The lifecycle of SARS-CoV-2. Scientific version

Summary

The script delves into the intricate process of SARS-CoV-2 infection, highlighting how the virus targets ciliated cells in the airways. It details the virus's structure, with its spike protein playing a crucial role in binding to the ACE-2 receptor on host cells. The narrative unfolds the viral entry, hijacking of the host's translation machinery, and replication within double membrane vesicles. It concludes with the assembly of new viral particles and their release, leading to cell death and further infection, encapsulating the lifecycle of SARS-CoV-2.

Takeaways

• 🔬 The air we breathe in our airways interacts with various healthy respiratory cells, including ciliated cells that move mucus.
• 🦠 SARS-CoV-2 targets ciliated cells in the airways, using its spike protein to initiate infection.
• 🧬 The virus is composed of a simple structure with an outer membrane, spike, envelope, and membrane proteins, and a nucleocapsid protein assembly holding its RNA.
• 🔗 The spike protein's glycosylation helps it evade the immune system, and mutations in this protein can increase the virus's infectiousness.
• 🔒 The virus binds to the ACE-2 receptor on host cells, with the spike protein undergoing a series of cleavages to facilitate entry.
• 🌐 Once inside the cell, the viral RNA is translated into a chain of non-structural proteins (nsps) that take over the host's translation machinery.
• ✂️ Nsp3 is crucial for cleaving the protein chain, allowing the virus to hijack the cell and begin producing viral components.
• 🔄 The viral RNA translation is regulated by a pseudoknot, which affects the production of different nsps and the overall replication process.
• 🌐 The endoplasmic reticulum (ER) is altered by nsps to form double membrane vesicles (DMVs), providing a safe environment for viral replication.
• 📦 New viral particles are assembled with the help of nucleocapsid proteins packaging the viral RNA and other structural proteins forming on the ER.
• 🚀 Viral particles are released from the host cell through budding and cell lysis, spreading to infect neighboring cells and continuing the cycle.

Q & A

What are the main targets of the SARS-CoV-2 coronavirus in our airways?

The main targets of the SARS-CoV-2 coronavirus in our airways are the ciliated cells, which have hairlike structures called cilia that move mucus along.

What are the three types of proteins found on the outer membrane of the SARS-CoV-2 virus?

The three types of proteins found on the outer membrane of the SARS-CoV-2 virus are spike, envelope, and membrane proteins.

How does the spike protein of the SARS-CoV-2 virus initiate infection?

The spike protein of the SARS-CoV-2 virus initiates infection by binding to a receptor on the host cell called ACE-2.

What is the function of the glycosylation of the spike protein?

The glycosylation of the spike protein provides a coat of sugars that helps to hide the virus from the body's immune system.

What is the role of the S1 and S2 domains of the spike protein during the viral entry process?

The S1 domain of the spike protein is the outer part that binds to the host cell, and after binding, it is cut off by furin. The S2 domain, once freed, anchors into the host cell membrane, facilitating the fusion of the viral and host cell membranes.

How does the SARS-CoV-2 virus take over the host cell's translation machinery?

The SARS-CoV-2 virus takes over the host cell's translation machinery by using non-structural proteins (nsps) that are produced after the viral RNA is translated. These nsps prevent the ribosome from reading the host cell's mRNA, focusing its efforts on viral RNA.

What is the purpose of the double membrane vesicle (DMV) created by the virus in the host cell?

The double membrane vesicle (DMV) created by the virus in the host cell provides a safe, enclosed environment for the viral genome to be copied and for the production of new viral components.

How are the subgenomic mRNA strands used in the production of new viral particles?

Subgenomic mRNA strands are processed by the host cell to create the proteins that go onto the new viral particle, including spike, membrane, envelope, and nucleocapsid proteins.

What is the role of the nucleocapsid protein in the packaging of the viral genome?

The nucleocapsid protein packages the viral genome RNA into what will become the contents of the new viral particles, sitting by the DMV pore ready to grab onto the viral genome RNA as it exits the DMV.

How does the new viral particle bud off from the host cell?

The new viral particle buds off from the host cell when the membrane compartment containing the viral particles fuses with the outer cell membrane, releasing the viral particles.

What happens to the host cell after it has produced a large number of viral particles?

After producing a large number of viral particles, the host cell dies, releasing a wave of new virus particles into the surrounding tissue, which are ready to spread and infect nearby cells.

Outlines

00:00

🦠 SARS-CoV-2 Infection Process

This paragraph explains how the SARS-CoV-2 virus infects human cells. It details the virus's structure, including its spike, envelope, and membrane proteins, as well as its single-stranded RNA. The spike protein's role in binding to the ACE-2 receptor on host cells is highlighted, along with the subsequent steps of viral entry facilitated by furin and TMPRSS2 enzymes. The paragraph also describes the hijacking of the host cell's machinery to produce viral proteins and the formation of double membrane vesicles (DMVs) for viral replication. The process of viral assembly and release from the host cell is also outlined.

