Biology of Coronavirus

Image of Coronavirus structure by David Goodsell

Image credit: David Goodsell

Disclaimer: This page is part of my Bio 6B course at De Anza College. My goal is to use some coronavirus examples to illustrate some of the fundamental molecular and cell biology concepts I would normally cover in the course. I do not intend to cover the illness or epidemiology, just the molecular biology. I'm not a medical doctor, and I don't know anything at all about medicine or public health, so please don't use any information you see here to make any health-related decisions!

Related reading on this site: Bats and coronavirus.

The COVID-19 pandemic is sweeping through the human population in early 2020, causing illness and death and disrupting the lives of almost everyone in the world. From the limited perspective of Bio 6B, this is having two major effects. First, I'm teaching the class completely online, for the first (and probably only) time. Second, there has been a vast outpouring of articles related to the biology of the virus. The relevance of cellular and molecular biology has never been more clear. I hope to take advantage of this as we move through the core topics of 6B.

Coronavirus replication overview

Covid Replication

Image credit: Features, Evaluation and Treatment Coronavirus (COVID-19), Cascella et al., 2020. (CC BY 4.0)

Viruses can't replicate themselves; they need to get inside cells and use cellular structures and energy systems to replicate the virus. The replication cycle of coronaviruses involves many structures within the host cell. Even viral features that are unique are connected to processes that normally occur in cells. Over the next few weeks, we'll look at some of these cellular processes in more detail. For now, here's an overview of the coronavirus replicative cycle.

Coronaviruses are enveloped RNA viruses

Compare the replicative cycle of a coronavirus to the generalized diagram of RNA viruses in Chapter 19 (Viruses) of Campbell. (The chapter also shows that viruses come in diverse forms; I recommend taking a look.) Viruses are categorized in terms of two main features:

  • Viral genome: Every virus has a genome. The genome can be either DNA or RNA. Some viruses with RNA genomes are classified as retroviruses, because they make a DNA copy of their RNA genome after entering the cell. Coronaviruses are RNA viruses, but not retroviruses; there's no DNA in the CoV cycle. In the diagram above, the CoV genome is labeled ssRNA, which means single stranded; some viruses have RNA or DNA genomes that are double-stranded.
  • Membrane envelope: Some viruses (including CoV) are surrounded by a membrane, composed of a phospholipid bilayer with proteins in it. Other viruses lack the envelope. All viruses package their genome in a capsid made of proteins; in enveloped viruses, the genome with its capsid coat is inside the envelope.

Thus, coronaviruses along with many other kinds of animal viruses, are considered enveloped RNA viruses.

Viruses bind to conserved receptor proteins

Viruses infect their hosts by binding to specific receptor proteins on the surface of the host cells. The term "receptor" in this case is applied to whatever protein the virus binds to. The receptor protein is typically found on the surface of the cell, and it's there because it does some essential job. In the case of the current coronavirus pandemic, the spike protein on the surface of the virus latches onto a human protein called ACE-2, which is shared by all mammals. You may have already encountered this protein in Bio 6A. 

ACE-2 is Angiotensin Converting Enzyme 2

Does that sound familiar? When you learned about kidney regulation in Bio 6A, did you learn about the renin-angiotensin-aldosterone system (RAAS)? You'll find the details in Campbell, Chapter 44, Osmoregulation and excretion. Here's a summary how that system works:

  • Low blood pressure signals for the production of angiotensin I.
  • The enzyme ACE (Angiotensin Converting Enzyme) cuts  a polypeptide called angiotensin I, converting it to the hormone angiotensin II, which has the effect of increasing blood pressure by causing vasoconstriction.
  • The enzyme ACE-2 (Angiotensin Converting Enzyme 2) cuts angiotensin II, converting it to angiotensin (1-7), which has the effect of reducing blood by vasodilation.

Thus, ACE and ACE-2 have opposite effects, and the balance between them helps to control blood pressure. On the diagram in Campbell, you'll see ACE but not ACE-2. Please don't memorize all these names of enzymes and substrates. From the point of view of coronavirus, is one simple point to make about ACE-2: it does an important job.

