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• SARS-CoV-2


  Exploits various cellular mechanisms and machinery to facilitate its entry and replication within host cells
• Spike protein


  • Plays a crucial role in hijacking host cell processes, enabling the virus to gain access and commandeer the cellular resources for its propagation
• Receptor Recognition and Binding

  1. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell surface

  2. The interaction is mediated by specific amino acid residues within the RBD and ACE2 interface, with key residues in the RBD (e.g., Gln493, Asn501, Gly502, and Tyr505) forming contacts with residues in the ACE2 receptor

  3. The binding affinity of the SARS-CoV-2 spike protein for ACE2 is higher than that of the SARS-CoV spike protein, contributing to the increased transmissibility of SARS-CoV-2
• Proteolytic Priming by Host Proteases

  1. After binding to ACE2, the SARS-CoV-2 spike protein undergoes proteolytic cleavage by host proteases, such as transmembrane protease serine 2 (TMPRSS2) or cathepsin L

  2. TMPRSS2 is a serine protease expressed on the surface of human airway epithelial cells and cleaves the spike protein at the S1/S2 and S2' sites

  3. Cathepsin L is an endosomal cysteine protease that can cleave the spike protein within endosomes after viral entry

  4. Proteolytic cleavage triggers conformational changes in the spike protein, exposing the fusion peptide within the S2 subunit, which is critical for viral membrane fusion
• Positive-sense single-stranded RNA ((+)ssRNA) viruses

  Include picornaviruses and coronaviruses, have evolved sophisticated mechanisms to exploit host cell machinery for their replication while evading cellular antiviral defenses
• Membrane Fusion and Viral Entry

  1. The exposed fusion peptide of the cleaved spike protein inserts into the host cell membrane, anchoring the viral envelope to the host membrane

  2. The heptad repeat regions (HR1 and HR2) of the S2 subunit undergo conformational rearrangements, forming a six-helix bundle that brings the viral and host cell membranes into close proximity

  3. This process facilitates the formation of a fusion pore, through which the viral genome is delivered into the host cell cytoplasm

  4. The fusion process is facilitated by the high-density clustering of spike proteins on the viral surface, which enhances the efficiency of membrane fusion
• Strategies employed by these viruses

  Hijack cellular resources and subvert host immune responses, particularly the interferon-mediated antiviral pathways
• Picornaviruses


  • Small, non-enveloped viruses that replicate their RNA genome in the cytoplasm of host cells
• Exploitation of Host Cell Machinery for Viral Replication

  1. Once inside the host cell, SARS-CoV-2 hijacks the cellular translational machinery to synthesize viral proteins from its positive-sense RNA genome

  2. The viral replicase complex, consisting of non-structural proteins (NSPs), is assembled and hijacks host cell membranes to create double-membrane vesicles (DMVs) that serve as sites for viral RNA replication

  3. SARS-CoV-2 exploits host cell enzymes and cofactors for its replication, such as RNA-dependent RNA polymerase (RdRp), helicase, and other accessory proteins

  4. The virus also manipulates host cell signaling pathways and processes, such as the innate immune response, autophagy, and apoptosis, to create a favorable environment for viral replication and spread
• Viral Entry and Uncoating

  1. Picornaviruses attach to specific cellular receptors, triggering receptor-mediated endocytosis and the subsequent release of their RNA genome into the cytoplasm

  2. Viral proteins interact with host cell factors involved in endocytic trafficking and membrane remodeling, facilitating viral entry and uncoating
• Viral Egress and Release

  1. Newly assembled viral particles acquire their envelope by budding into the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) or other host cell membrane compartments

  2. The viral envelope acquires the spike protein during the budding process, enabling the virus to infect new host cells

  3. The viral particles are then released from the host cell through exocytosis or cell lysis, allowing them to spread and infect neighboring cells or be transmitted to new hosts
• Translation of Viral Proteins

  1. The positive-sense RNA genome of picornaviruses serves as mRNA, which is directly translated by the host cell's ribosomes

  2. Picornaviruses hijack the host translation machinery, utilizing cellular factors like initiation factors and tRNA for their protein synthesis

  3. Some picornaviruses, such as poliovirus, cleave host translation initiation factors (e.g., eIF4G) to shut down host protein synthesis and preferentially translate viral proteins
• Throughout the viral entry and replication process, SARS-CoV-2 exploits various host cell components and mechanisms to its advantage
• Replication of Viral RNA

  1. Picornaviruses remodel host cell membranes, such as those derived from the endoplasmic reticulum (ER), to create replication complexes

