The Role of Molecular Chaperones in Virus Infection and Implications for Understanding and Treating COVID-19

Abstract

The COVID-19 pandemic made imperative the search for means to end it, which requires a knowledge of the mechanisms underpinning the multiplication and spread of its cause, the coronavirus SARS-CoV-2. Many viruses use members of the hosts' chaperoning system to infect the target cells, replicate, and spread, and here we present illustrative examples. Unfortunately, the role of chaperones in the SARS-CoV-2 cycle is still poorly understood. In this review, we examine the interactions of various coronaviruses during their infectious cycle with chaperones in search of information useful for future research on SARS-CoV-2. We also call attention to the possible role of molecular mimicry in the development of autoimmunity and its widespread pathogenic impact in COVID-19 patients. Viral proteins share highly antigenic epitopes with human chaperones, eliciting anti-viral antibodies that crossreact with the chaperones. Both, the critical functions of chaperones in the infectious cycle of viruses and the possible role of these molecules in COVID-19 autoimmune phenomena, make clear that molecular chaperones are promising candidates for the development of antiviral strategies. These could consist of inhibiting-blocking those chaperones that are necessary for the infectious viral cycle, or those that act as autoantigens in the autoimmune reactions causing generalized destructive effects on human tissues.

Keywords: COVID-19; Coronaviridae; SARS-CoV-2; chaperonopathies; chaperonotherapy; molecular chaperones; virus.

Figure 1

CoVs and molecular chaperones. (A) GRP78 or 74-kDa heat shock cognate protein 70 (Hsc70) can be part of the receptor complex recognized by the CoVs and can modulate virus entry [82,83,84]. (B) Molecular chaperones, such as GRP78 and GRP94, participate in the folding of CoV proteins, counteracting the effect of the stress of the host cell caused by viral infection. Accumulation of unfolded proteins induces the transcription of GRP78 and GRP94. In the endoplasmic reticulum (ER) lumen, the release of GRP78 and GRP94 from PERK are protective, inducing the unfolded protein response and controlling proteins folding. Under these conditions, ER homeostasis is restored [85]. (C) Non-structural proteins, such as 3C-like serine protease (3CLpro), induce apoptosis thought caspase’s pathways, causing a significant increase in reactive oxygen species (ROS) [86]. Other abbreviations: RBD, receptor-binding domain (of the S protein); PLpro, papain-like cysteine protease; RdRp, RNA-dependent RNA polymerase; PERK, PKR-like endoplasmic reticulum kinase; ERGIC, Endoplasmic reticulum-Golgi intermediate compartment.

Figure 2

Molecular mimicry mechanisms. Molecular mimicry of host proteins by viral proteins means that there are cross-reacting antigenic epitopes shared between SARS-Cov-2 and host proteins (e.g., molecular chaperones), which induce humoral and cellular immunological reactivity against the host. The SARS-Cov-2 antigens involved probably occur in peptides of Replicase 1ab, Nucleocapsid Phosphoprotein, and Spike glycoprotein, and they induce B and/or T cells. The former cells produce antibodies reacting against the virus and also against the host crossreactive antigens. Similarly, the induced T cells react with host tissues. In both instances, autoimmunity occurs, damaging host’s tissues and organs. Abbreviation: APC, antigen-presenting cell.