How does a virus take control over the host cell?

How does a virus take control over the host cell?

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When the virus integrates its DNA with the hosts and enters the lytic pathway, do the viral proteins that produced destroy the cells DNA? Do they deactivate it? Also does the cell function in the same way as before?

A virus does not typically destroy its host's DNA. Rather, the virus makes the host cell express viral proteins at an elevated rate compared to the host's own proteins. This is usually achieved because the viral genome contains a strong constitutive promoter, possibly coupled to an enhancer sequence. The virus may also preferentially insert itself into transcriptionally active sections of the host DNA.

As I said earlier, expression of the host's own genes as a whole is not directly regulated by the virus, though specific genes may be up- or down-regulated (immune-system related genes are often primary targets). However, the host's genes will usually be expressed at a reduced level because of the resources being diverted to make virions.

Remember however, that the virus relies totally on the host's machinery to make viral proteins. So, anything that kills the cell before sufficient viral particles are assembled is going to be selected against. This doesn't mean that the cell is healthy though. A significant chunk of the cell's resources have been hijacked by the virus, and a virus infected cell is typically just limping along, clinging to life, as it were.

Depending on the virus, once sufficient virions have been assembled inside the cell, the virus may enter a lytic phase, where the cell literally bursts to release the virions into the surrounding environment to infect new cells. At this point, the cell is obviously dead.

Virus replication

As viruses are obligate intracellular pathogens they cannot replicate without the machinery and metabolism of a host cell. Although the replicative life cycle of viruses differs greatly between species and category of virus, there are six basic stages that are essential for viral replication.

1. Attachment: Viral proteins on the capsid or phospholipid envelope interact with specific receptors on the host cellular surface. This specificity determines the host range (tropism) of a virus.

2. Penetration: The process of attachment to a specific receptor can induce conformational changes in viral capsid proteins, or the lipid envelope, that results in the fusion of viral and cellular membranes. Some DNA viruses can also enter the host cell through receptor-mediated endocytosis.

3. Uncoating: The viral capsid is removed and degraded by viral enzymes or host enzymes releasing the viral genomic nucleic acid.

4. Replication: After the viral genome has been uncoated, transcription or translation of the viral genome is initiated. It is this stage of viral replication that differs greatly between DNA and RNA viruses and viruses with opposite nucleic acid polarity. This process culminates in the de novo synthesis of viral proteins and genome.

5. Assembly: After de novo synthesis of viral genome and proteins, which can be post-transrciptionally modified, viral proteins are packaged with newly replicated viral genome into new virions that are ready for release from the host cell. This process can also be referred to as maturation.

6. Virion release: There are two methods of viral release: lysis or budding. Lysis results in the death of an infected host cell, these types of viruses are referred to as cytolytic. An example is variola major also known as smallpox. Enveloped viruses, such as influenza A virus, are typically released from the host cell by budding. It is this process that results in the acquisition of the viral phospholipid envelope. These types of virus do not usually kill the infected cell and are termed cytopathic viruses.

After virion release some viral proteins remain within the host’s cell membrane, which acts as potential targets for circulating antibodies. Residual viral proteins that remain within the cytoplasm of the host cell can be processed and presented at the cell surface on MHC class-I molecules, where they are recognised by T cells.

Virus replication © The copyright for this work resides with the author

How Influenza Virus Hijacks Human Cells

Influenza is and remains a disease to reckon with. Seasonal epidemics around the world kill several hundred thousand people every year. In the light of looming pandemics if bird flu strains develop the ability to infect humans easily, new drugs and vaccines are desperately sought. Researchers at the European Molecular Biology Laboratory (EMBL) and the joint Unit of Virus Host-Cell Interaction (UVHCI) of EMBL, the University Joseph Fourier (UJF) and the National Centre for Scientific Research (CNRS), in Grenoble, France, have now precisely defined an important drug target in influenza.

In the journal Nature they publish a high-resolution image of a crucial protein domain that allows the virus to hijack human cells and multiply in them.

When the influenza virus infects a host cell its goal is to produce many copies of itself that go on to attack even more cells. A viral enzyme, called polymerase, is key to this process. It both copies the genetic material of the virus and steers the host cell machinery towards the synthesis of viral proteins. It does this by stealing a small tag, called a cap, from host cell RNA molecules and adding it onto its own. The cap is a short extra piece of RNA, which must be present at the beginning of all messenger RNAs (mRNAs) to direct the cell's protein-synthesis machinery to the starting point. The viral polymerase binds to host cell mRNA via its cap, cuts the cap off and adds it to the beginning of its own mRNA &ndash a process known as 'cap snatching'. But exactly how the polymerase achieves this and which of the three subunits of the enzyme does what, has remained controversial.