ACE-2 is strongly conserved

Proteins that do essential jobs often change very little over evolutionary time; they can't change very much without interfering with their essential function. The amino acid sequence and tertiary structure (shape) of the ACE-2 protein are very similar for most mammals, including humans and bats, because the essential job of this protein hasn't changed much over tens of millions of years. Proteins like this are said to be strongly conserved. Because ACE-2 is strongly conserved, the bat version closely resembles the human version, making it easier for the virus to jump from one species to another by binding to those proteins.

ACE-2 is widely expressed

ACE-2 protein is produced (expressed) in various cells of the body, including the epithelial cells on the surface of cells in alveoli of the lungs. Since SARS-CoV-19 infects cells by binding to ACE-2, the virus can only infect cells carrying that protein, and since the lung cells are most likely to meet with a virus from the air, those cells are the usual site of infection. Once the virus infects the cell of the alveoli, it may spread to other cells that express ACE-2, including those lining blood cells.

If ACE-2 functions as part of a system for controlling blood pressure, why is it so widely expressed in cells outside the blood vessels? I don't think the answer to this is fully understood, but it's likely that ACE-2, like many proteins, has more than one job.

Viral entry

Once CoV binds to the surface of a cell, the virus must be brought into the cell to continue its replicative cycle. This viral entry process involves multiple interactions between viral and host cell proteins. As far as I can tell, the details have not been worked out completely, but it may involve a process called endocytosis, in which a piece of the cell's outer membrane (the plasma membrane) wraps around the virus and brings it into the cell.

Endocytosis is a normal process by which eukaryotic cells bring things into the cell; some viruses can take over the process to gain entry into the cell.

Viral genes are expressed inside the host cells

"Gene expression" means making a gene product; in this case, that means making proteins. Viruses accomplish this by taking over the host cell's machinery for the two fundamental steps of gene expression: transcription and translation.

Transcription

Transcription is the process of synthesizing RNA. In eukaryotic cells, transcription normally means making an RNA copy of a section of DNA, and it happens in the nucleus. The genome of coronaviruses is RNA, though; there is no DNA involved. For these viruses, transcription means making an RNA copy of RNA. Copying RNA to RNA doesn't normally occur in cells, so it requires a special viral protein, called replicase, or RNA-dependent RNA polymerase.

There are two kinds of RNAs produced by transcription in coronaviruses:

  • Genomic RNA (gRNA): full-length copies of the viral genome, ready to be packaged into new viruses.
  • Subgenomic RNA (sgRNA): copies of the particular segments of RNA that encode proteins. The subgenomic RNA of CoV corresponds to the messenger RNA (mRNA) produced by cells.

Translation

Translation means reading RNA information to produce a polypeptide. This process is carried out by ribosomes. Viruses don't have their own ribosomes, so they take over the cell's ribosomes to do the job. We'll investigate the process of translation later this quarter.

In translation, ribosomes must recognize open reading frames (ORFs), which are regions of RNA that could potentially encode proteins. This is true for both viral genes and the cell's genes. You'll investigate ORFs in sequence analysis exercise later this quarter.

Cytosolic proteins & membrane proteins

The viral proteins shown in the diagram can be divided into two categories: cytosolic and membrane-associated.

  • Cytosolic proteins: The nucleocapsid proteins, which bind to the CoV genome RNA, are free in the cytoplasm of the cell. Such free proteins are called cytosolic proteins. Many proteins, whether viral or cellular, are cytosolic proteins.  Cytosolic proteins are produced by free ribosomes — in other words, ribosomes that are not bound to the cell's internal membranes.
  • Membrane & secreted proteins: In the diagram, note the text, "Translation of viral structural proteins. S, M, and E proteins at ER membrane." These proteins will become part of the viral membrane. Membrane proteins (whether viral proteins or cellular proteins) are produced by bound ribosomes, meaning that these ribosomes are bound to the cell's endoplasmic reticulum (ER). The endoplasmic reticulum is a set of internal membranes found on all eukaryotic cells; it is part of the cell's endomembrane system. All eukaryotic cells need to produce membrane proteins, so bound ribosomes are always present. These ribosomes also produce proteins that will be secreted (transported out of the cell).

The distinction between cytosolic proteins, produced by free ribosomes, and membrane proteins, produced by bound ribosomes, is always important in cells, not just for viruses. Later we'll look at how proteins in each category are targeted to the appropriate destination.

