For all the mysteries that remain about the novel coronavirus and the COVID-19 disease it causes, scientists have generated an incredible amount of fine-grained knowledge in a surprisingly short time.
In the graphics that follow, Scientific American presents detailed explanations, current as of mid-June, into how SARS-CoV-2 sneaks inside human cells, makes copies of itself and bursts out to infiltrate many more cells, widening infection. We show how the immune system would normally attempt to neutralize virus particles and how CoV-2 can block that effort. We explain some of the virus's surprising abilities, such as its capacity to proofread new virus copies as they are being made to prevent mutations that could destroy them. And we show how drugs and vaccines might still be able to overcome the intruders. As virologists learn more, we will update these graphics on our Web site (www.scientificamerican.com).
For a static version of this content as it appears in the July 2020 issue of Scientific American, please click here.
Gene Machine
A SARS-CoV-2 virus particle wafting into a person's nose or mouth is about 100 nanometers in diameter--visible only with an electron microscope. It is a near sphere of protein (cross section shown) inside a fatty membrane that protects a twisting strand of RNA--a molecule that holds the virus's genetic code. Proteins called "S" form spikes that extend from the surface and grab onto a human cell, hundreds of times larger, so the particle, or virion, can slip inside; the crown, or corona, appearance gives the virus its name. Structural proteins--N, M and E--move inside the cell, where they help new virions form.
1. The virus: The SARS-CoV-2 virus particle is a ball of proteins wrapped in a protective fatty coating.
2. RNA (red): This twisting strand of RNA is the blueprint the virus uses to replicate itself inside of you.
3. Entry spikes (Orange): The virus uses its spike-shaped S proteins, which stud the surface, to grab onto human cells.
4. Protective shell: This lipid bilayer protects the virus's genetic cargo as it travels inside the body.
5. N Protein (Blue): This protein helps keep the viral RNA stable.
6. E Protein (Yellow): This protein helps new virus particles form.
7. M Protein (Purple): This protein helps new virus particles form.
How the Virus Invades
A SARS-CoV-2 particle enters a person's nose or mouth and floats in the airway until it brushes against a lung cell that has an ACE2 receptor on the surface. The virus binds to that cell, slips inside and uses the cell's machinery to help make copies of itself. They break out, leaving the cell for dead, and penetrate other cells.
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First, It Binds to a Lung CellWhen a virus spike protein latches onto an ACE2 receptor, a protease enzyme slices off the spike's head. (ACE2 normally helps regulate blood pressure.)
Next, It Slips InsideThis releases fusion machinery, part of the spike's stem that is compressed in a springlike state. The virus and lung-cell membranes fuse. Spike decapitation allows the fusion machinery to unfold.
The machinery inserts itself into the cell membrane and a channel forms, allowing N proteins and RNA (genetic instructions) to enter the lung cell.TIME ELAPSED: ABOUT 10 MINUTES
It ReplicatesOnce virus RNA is inside a cell, it presents about two dozen genes to the cell's ribosomes, which translate genes into proteins. Some of those proteins stretch the endoplasmic reticulum, creating protective vesicles, or sacs.
The virus uses its own RNA copying machine, called a polymerase, to make duplicates of RNA inside the vesicles. Some of the copies are utilized to make more viral proteins, such as the spike. Others are packaged into new virus particles, which break out of the lung cell.
N proteins link to RNA to help keep it stable.
Additional vesicles (that come from the endoplasmic reticulum and Golgi complex) assemble spike, M and E proteins.
Finally, It Breaks OutVesicles carrying newly formed viruses merge with the cell membrane, opening a channel that allows the viruses to exit.
One cell can release hundreds of virus copies. It typically dies because its resources have been used up, or it is killed by the immune system. Some viruses head off to infect more cells. Others are exhaled into the air.TIME ELAPSED: ABOUT 10 HOURS
How the Immune System Responds
Infected cells send out alarms to the immune system to try to neutralize or destroy the pathogens, but the viruses can prevent or intercept the signals, buying time to replicate widely before a person shows symptoms. When infection begins, the innate immune system tries to immediately protect lung cells. The adaptive immune system gears up for a greater response.
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The Innate Immune System Acts First: An infected cell releases interferon proteins that alert neighboring cells to create molecules that try to stop virus particles (red dots) from entering or reproducing. Interferon also beckons cells such as macrophages in the bloodstream that can engulf virus particles.TIME ELAPSED: 0–3 DAYS
The Adaptive Immune System Follows: Interferon also alerts B cells. They produce “neutralizing antibodies” that might recognize parts of the spike protein and bind to it, preventing the spike from grabbing onto a lung cell.
