How can we predict what a SARS-CoV-2 particle looks like?
Viruses are extremely small. Most of the cells in our body are about a tenth of a millimetre across in size, bacterial cells are ten times smaller than our cells and viruses are typically ten times smaller again. The majority of viruses are smaller than the wavelength of light, which means that they cannot be seen using traditional light microscopy. One method we can use to learn more about the overall virus structure and its building blocks is electron microscopy, which allows us to see objects smaller than the wavelength of light by sending a beam of electrons through a thin slice of film or material. As the electron beam passes through the virus particle, the denser areas absorb the electrons, while other areas allow the electrons to pass through and be detected by a photographic plate.
The images of SARS-CoV-2 shown below were constructed using data from studies that used several different methods including: structural biology of isolated virus proteins, computer predictions of protein structures, and low-resolution images of individual virus particles collected by electron microscopy. Currently, the evidence used to predict the structure of SARS-CoV-2 draws heavily on historical studies of related coronaviruses, particularly SARS-CoV-1 (the cause of SARS during the 2003 outbreak) and mouse hepatitis virus.
What does the SARS-CoV-2 virus particle look like?
Viruses are often described as obligate parasites because they need the existing processes and machinery present within living cells to produce new virus particles. The primary activity of a coronavirus particle is to safely deliver its genetic information (RNA) to the appropriate host cell and initiate a new infection. SARS-CoV-2 is an enveloped virus, which means that the RNA is packaged within an outer fatty or lipid membrane. While enveloped viruses do not always have a defined structure, coronaviruses are mostly spherical, although more irregular bean-like shapes have also been seen. The fatty membrane of SARS-CoV-2 contains virus proteins, and acts like a bag that holds and protects the RNA. The membrane needs to be sufficiently stable to protect the RNA from the surrounding environment, but not so stable that it cannot break open inside the host cell to release the RNA. This balance between structural stability and the ability to release RNA is essential for transmission and replication of the virus, but also renders the membrane susceptible to being destroyed by soap or detergent.
The virus genome provides the necessary genetic information required to produce the four structural proteins; the Spike (S), Envelope (E) and Membrane (M) proteins that form the outer layer of the virus particle and the Nucleocapsid (N) protein that tightly packs around and protects the RNA (Figure). The virus genome also contains information to produce additional proteins that are not incorporated into the virus particle but play key roles in viral infection. For example, ‘non-structural protein-1’ slows down the production of the cell’s own proteins in favour of the production of new virus proteins.
What’s in a coronavirus particle?
The large S protein within the SARS-CoV-2 lipid membrane is essential for the virus to attach to and enter uninfected cells. The overall structure of the S protein was described during the COVID-19 outbreak by researchers using the technique known as cryo-electron microscopy. The individual S proteins are arranged in groups of three on the outer membrane, giving the virus a distinctive crown or ‘corona’-like appearance that is typical of coronaviruses.
The M protein is also embedded in the outer lipid membrane and is the most abundant of all the structural proteins, giving the virus particle its shape and integrity. M is also thought to play a role in the final stages of infection, when new virus proteins are assembled into particles before they are released and move on to infect new cells.
The E protein is found in relatively low numbers in the virus particle and is thought to have several functions that contribute to virus growth and its ability to cause disease. These functions are not completely understood but include: the ability to form small pores that alter the properties of host cell membranes, preventing the M protein from clumping together and the transport and assembly of virus particles within the host cell.
The coronavirus RNA molecule is one of the largest amongst all RNA viruses at 30,000 ‘letters’ long, which is about twice the size of the influenza A genome, but still 100,000 times smaller than the human genome (over 3 billion ‘letters’ long). To effectively package the viral RNA, N protein binds RNA, with multiple copies of the N protein linking together to form a spiral that tightly wraps and coils the RNA. This allows the long RNA molecule to fit into the small virus particle and forms a protein coat around the RNA that protects it from damage. The N protein also has an important function in the early stages of infection when the RNA molecule is first released into the host cell, acting to reduce the cell’s natural defences against the virus.
In addition to the viral genome and four structural proteins, it is likely that the SARS-CoV-2 particle contains host cell proteins picked up by the virus as it escapes an infected cell, but what might be included has not yet been established.