05:01

🌡️ SARS-CoV-2 Viral Lifecycle and Host Cell Interaction

The second paragraph delves into the lifecycle of SARS-CoV-2 within a host cell. It describes the translation of viral RNA into proteins, the packaging of the viral genome by nucleocapsid proteins, and the maturation of new viral particles in the ERGIC. The paragraph explains how viral particles are assembled and eventually released from the cell, leading to cell death and the spread of the virus to infect neighboring cells. This cycle highlights the virus's strategy for propagation and the host's cellular response to infection.

Keywords

💡Respiratory cells

Respiratory cells are the biological cells that line the respiratory tract and are involved in the process of respiration. In the context of the video, these cells are crucial as they are the first point of contact for the SARS-CoV-2 virus when it enters the body through the airways. The script mentions that 'the air we breathe comes into contact with a mixture of different types of healthy respiratory cells,' highlighting their role in the initial stages of infection.

💡Cilia

Cilia are hairlike structures found on some cells, including certain respiratory cells, and they play a role in moving mucus along the respiratory tract. The video script explains that 'some respiratory cells have cilia, hairlike structures that move the mucus along,' which is a natural defense mechanism to clear the airways. However, these ciliated cells are also the main target for the SARS-CoV-2 virus, indicating their strategic importance in the virus's infection process.

💡SARS-CoV-2

SARS-CoV-2 is the virus responsible for COVID-19. The video script describes it as 'deceptively simple,' yet highly effective, due to its ability to infect human cells. It is the central focus of the video, as it details how the virus interacts with respiratory cells, enters the host, and replicates, leading to the infection of the host organism.

💡Spike protein

The spike protein is a key component of the SARS-CoV-2 virus, as it is responsible for binding to the host cell receptor, initiating the infection process. The script states that 'the spike protein is responsible for making contact with the host cell and starting the infection.' It is also mentioned that the spike protein is glycosylated, which means it has a sugar coating that can help it evade the host's immune system, and that mutations in this protein can influence the virus's infectivity.

💡ACE-2 receptor

The ACE-2 receptor is a protein found on the surface of certain cells, including those in the respiratory system, and it serves as the entry point for the SARS-CoV-2 virus. The video explains that 'its spike proteins open up, and bind to a receptor on the host cell called ACE-2,' which is a critical step in the virus's ability to infect cells.

💡TMPRSS2

TMPRSS2 is an enzyme that plays a role in the activation of the SARS-CoV-2 virus by cleaving the spike protein, allowing the virus to enter the host cell. The script describes this process: 'furin cuts off the outer part of the spike protein... This frees the inner core of the spike protein, called the S2 domain, which is cut by TMPRSS2.' This enzyme is essential for the virus's ability to infect cells and initiate the replication process.

💡Ribosome

A ribosome is a cellular structure that translates genetic code into proteins. In the context of the video, the ribosome 'meets the viral RNA, and starts to translate its genetic code,' which is a part of the virus's hijacking of the host cell's machinery to produce viral proteins. This is a key step in the virus's replication cycle, as it allows the virus to produce the components necessary for new viral particles.

💡Nsp3

Nsp3 is one of the non-structural proteins (nsps) produced by the translation of the viral RNA. The video script mentions that 'Nsp3 is the first one that can cleave its neighbours,' which means it can cut the long protein chain to release other nsps. This is significant because it allows the virus to take control of the cell's machinery and begin producing more viral components.

💡Pseudoknot

A pseudoknot is a structural feature of the viral RNA that affects the translation process. The script explains that 'there is a pseudoknot in the viral RNA' which 'prevents the remaining RNA, which codes for proteins involved in viral genome replication, from passing through the ribosome.' This feature influences the types and amounts of proteins produced by the host cell, favoring the production of certain nsps over others, which is crucial for the virus's replication strategy.

💡Double membrane vesicle (DMV)

A double membrane vesicle (DMV) is a structure formed within the host cell that provides a protected environment for viral replication. The video describes how 'the three nsps that are embedded into the endoplasmic reticulum membrane cause it to curve,' creating DMVs. These structures are important for the virus's ability to replicate its genome and produce new viral particles without interference from the host cell's normal functions.

💡Subgenomic mRNA

Subgenomic mRNA are shorter strands of RNA that are produced during the replication of the SARS-CoV-2 virus. The script states that 'a set of shorter RNA strands is also created,' which are 'called subgenomic mRNA, and will be processed by the host cell to create the proteins that go onto the new viral particle.' These strands are essential for the production of the structural proteins of the virus, such as the spike, envelope, and membrane proteins.

Highlights

Respiratory cells with cilia are the primary target for SARS-CoV-2.

SARS-CoV-2 is a simple virus with an outer membrane and a single strand of viral RNA.

The spike protein on the virus is glycosylated, which helps it evade the immune system.

Variants of SARS-CoV-2 are often characterized by mutations in the spike protein.

The spike protein binds to the ACE-2 receptor on host cells to initiate infection.

Furin and TMPRSS2 enzymes play crucial roles in the activation of the spike protein.

The virus hijacks the host cell's ribosome to translate its genetic code into proteins.

Nsp3 is the first non-structural protein to cleave and release other proteins, taking over the cell's machinery.

