This book gives an overview of viruses with focus on SARS-CoV-2's structure and genes. It shows how the virus has evolved and describes vaccine technologies being used to create a Covid-19 vaccine.

Viruses: A Close-Up of SARS-CoV-2

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Viruses are not living cells as they lack most of the "characteristics of life". Although viruses have genetic material –DNA or RNA– they cannot reproduce or synthesize proteins on their own and they cannot maintain homeostasis, metabolize energy or respond to stimuli. Instead, viruses infect cells, take over the cell's molecular machinery, and steal the molecular building blocks they need to build proteins and replicate. Viruses are invisible to the naked eye, but can be seen with an electron microscope (figure 1).

Figure 1: Covid-19 virus (pink) exploding from an infected cell (green). Virus particles are about 500X smaller than a human skin cell (scanning electron microscope image, Image credit (and book cover):NIAID-RML/de Wit/Fischer.

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Figure 3: A SARS CoV-2 virus particle showing structures and functions, including the membrane envelope and (+) single-stranded helical RNA covered by N-protein.

The SARS-CoV-2 virus causes a flu-like disease called Covid-19. Its genetic material is single-stranded RNA (+sense), has ~14 genes and codes for ~29 potential proteins. It has a lipid membrane envelope, which anchors several membrane proteins like the spike protein (shown in blue in figure 3). As a comparison, the human genome has 3 billion base pairs and ~28,000 genes.

In Figure 8: SARS-CoV-2 evolution and transmission routes around the globe from 12-2019 to April 2020. Click the blue link (left) and then click the green "play" button to see current Covid-19 trends.

Covid-19 Phylogenetic Tree and Map

Figure 4: Diagram of the SARS-CoV2 genome stretched out from beginning (5') to the end (3'). The location of its 14 genes is shown. Some genes are color coded and correspond with proteins in figure 3. A mutation in gene number 8 (*) allowed the virus to jump from infecting bats to infecting humans.

The SARS-CoV-2 virus genome is about 30,000 bases long (figure 4). Scientists have sequenced the virus's genome and deciphered its genetic code. The largest gene codes for a protein called RNA replicase, which is an enzyme that is needed to make new copies of the virus RNA genome.

Click the UC Santa Cruz genetic database link (right), then click the box marked "base" to see the RNA code (A-U-G-C) of the virus. Bioinformatic tools embedded in the website determined the amino acid sequence of the virus proteins.

UCSC Genetic Database 

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Deborah Landry, Ph.D. is founder and executive director of IXplore STEM, a nonprofit formed to build science, technology, engineering and math (STEM) literacy and proficiency and to encourage K-12 students to pursue STEM degrees and careers. Dr. Landry has over 25 years of experience as a science educator and curriculum developer for K-16 classrooms. She received her Ph.D. in Molecular and Cellular Biology from Brandeis University, focusing on genes in the immune system; and is an adjunct professor at the University of New England. In her spare time, Deborah enjoys exploring the woods and waters of Maine.

The SARS-CoV-2 virus is mutating over time. Nextstrain.org tracks many types of viral outbreaks globally. It compiles viral genetic information and uses bioinformatics to create a phylogenetic tree, allowing us to see how the virus genome is changing (figure 7 and 8). A branching point in the tree represents a mutation; length of the branches relates to time; and branches are colored by country: USA and Mexico, red; parts of Europe, green; parts of Asia, dark purple.

Figure 7: SARS-CoV-2 Phylogenetic Tree from December 2019 to April 2020 <a href="https://nextstrain.org/ncov/global">https://nextstrain.org/ncov/global</a>

A vaccine is a medical treatment designed to resemble (all or part of) a foreign disease-causing microbe. A vaccine stimulates the body's&nbsp;immune system&nbsp;to recognize and destroy the foreign agent without causing disease. Later, if the body encounters the "real" microbe, the immune system rapidly destroys it before the host gets sick. More than 270 Covid-19 vaccines are in development (as of April 28, 2022; see <a href="https://covid-19tracker.milkeninstitute.org/">Vaccine &amp; Treatment Tracker</a> for updates). Around the globe, there are 24 vaccines in use. Two mRNA vaccines are USDA approved in the US (figure 9) made by Moderna and Pfizer and one recombinant virus vaccine, made by Johnson &amp; Johnson, is approved in the US for emergency use. The six main strategies used to create a Covid-19 vaccine are:

Killed virus vaccine. Weakened or attenuated virus vaccine (a non-disease causing virus). Recombinant protein vaccine is a genetically engineered spike protein. Recombinant virus vaccine is a non-replicating virus carrying the spike gene. Recombinant plasmid vaccine is circular DNA carrying the spike gene. Lipid nanoparticle vaccine consists of spike mRNA in lipid droplets.

