The Virus Behind COVID-19
Coronavirus disease 2019 (COVID-19) is a disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). These have become household terms since the start of the global COVID-19 pandemic, but the microscopic size of the virus means that most people are unfamiliar with what the infection process actually looks like, even though many have experienced it themselves. This set of images and animations uses the incredible power of electron microscopy to unmask SARS-CoV-2.
Written by Kasey Christopher; Duquesne University; Pennsylvania, USA
Background image by National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health (NIH)
What is SARS-CoV-2?
SARS-CoV-2 is a member of a family called coronaviruses, so named for the crown or “corona” of spike-shaped proteins that decorate their surfaces. These spikes serve a critical purpose in the life cycle of the virus, allowing it to attach to and enter host cells. Like all viruses, coronaviruses lack much of the cellular machinery needed to build the molecules of life and therefore must enter host cells and borrow their machinery to replicate and spread. In this image, a host cell (green) has been infected with SARS-CoV-2 (purple) isolated from a human patient; the virus has replicated extensively and is now being released from the cell, which is undergoing apoptosis (programmed cell death) due to the stress of infection.
Image by National Institute of Allergy and Infectious Diseases, NIH
What does the SARS-CoV-2 virus look like?
The SARS-CoV-2 virus particle has three key structural components, two of which can be seen in this image: the genome, which is composed of RNA packaged with proteins called nucleocapsids (not visible here); the envelope (yellow), which encloses the genome and is composed of membrane lipids and proteins; and the spike proteins (green), which decorate the surface of the envelope. These spike proteins bind specifically to receptors on the surface of human host cells to allow the attachment and entry of the viral genome. Even if the sight of these components is unfamiliar, you may have experienced direct interactions with them before. COVID-19 detection tests look for the presence of nucleocapsid or spike proteins, and most SARS-CoV-2 vaccines stimulate the immune system to recognize the spike protein.
Image by National Institute of Allergy and Infectious Diseases, NIH
How does SARS-CoV-2 enter a host cell?
A single host cell, such as the lung epithelial cell shown here in yellow, can be infected by numerous individual virus particles, shown in purple. ACE2 is a receptor found on the surface of human cells; this protein normally plays a role in regulating blood pressure. However, in the case of a SARS-CoV-2 infection, interactions between ACE2 and the spike protein result in the virus being imported into the host cell.
Image by National Institute of Allergy and Infectious Diseases, NIH
The virus entering a cell
The flexible movement of the spike proteins (shown in green in this animation) brings the host and viral membranes (shown in gray) together, allowing them to fuse so that the viral genome (the orange strand of RNA wrapped around the gray nucleocapsid proteins) ends up inside the cytoplasm of the host cell.
Video by Animation Lab; University of Utah; Utah, USA
The virus co-opting the host cell’s machinery to replicate
Once the viral genome is inside the host cell, the host’s own ribosomes (shown in green in this animation) move along the viral RNA (shown in orange), translating a variety of viral proteins (purple). As the ribosomes move, they displace the nucleocapsid proteins (gray) associated with the RNA.
Video by Animation Lab, University of Utah
The host cell’s secretion system exporting assembled viruses
The newly translated viral RNA polymerases make additional copies of the RNA genome, which are then packaged with freshly made nucleocapsid proteins. As shown in this animation, this organized viral RNA-protein complex (in orange and gray) enters the transition zone between the endoplasmic reticulum and the Golgi apparatus, an organelle involved in protein transport, where it is enclosed in a membrane that will ultimately serve as its envelope or viral membrane.
Video by Animation Lab, University of Utah
How is the host cell secretion system used to export assembled viruses?
This image shows what the new viral particles look like when completely assembled. Inside this host cell, viral genomes have already been packaged into envelopes by the host cell’s Golgi apparatus. The fully assembled viral particles, shown here in pink within vesicles inside the teal cytoplasm of the host, must next be secreted outside the cell.
