal roles in evading the host’s defenses.

The Crucial Role of ORF6 in Innate Immune Suppression

In this study, we focus on the role of ORF6 in suppressing the host’s innate immune response. ORF6 has been found to interact with the Nup98-Rae1 complex at the nuclear pore, influencing nucleocytoplasmic trafficking through two distinct mechanisms:

  • Inhibition of Nuclear Import: ORF6 selectively inhibits karyopherin-mediated nuclear import pathways. This leads to the blockade of STAT1 and STAT2 nuclear translocation, hampering the expression of interferon-stimulated genes (ISGs).
  • Modulation of Host mRNA Export: ORF6 also interferes with the export of host cell mRNA, contributing to the shutoff in protein synthesis during infection. This phenomenon is facilitated by the interaction of ORF6 with the Nup98-Rae1 complex and competition with mRNA export processes.

The Impact of ORF6 Mutations on Viral Pathogenesis

To understand the consequences of ORF6 in viral pathogenesis, experiments were conducted in Syrian Golden hamsters and K18 human ACE2 mice.

In both cases, ORF6-deficient viruses led to less body weight loss, reduced lung injury, and decreased AT2 cell hyperplasia. This correlated with increased STAT2 translocation and ISG expression in the lungs. Interestingly, the ORF6M58R mutant virus, which lacks the ability to disrupt Nup98-Rae1 nuclear transport functions, also appeared to be less pathogenic.

However, it is noteworthy that this did not result in significantly lower levels of viral replication in the respiratory tract, indicating that the impact of ORF6 on viral replication may be subtle.

Variants and Their Impact on Innate Immune Evasion

As SARS-CoV-2 has evolved, new variants with major genomic changes have emerged. These variants of concern (VOCs) often display resistance to neutralizing antibodies and increased transmissibility and virulence. Importantly, VOCs have evolved non-S mutations that enhance the expression of innate immune antagonists like ORF9B and ORF6, ultimately strengthening the virus’s ability to suppress the host’s innate immune response.

The Omicron Variant and ORF6D61L Mutation

The study highlighted the ORF6D61L mutation shared by the Omicron variants BA.2, BA.4, and the XBB sublineages, which affects the virus’s ability to inhibit nuclear import and block host mRNA export. Variants with this mutation have demonstrated superior fitness and dominance in human transmission.

A New Role of ORF6 in Modulating Viral Protein Expression

Surprisingly, the research also uncovered a previously unobserved role of ORF6 in modulating viral protein expression. ORF6-deficient SARS-CoV-2 viruses favored the expression of structural and accessory viral genes, which was not significantly impacted by the ORF6M58R mutation. This suggests that ORF6 may directly or indirectly regulate viral gene expression, potentially influencing the virus’s replication and pathogenicity.


In summary, this study sheds light on the multifaceted strategies employed by SARS-CoV-2 to evade the host’s innate immune response, with a particular focus on the innate immune antagonist, ORF6, and its variant polymorphisms. Understanding these mechanisms is crucial for developing effective therapeutic strategies and vaccines to combat COVID-19, as well as for monitoring the evolution and transmission of SARS-CoV-2 variants.



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