Interferon also recruits T cells, which can destroy viruses and also kill infected cells before viruses inside them burst out. Some B and T cells become memory cells that can quickly identify and fight a future invasion by the virus.TIME ELAPSED: 6–11 DAYS
The Virus Takes CountermeasuresSARS-CoV-2 uses several tactics to thwart the immune system’s response.
Tactic 1: The virus spike may camouflage itself with sugar molecules. They flex and swing, potentially blocking antibodies from attaching to the virus, neutralizing it.
Normally, sensor proteins recognize incoming viruses as foreign and tell the cell nucleus to turn on genes for making messenger RNA molecules. The molecules deliver instructions to ribosomes to make interferon proteins that exit the cell to alert immune system cells.
Tactic 2: Several SARS-CoV-2 proteins are thought to block sensor proteins from acting or to interfere with instructions to the ribosome.
Drug and Vaccine Interventions
Commercial and university labs are investigating well over 100 drugs to fight COVID-19, the disease the SARS-CoV-2 virus causes. Most drugs would not destroy the virus directly but would interfere with it enough to allow the body's immune system to clear the infection. Antiviral drugs generally stop a virus from attaching to a lung cell, prevent a virus from reproducing if it does invade a cell, or dampen an overreaction by the immune system, which can cause severe symptoms in infected people. Vaccines prepare the immune system to quickly and effectively fight a future infection.
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Drug Target 1Prevent the Virus from Entering the Cell: A drug or therapeutic antibodies could lock on to the spike protein, preventing it from binding to a lung cell’s ACE2 receptor. A drug could also attach to the protease enzyme and prevent it from cutting the spike protein so the virus cannot fuse with the cell.
Drug Target 2Encourage Defective Viruses: A drug could interfere with the viral RNA polymerase enzyme, which works with another enzyme called ExoN (not shown) to fix mistakes in copied viruses that would disable those viruses,leading to more bad copies and fewer good ones.
Drug Target 3Shut Down Virus: A drug could interfere with lung cell proteins the virus needs, such as those involved in making virus proteins or in making the vesicles the virus uses to copy its genome.
Drug Target 4Reduce Hyperimmune Response: Immune cells can destroy too many lung cells, creating enough mucuslike waste to suffocate the lungs, forcing victims onto ventilators. Overproduction of an alarm protein, or cytokine, such as interleukin-6 can put immune cells into overdrive. Drugs could inhibit some of the cytokines by binding to them.
Vaccine OptionsA vaccine exposes the immune system to a safe version of a virus so it can practice making antibodies that will stop the pathogen and commit the exercise to memory so it is ready to fight the real virus during an infection. Vaccine makers are pursuing a variety of strategies for formulating and mass-producing vaccines.
How Vaccines WorkAntibody Preparation: The vaccine version of a SARS-CoV-2 virus presents various molecules called antigens that belong to the real virus. Antigen-presenting cells grab them and provide them to helper T cells and B cells.
The T cells help B cells turn on to produce antibodies that could bind to the actual virus.
The helper T cells also tell killer T cells to devise ways to destroy lung cells that are infected.
Some of the B and helper T cells turn into memory cells that store the instructions so they can quickly spark B and T cells into action during an infection.
SARS-CoV-2 Vaccine Development StrategiesExperts are exploring at least six strategies for making vaccine versions of the virus. Three of them involve injecting a modified version of the virus into people....
Three involve mapping genes from the virus, such as those for the spike protein, inserting the blueprints into DNA, RNA or a safe virus and injecting those into people.
The Remarkable and Mysterious Coronavirus Genome
The SARS-CoV-2 genome is a strand of RNA that is about 29,900 bases long--near the limit for RNA viruses. Influenza has about 13,500 bases, and the rhinoviruses that cause common colds have about 8,000. (A base is a pair of compounds that are the building blocks of RNA and DNA.) Because the genome is so large, many mutations could occur during replication that would cripple the virus, but SARS-CoV-2 can proofread and correct copies. This quality control is common in human cells and in DNA viruses but highly unusual in RNA viruses. The long genome also has accessory genes, not fully understood, some of which may help it fend off our immune system.
ProofreadingBecause the SARS-CoV-2 genome is so long, it can encode a huge amount of information, enabling the novel coronavirus to create more proteins and perhaps carry out more sophisticated replication strategies than other RNA viruses. One of these advantageous proteins is an enzyme called exonuclease (ExoN), which helps the virus proofread and correct copies as they are made. Only viruses with genomes longer than about 20,000 bases make this enzyme.
Once a SARS-CoV-2 virus has infected a lung cell, an enzyme called polymerase starts to make copies of its RNA while another enzyme, ExoN, finds random mutations and expels these genetic mistakes from the copies.
Accessory GenesUnusual, short bits of the genome called accessory genes are clustered with the structural protein genes. Researchers are not yet sure what they do. Several are thought to encode proteins that help the virus evade the immune system.
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