In an uninfected human cell, the endomembrane system functions to build and release molecules through an assembly line of membrane compartments, until a vesicle or endosome ultimately fuses with the plasma membrane to release the contents outside the cell. You have already seen how the new viruses are packaged by the Golgi apparatus, an organelle involved in protein transport, within the endomembrane system. From there, the viruses move through vesicles to the plasma membrane for release into the extracellular environment, just like the cell’s normal secretion pathway.
Image by National Institute of Allergy and Infectious Diseases, NIH
How does the virus exit the cell?
Thus SARS-CoV-2 co-opts the host cell’s own pathways to distribute many copies of the virus. Each endosome of this olfactory epithelial cell (pink) contains numerous viral particles (green and blue). These cell types line the nasal passages in humans. In an infected individual, such cells would release viruses into the airway or bloodstream, where they can spread within the body as well as to other human hosts.
Image by National Institute of Allergy and Infectious Diseases, NIH
The virus being released from the host cell
In order to be released into the extracellular environment, the viruses are passed through multiple membrane compartments, as shown in this video. When the membrane of the final compartment fuses with the plasma membrane, the viral particles within are released from the cell.
Video by Animation Lab, University of Utah
How does the virus exit the cell?
In this image, an endosome has already fused with the plasma membrane (green) to release viruses (pink). If this extracellular environment were the human airway, the virus particles could then be expelled through a cough or sneeze, resulting in droplet transmission through the air. The next time you don a mask, you might imagine it capturing this dramatic cloud of viral particles being released from your cells.
Image by National Institute of Allergy and Infectious Diseases, NIH
How are host cells impacted by infection?
This high-magnification view of a single infected T cell shows many virus particles (yellow) budding from the surface of the cell (blue). Each virus begins to emerge as a domed shape that becomes more spherical (yellow) as its membrane separates from that of the host cell. The structural integrity of the host cell is also compromised, as evidenced by blebs forming from the membrane, which can indicate the start of apoptosis (programmed cell death).
Image by National Institute of Allergy and Infectious Diseases, NIH
How else can host cells be impacted?
An infected cell (green) may also extend tentacle-like protrusions called filopodia. These filopodia attach to neighboring cells and promote further transmission of the virus (pink) by increasing cell-cell contact, continuing to spread the virus within the host.
Image by National Institute of Allergy and Infectious Diseases, NIH
What is the effect of a COVID-19 infection on lung tissue?
Given the extensive changes in infected cells, it is not surprising that SARS-CoV-2 can have dramatic effects on human tissues. For example, examination of COVID-19 patients has shown damage to the alveoli of their lungs, including deposits in their airways of fibrin clots that could impact their ability to breathe (Erickson et al. Nature Communications 2023). Fibrin, derived from a circulating blood clotting factor called fibrinogen, typically clumps at injury sites throughout the body. In this image, you can compare the presence of fibrin clots (red) in infected human lung tissue on the left and in uninfected human lung tissue on the right.
While a small amount of fibrin accumulation is consistent with the repair of normal wear and tear in the lungs, the extensive clotting found after infection with SARS-CoV-2 can negatively impact the lungs’ flexibility and elasticity and therefore ultimately their function. The outcome of cellular processes like this and others have been felt by COVID-19 patients throughout the world, particularly those with so-called long COVID, who continue to experience symptoms long after the viral infection has been cleared.
Image by National Institute of Allergy and Infectious Diseases, NIH
Conclusion
Nearly everyone on earth has experienced some personal impact from the global COVID-19 pandemic. As shown in this series of images and animations, the SARS-CoV-2 virus interacts extensively with its host to replicate and cause cellular damage. Each time the virus is transmitted, it represents a new opportunity for random mutations to arise. While most mutations are neutral or decrease viral survival or replication, a subset of these mutations can provide beneficial functions that will be selected for in future generations. This provides potential for the virus to evolve better host binding, more efficient replication, or higher viral loads, such as the heavy infection with virus particles (teal and purple) seen in this T cell (pink). Continued work by scientists in this arena aims to understand how cells respond to SARS-CoV-2 infection, how the virus is evolving, and how it can be targeted through medications and vaccines.
Image by National Institute of Allergy and Infectious Diseases, NIH
For suggestions on how to incorporate this journey into your teaching, see our “Implementation Suggestions.”