Polyprotein

Translation produces polypeptides. In many cases, a single peptide then gets folded to become a functional protein. For CoV, one of the translation products is a polyprotein: a large polypeptide that must be cleaved (cut) into separate, smaller polypeptides that then get folded into separate proteins with different functions. So one gene codes for one polypeptide, which gets turned into several proteins. (This step isn't shown in the diagram above).

Virions are released from the cell

Once the genomic RNA and proteins are produced, they can be packaged into virions (individual viruses that can be released from the cell). The nucleocapsid proteins recognize the viral RNA and package it. The assembly of the viral envelope requires multiple steps involving the endoplasmic reticulum (ER) and the Golgi apparatus. The Golgi apparatus, which is another part of the cell's endomembrane system, modifies the membrane proteins produced by the bound ribosomes on the ER and eventually prepares a small piece of membrane, containing viral proteins, to become the viral envelope. When the Golgi is finished, it wraps the virion in a small membrane compartment called a vesicle. The vesicle is then transported to the cell surface, where it fuses with the cell's outer plasma membrane to release its contents in a process called exocytosis. This set of steps (membrane proteins produced by bound ribosomes on the ER, then modified by the Golgi, carried by a vesicle, then released by exocytosis) is a normal part of cell activities, but in this case it's taken over for virus production.

Naming

The current pandemic disease is called COVID-19. The virus that's causing it is named SARS-CoV-2. This name, designated by  International Committee on Taxonomy of Viruses, highlights the close similarity of this virus to the one that caused the SARS epidemic that peaked in 2002-2003 (that virus is called SARS-CoV-1). Because the names (and the viruses) are so similar, the World Health Organization (WHO) has decided to refer to SARS-CoV-2 as "the COVID-19 virus" to avoid confusion. On this website, I am sometimes going to call it coronavirus or CoV, because much of the basic biology is the same for various coronaviruses.

Review

This page describes some of the steps in the replicative cycle of CoV, and on of my goals is that you'll understand a littel bit about how the virus works. I also have another goal in preparing this page: to introduce you to a number of structures and processes that play fundamental roles in all eukaryotic cells. I hope the specific information on this page will give you some context for the broader picture presented in Campbell Chapter 6: A Tour of the Cell, as well as for later chapters on gene expression.

Soon, I'll give you a coronavirus quiz on Canvas, similar to the earlier quiz on Bats and viruses.

Vocabulary & concepts

  • ACE-2
  • Capsid (nucleocapsid)
  • Conserved genes and proteins
  • Cytosolic vs. membrane proteins
  • Enveloped virus (membrane envelope)
  • Endocytosis
  • Endoplasmic reticulum
  • Endomembrane system
  • Exocytosis
  • Golgi apparatus
  • Open reading frame
  • Plasma membrane
  • Polyprotein
  • Ribosome (bound or free)
  • RNA virus
  • Spike protein
  • Transcription
  • Translation
  • Vesicle
  • Virion

Review questions

  1. Compare and contrast RNA viruses, retroviruses, and DNA viruses.
  2. What does the viral enzyme replicase do that wouldn't normally be happening in eukaryotic cells?
  3. What is the CoV genome made of? Is this true for all viruses? (See the Viruses chapter in Campbell for more information.)
  4. What human protein does SARS-CoV-2 attach to on the surface of human cells, and what does this human protein normally do? Which viral protein attaches to the human protein?
  5. Which coronavirus proteins are produced by bound ribosomes?

Looking ahead: more CoV questions

Throughout the quarter, I hope to address somebasic questions about coronavirus, including:

  • How is CoV connected to bats? I hope you have read this one already: Bats and coronavirus.
  • What are the genes in the CoV genome?
  • How do CoV tests work?
  • How can a vaccine be developed?
  • What kinds of therapies are being investigated? What aspects of the virus life cycle are targeted by these therapies?

My goal is to use these as examples for more general concepts. As you can see, I'm not attempting to address any questions about the illness caused by the virus or about epidemiology; my approach will be confined to the cellular and molecular biology topics that would normally be part of this course. As I hope you'll see, the specific questions about coronavirus are going to be connected to more basic topics such as:

  • Protein structure
  • Eukaryotic cell structure
  • Gene expression
  • Cellular respiration
  • Cell cycle control

My point isn't that Bio 6B is now all about coronavirus; it's that coronavirus is connected to many aspects of Bio 6B.