  2. These replication complexes provide a scaffold for viral RNA replication and protect the viral RNA from host cell nucleases and antiviral defense mechanisms

  3. Viral proteins recruit and interact with host cell factors, such as lipids and enzymes, to facilitate viral RNA synthesis
• The spike protein plays a crucial role in initiating the infection by interacting with host cell receptors and facilitating membrane fusion
• Once inside the host cell, the virus subverts cellular machinery, such as the translational apparatus, membrane compartments, and signaling pathways, to create an environment conducive for viral replication and propagation
• This abuse of host cell machinery highlights the intricate interplay between SARS-CoV-2 and its host cells, contributing to the virus's ability to cause infection and spread
• Viral Release and Spread

  1. Picornaviruses induce host cell lysis and apoptosis, leading to the release of progeny virions

  2. Viral proteases cleave host cell proteins involved in cytoskeleton organization and membrane trafficking, facilitating viral release and cell-to-cell spread
• Host Defense Mechanisms against Picornaviruses

  • Interferon Response: Picornaviruses are recognized by cellular pattern recognition receptors (PRRs), such as RIG-I and MDA5, which detect viral RNA and initiate the interferon response
  • RNA Interference (RNAi): The cellular RNAi machinery can recognize and degrade viral RNA, limiting viral replication
  • Stress Response Pathways: Picornaviruses activate cellular stress response pathways, including the unfolded protein response (UPR) and the integrated stress response (ISR), leading to the inhibition of viral protein synthesis and the induction of apoptosis
• Coronaviruses


  • Enveloped viruses with a positive-sense RNA genome that replicate in the cytoplasm of host cells
• Viral Entry and Membrane Fusion

  1. Coronaviruses bind to specific cellular receptors, such as ACE2 for SARS-CoV-2, through their spike (S) protein

  2. Viral entry is facilitated by host cell proteases, such as TMPRSS2, which cleave the S protein and enable membrane fusion between the viral envelope and host cell membrane
• Translation of Viral Proteins

  1. The coronavirus RNA genome is translated by the host cell's ribosomes, producing viral proteins essential for replication and assembly

  2. Coronaviruses encode specialized sequences, like the 5' cap structure and the 3' poly(A) tail, to hijack the host translation machinery
• Replication of Viral RNA

  1. Coronaviruses induce the formation of double-membrane vesicles (DMVs) derived from the endoplasmic reticulum (ER) and other cellular membranes

  2. These DMVs serve as replication complexes, protecting the viral RNA from host nucleases and concentrating viral replication proteins and host factors necessary for viral RNA synthesis

  3. Viral proteins interact with and recruit host enzymes, such as RNA-dependent RNA polymerases (RdRps) and helicases, to facilitate viral RNA replication
• Viral Assembly and Release

  1. Newly synthesized viral RNA and structural proteins assemble into virions within the ER-Golgi intermediate compartment (ERGIC) or other cellular compartments

  2. Virions are released from the host cell through exocytosis or cell lysis, facilitated by interactions between viral proteins and host membrane trafficking machinery
• Host Defense Mechanisms against Coronaviruses

  • Interferon Response: Coronaviruses are recognized by cellular PRRs, such as RIG-I and MDA5, triggering the production of interferons and the induction of ISGs
  • Stress Response Pathways: Coronavirus infection activates cellular stress response pathways, including the UPR and the ISR, leading to the inhibition of viral protein synthesis and the induction of apoptosis
  • Innate Immune Responses: Coronaviruses are recognized by other components of the innate immune system, such as Toll-like receptors (TLRs) and inflammasomes, triggering pro-inflammatory responses and the release of cytokines
  • Adaptive Immune Responses: Coronaviruses elicit adaptive immune responses, including the production of neutralizing antibodies and the activation of cytotoxic T cells
• Both picornaviruses and coronaviruses have evolved various mechanisms to evade and counteract host antiviral defenses, allowing them to replicate efficiently and establish infection
• These mechanisms include the suppression of interferon signaling, the inhibition of antiviral effectors like PKR and RNase L, and the modulation of host immune responses
• Understanding the intricate interplay between these viruses and their host cells at the cellular and molecular levels is crucial for developing effective antiviral strategies and therapeutic interventions
• Budding


  A process where the virus acquires its envelope from the host cell by pinching off from the cell membrane.
• ER-Golgi Intermediate Compartment (ERGIC)


  An intermediate compartment in the host cell where the Golgi apparatus processes and modifies proteins and lipids.
• Receptor-binding domain (RBD)


  A specific part of the SARS-CoV-2 spike protein that binds to the ACE2 receptor on human cells