Figure 6: Diagram showing the life cycle of the SARS-CoV-2 virus.

By Deborah Landry, Ph.D.

What is in the Covid-19 mRNA Vaccine?

The Covid-19 mRNA vaccine is a solution of very small lipid droplets filled with spike mRNA. The vaccine is injected into arm muscle and the droplets are taken up by macrophages, dendritic cells, antigen presenting cells and muscle cells, which use the mRNA code to build the spike protein. This foreign protein will activate the immune system, which creates memory B and T cells that remain in the body and protect you from infection in the future.

Figure 9. Covid-19 Vaccine Strategies. Six vaccine strategies are shown. Some strategies (gold boxes) had not been used in humans prior to 2020.

Figure 2: Viral structures for HIV (human immunodeficiency virus), bacteriophage (a bacterial virus), influenza virus (causes the flu), and SARS-CoV-2 (causes Covid-19).

Although there are more than a million different types of viruses, they all have several structures in common (figure 2). All viral particles have genetic material—double-stranded or single stranded DNA or RNA— and a "nucleocapsid" protein cover to protect the genetic material. Most, but not all animal viruses, have a lipid membrane envelope covering as well.

References Callaway, E. The coronavirus is mutating—does it matter? Nature 585, 174-177 (2020) <a href="https://doi.org/10.1038/d41586-020-02544-6">https://doi.org/10.1038/d41586-020-02544-6</a> Centers for Disease Control and Prevention: U.S. Covid-19 Vaccine Product Information. Visited 1-18-21. <a href="https://www.cdc.gov/vaccines/covid-19/info-by-product/index.html">https://www.cdc.gov/vaccines/covid-19/info-by-product/index.html</a> Connors, M et al. SARS-CoV-2 vaccines: Much accomplished, much to learn. Annals of Internal Medicine 2021.<a href="https://www.acpjournals.org/doi/10.7326/M21-0111">https://www.acpjournals.org/doi/10.7326/M21-0111</a> Milken Institute: Covid-19 Vaccine and Treatment Tracker. Visited 1-12-21. <a href="https://covid-19tracker.milkeninstitute.org/">https://covid-19tracker.milkeninstitute.org</a> NextStrain.org: Genomic epidemiology of novel coronavirus - Global subsampling, 01-18-21. <a href="https://nextstrain.org/ncov/global">https://nextstrain.org/ncov/global</a> Trougakos, I.P., Stamatelopoulos, K., Terpos, E. et al. Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications. J Biomed Sci 28, 9 (2021).<a href="https://doi.org/10.1186/s12929-020-00703-5">https://doi.org/10.1186/s12929-020-00703-5</a> UCSC Genome Browser: SARS-CoV-2 Sequence, Jan. 2020/NC_045512.2 Assembly (wuhCor1). Visited 01-18-21. <a href="https://rb.gy/jsowwd">https://rb.gy/jsowwd</a> Zhou, P., Yang, XL., Wang, XG. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). <a href="https://doi.org/10.1038/s41586-020-2012-7">https://doi.org/10.1038/s41586-020-2012-7</a> (Some graphics were built using <a href="https://biorender.com/">BioRender.com</a> online software)

Watch killer T-CELLS kill virally infected cells and cancer cells!

Cells in Our Immune System Kill Infected Cells

Cambridge University https://youtu.be/ntk8XsxVDi0

How does SARS-CoV-2 infect cells? 1. The viral particle enters the lungs when a person (host) inhales air droplets containing the virus (this is the most common route of entry) (figure 6). 2. The virus enters the cell when the virus's spike protein binds to the ACE-2 receptor on the surface of a host cell. This process is called endocytosis. 3. In the cytoplasm, the virus "un-coats" and releases its viral RNA. 4. The viral RNA highjacks the cell's translation machinery by binding to a cellular ribosome then translating the viral protein (using host cell amino acids). 5. When the RNA replicase protein is translated by the cell, it can build new copies of the viral RNA genome by stealing the host cell's RNA subunits. 6. Once all the parts (proteins and RNA) of the virus are created, the virus self-assembles into a new viral particle. 7. The host cell releases new viral particles by exocytosis or by cell lysis.

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