Naming

The current pandemic disease is called COVID-19. The virus that's causing it is named SARS-CoV-2. This name, designated by  International Committee on Taxonomy of Viruses, highlights the close similarity of this virus to the one that caused the SARS epidemic that peaked in 2002-2003 (that virus is called SARS-CoV-1). Because the names (and the viruses) are so similar, the World Health Organization (WHO) has decided to refer to SARS-CoV-2 as "the COVID-19 virus" to avoid confusion. On this website, I am sometimes going to call it coronavirus or CoV, because much of the basic biology is the same for various coronaviruses.

References & further reading

Coronavirus scientific news

Nature Coronavirus Collection. The latest from a scientific publisher.

Coronavirus news from MIT Technology Review. Good scientific background from a trusted source.

Science Magazine from the American Association for the Advancement of Science; has a page for Covid-19 research and news.

Videos

COVID-19, SARS-CoV-2 and the Pandemic. An open online course for undergraduates from MIT Biology. The course site includes 14 excellent, detailed lecture videos from experts in the field. I strongly recommend this course if you want to go deep on COVID-19, but it's too detailed to be a useful study aid for Bio 6B.

COVID-19 | Coronavirus: Epidemiology, Pathophysiology, Diagnostics. Ninja Nerd Science. This 50-minute video gives a detailed look at the virus and the illness. It's worth watching for 6B students, even though the medical point of view isn't what you'll be tested on in this class.

Virus life cycles

Viruses. Chapter 19 in Campbell Biology. The textbook chapter gives an excellent overview of viruses in general.

How Coronavirus Hijacks Your Cells. Corum & Zimmer, 2020. New York Times. Simple infographic of the life cycle.

A Visual Guide to the SARS-CoV-2 Coronavirus. Scientific American, July 2020. Excellent graphics showing how the virus works.

Human Coronavirus: Host-Pathogen Interaction. To Sing Fung and Ding Xiang Liu, 2019. If you want to go deep into viral biology, start here. Though apparently written just before SARS-CoV-2 was characterized, this article gives an excellent explanation of how coronaviruses work. As a bio student, I think you'd be able to read this, but you'd probably have to look up a lot of terms.

How does SARS-CoV-2 cause COVID-19? Matheson & Lehner, 2020, Science Magazine. Gives a good cell-level description of how the virus causes disease.

Features, Evaluation and Treatment Coronavirus (COVID-19), Cascella et al., 2020. This article is more about medicine than molecular biology, but it contains the life cycle diagram I used above.

Epidemiology

Coronavirus Resource Center from Johns Hopkins. The best site for accurate, up-to-date information about the outbreak. Also see the dashboard for a global overview.

The pandemic was predicted

You may hear people (politicians, for example) say that the current pandemic couldn't have been predicted, but experts in the field have been predicting it for years. "New" viruses don't come out of nowhere; they evolve from existing viruses.

A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence Menachery et al.,  Nature Medicine 2015. Quote: "Our work [in Chinese horseshoe bats] suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations."

Are RNA Viruses Candidate Agents for the Next Global Pandemic? A Review. Carrasco-Hernandez et al., 2017. ILAR Journal. In case you were wondering, the answer to the question posed in the title of this article turned out to be yes.

ACE-2

This isn't part of Bio 6B, but since the RAAS pathway controls blood pressure, it's a potential target for drugs that treat high blood pressure (hypertension). ACE inhibitors are often used to control hypertension, and drugs that increase the activity of ACE-2 are also under investigation.

Angiotensin-Converting Enzyme 2: The First Decade. Clarke, 2012. Way more than you want to know, but this review might address any questions you might have.

Mutation rates

RNA viruses can evolve rapidly because their polymerases are error-prone, frequently producing mutations when copying RNA. High mutation rates are part of the reason why these viruses can evolve so rapidly.

Why are RNA virus mutation rates so damn high? Duffy 2018, PLOS Biology."Mutation rates are evolvable and can respond to selection." In other words, mutation isn't exactly an uncontrolled accident.

Research preprints

MedRxiv.org. Most of the important research articles will appear here first. Beware: these are preprints, meaning that they are articles that haven't completed peer review or been published yet. Some of them will turn out to be wrong, and all are written for an expert scientific audience. This isn't the place to start learning, but if you understand the basics and want to challenge yourself with cutting-edge research, this is a useful site.

 

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