Intrinsic Factors Behind Long COVID: VI. Combined Impact of G3BPs and SARS-CoV-2 Nucleocapsid Protein on the Viral Persistence and Long COVID

Abstract

The efficient transmission of SARS-CoV-2 caused the COVID-19 pandemic, which affected millions of people around the globe. Despite extensive efforts, specific therapeutic interventions and preventive measures against COVID-19 and its consequences, such as long COVID, have not yet been identified due to the lack of a comprehensive knowledge of the SARS-CoV-2 biology. Therefore, a deeper understanding of the sophisticated strategies employed by SARS-CoV-2 to bypass the host antiviral defense systems is needed. One of these strategies is the inhibition of the Ras GTPase-activating protein-binding protein (GAP SH3-binding protein or G3BP)-dependent host immune response by the SARS-CoV-2 nucleocapsid (N) protein. This inhibition disrupts the formation of stress granules (SGs), which are crucial for antiviral defense. By preventing SG formation, the virus enhances its replication and evades the host's immune response, leading to increased disease severity. Given the involvement of G3BP1 in SG formation and its ability to interact with viral proteins, along with the crucial role of the N protein in the replication of the virus, we hypothesize that these proteins may have a potential role in the pathogenesis of long COVID. Despite the current lack of direct evidence linking these proteins to long COVID, their interactions and functions suggest a possible connection that warrants further investigation.