A pseudoknot in the viral RNA prevents the ribosome from translating certain proteins.

Three nsps embedded in the endoplasmic reticulum membrane cause it to form double membrane vesicles (DMVs).

DMVs provide a safe environment for viral genome replication.

Subgenomic mRNA is processed by the host cell to create proteins for new viral particles.

The nucleocapsid protein packages the viral genome RNA into new viral particles.

Viral particles are assembled and bud off from the ERGIC membrane.

The host cell eventually dies, releasing a wave of new virus particles to infect surrounding cells.

This lifecycle of SARS-CoV-2 demonstrates the virus's strategy for replication and spread.

Transcripts

In our airways, the air we breathe comes into contact

with a mixture of different types of healthy respiratory cells.

Some respiratory cells have cilia

hairlike structures that move the mucus along.

These ciliated cells in our airways are the main target

for the SARS-CoV-2 coronavirus.

The virus itself is deceptively simple.

It only consists of a few parts, but together

these parts create a highly effective virus.

It has an outer membrane with three types of proteins on it

spike

envelope

and membrane proteins.

Inside the virus, an assembly of nucleocapsid proteins

hold together its genetic material: a single strand of viral RNA.

The spike protein is responsible for making contact

with the host cell and starting the infection.

It’s glycosylated, meaning it has a coat of sugars

that hides it from the body’s immune system.

Many of the variants of SARS-CoV-2 are characterised by mutations on this spike protein

that can influence its function, some making the virus more infectious.

Many of these mutations are unique to each variant

but some, like D416G, are found on each of the variants of concern.

When the virus closes in on a host cell, its spike proteins open up

and bind to a receptor on the host cell called ACE-2.

After the spike protein makes contact

furin cuts off the outer part of the spike protein, called the S1 domain.

This frees the inner core of the spike protein, called the S2 domain

which is cut by TMPRSS2.

The spike protein then unfolds and anchors into the host cell membrane

pulling the virus closer until the cell membrane and the viral membrane fuse

allowing the viral genome to enter the host cell.

Inside the cell, a ribosome meets the viral RNA

and starts to translate its genetic code.

The result is a long protein chain

containing non-structural proteins, or nsps.

Initially, these nsps are all attached to one another

but some of the nsps are able to cut the chain.

Nsp3 is the first one that can cleave its neighbours.

It cuts and releases the first nsp

which is able to grab onto a ribosome

and occupy it in such a way that the ribosome can only read viral RNA

and not the host cell’s own mRNA.

This means that the virus takes over the cell’s translation machinery

turning the host cell into a virus-building factory.

Meanwhile, nsp3 cuts other neighbours before it cuts and frees itself.

Eventually, the production of nsps stops

because there is a pseudoknot in the viral RNA.

This prevents the remaining RNA

which codes for proteins involved in viral genome replication

from passing through the ribosome.

By now, a second cutting nsp has been made

which cuts itself and its neighbours.

The translation can either stop here

or the pseudoknot in the viral RNA can slip

allowing the remaining viral RNA to be read.

The second cutting nsp is now able to cut all of the remaining proteins.

Because of the pseudoknot, the translation of the viral RNA often stops prematurely.

As a result, the host cell produces fewer

of the RNA-processing nsps from beyond the knot

than the various membrane-modifying nsps from before the pseudoknot.

The three nsps that are embedded into the endoplasmic reticulum membrane cause it to curve.

This disrupts the sheet-like shape of the ER

and creates a structure called a double membrane vesicle, or DMV.

These DMVs create a safe, enclosed environment for the viral genome to be copied.

Inside the DMV, the newly created nsps

will become the machinery to create new viral RNA.

Firstly, a complementary strand is made to act as a reference.

This reference then becomes the template for a new strand identical to the original viral genome.

In addition to the full length viral genome

a set of shorter RNA strands is also created.

These shorter strands are called subgenomic mRNA

and will be processed by the host cell

to create the proteins that go onto the new viral particle.

The subgenomic mRNA exits into the cytosol through an nsp pore in the DMV.

After exiting, it makes its way back to a ribosome

and is translated to make the main proteins that will constitute the new SARS-CoV-2 viral particle

the spike, membrane, envelope, and nucleocapsid proteins.

The newly created nucleocapsid protein sits right by the DMV pore

ready to grab onto the viral genome RNA as it exits the DMV.

The nucleocapsid protein then begins packaging the RNA

into what will become the contents of the new viral particles.

After the spike, envelope, and membrane proteins have been made on the ER membrane

they go to a different membrane compartment called the ERGIC.

On the ERGIC, the membrane proteins are able to catch

the nucleocapsid proteins and viral genome.

This makes the membrane bend inwards

and a new viral particle eventually buds.

When the membrane compartment containing the viral particles

fuses with the outer cell membrane

the viral particles are then released from the cell.

But that’s only the first wave of SARS-CoV-2 particles that will be expelled.

Eventually, the host cell produces so many viral particles that it dies

and releases a whole wave of new virus particles into the surrounding tissue

ready to spread and infect nearby cells.

This completes the lifecycle of a single SARS-CoV-2 coronavirus.