How SARS-CoV-2 dodges immune surveillance and facilitates infection: an analytical review

ABSTRACT

Introduction

Effective treatments for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are limited. The virus has evolved strategies to evade the immune system or hijack immune responses to facilitate infection and escape immune surveillance. Mechanistically, SARS-CoV-2 takes advantage of TLR4 and cytokine-induced integrins to promote its entrance into the cell. Furthermore, the activation of pattern recognition receptors (PRR)-mediated signaling pathways is compromised by SARS-CoV-2 non-structural proteins (NSPs), accessory protein open reading frames (ORFs), and structural proteins upon infection, contributing to viral infection and replication. Host factors necessary for cellular protein synthesis, metabolism, and viral replication can also be inhibited by the SARS-CoV-2 proteins. Exploring specific mechanisms would optimize the therapy methods and benefit drug research and development.

Areas covered

We describe pathways and mechanisms by which SARS-CoV-2 evades immune system; these include the mechanisms that operate during virus entry, signaling pathways involved, and processes at RNA and protein levels.

Expert opinion

Increased understanding of how viruses interfere with immune responses would provide more evidence for drug development. Drugs targeting conserved viral proteins to inhibit their replication or host factors to enhance immune responses would minimize the impact of virus mutations and prepare for future coronavirus outbreaks.

KEYWORDS:

• SARS-CoV-2
• immune response
• regulatory mechanisms
• immune evasion

Article highlights

• The escape of SARS-CoV-2 from the immune system significantly affects vaccine efficacy and therapeutic effect.

• Upon infection, SARS-CoV-2 hijacks TLR4 and cytokine-induced integrins to promote its cell entrance.

• Most factors involved in PRR-mediated signaling pathways, such as RIG-I and MDA5, can be bind directly or indirectly to SARS-CoV-2 proteins, revealing potent interference to innate immunity of the host.

• The immune evasion of SARS-CoV-2 is sophisticatedly regulated; mechanisms include altered protein–protein interaction, phosphorylation, ubiquitination, and ISGylation, which lead to regulated protein stability, localization, and activity.

• At the RNA level, SARS-CoV-2 utilizes NSP1, NSP14, and NSP16 to achieve viral RNA processing, maturation, and subsequent translation, while inhibiting host protein synthesis including anti-viral proteins.

• Exploration and targeting of viral factors essential for both replication and immune evasion via siRNAs or antisense RNAs would contribute to prophylactic therapy and inhibit viral replication from the initiation stages of viral invasion.

Acknowledgments

The authors gratefully acknowledge the financial supports provided by the Emergency Key Program of Guangzhou Laboratory. Figures 2-4 are created with BioRender.com.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by the Emergency Key Program of Guangzhou Laboratory (No. EKPG21-30-1).