Researchers of the groups of Rob Ruigrok at the UVHCI and Stephen Cusack at EMBL have now discovered that part of a polymerase subunit called PA is responsible for cleaving the cap off the host mRNA.

"Our results came as a big surprise, because everybody thought that the cleaving activity resides in a different part of the polymerase," explains Rob Ruigrok, Vice-Director of the UVHCI.

"These new insights make PA a promising antiviral drug target. Inhibiting the cleaving of the cap is an efficient way to stop infection, because the virus can no longer multiply. Now we know where to focus drug design efforts," adds Stephen Cusack, Head of EMBL Grenoble and Director of the UVHCI.

The researchers produced crystals of the crucial PA domain and examined them with the powerful X-ray beams of the European Synchrotron Radiation Facility (ESRF) in Grenoble. The high-resolution image of the domain reveals the individual amino acids that constitute the active site responsible for cleaving the RNA information that could guide the design of future antiviral drugs.

Only a few months ago the same group of scientists had already identified another key part of the influenza polymerase a domain in the subunit called PB2 that recognises and binds to the host cap. Taken together the two findings provide a close-to-complete picture of the cap snatching mechanism that allows the influenza virus to take control over human cells.

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Materials provided by European Molecular Biology Laboratory. Note: Content may be edited for style and length.

How Long Does It Take a Virus to Infect a Cell?

Viruses are as simple as they are “smart”: too elementary to be able to reproduce by themselves, they exploit the reproductive “machinery” of cells, by inserting pieces of their own DNA so that it is transcribed by the host cell.

To do this, they first have to inject their own genetic material into the cells they infect. An international team of researchers, including Cristian Micheletti from SISSA (the International School for Advanced Studies in Trieste), has studied how this occurs and how long it takes for this process to be completed.

Micheletti and colleagues constructed a computer model of viral DNA and then simulated the release of genetic material from the viral capsid into the host cell nucleus. Far from being a fluid process, this ejection is subject to frictional forces that depend on the conformation of the DNA strand. “Fluidity of the process depends on how and how tightly the viral DNA is entangled”, explains Micheletti. “The more topologically ordered is the double strand of the genome, the faster it is ejected from the virus. The situation is somewhat similar to the behaviour of an anchor line that has been correctly coiled: when the anchor is thrown overboard, the line uncoils neatly without stops or jerks due to tangles.”

DNA has an intrinsic characteristic that makes its pattern of spontaneous arrangement very singular. Because it has two strands, DNA has a tendency to form highly ordered coils, just like anchor lines or thread spools. This isn’t the case with generic polymers, which form complex and chaotic tangles. The simulations by Micheletti and colleagues compared the behaviour of a model strand of DNA and a simple strand of generic polymer. “In 95% of cases the model DNA slid through the exit pore of the virus much faster than the simple polymer, as a result of the greater spontaneous order of its conformation”, comments Micheletti. “The simple strands may be even ten times slower than the DNA strands. Another interesting thing is that, although much more slowly, the simple strands in our observations always succeeded in leaving the virus completely. By contrast, in a small minority of cases, the DNA remained totally blocked, and this too is related to its tendency to form a spool that may sometimes present such complex torus knots – i.e., doughnut-like – to completely block ejection from the virus”.

The process timescales observed by Micheletti and colleagues are perfectly consistent with empirical observations, “including all cases of complete DNA stalling that have been reported, though not explained, in some experiments”, concludes Micheletti. “Our study, which estimated the time it takes viral DNA to leave the capsid in relation to its length and degree of packing could provide the starting point for designing artificial viral vectors”.

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The above story is reprinted from materials provided by Scuola Internazionale Superiore di Studi Avanzati

The Lytic and Lysogenic Cycles of Bacteriophages

Bacteriophages, viruses that infect bacteria, may undergo a lytic or lysogenic cycle.

Learning Objectives

Describe the lytic and lysogenic cycles of bacteriophages

Key Takeaways

Key Points

  • Viruses are species specific, but almost every species on Earth can be affected by some form of virus.
  • The lytic cycle involves the reproduction of viruses using a host cell to manufacture more viruses the viruses then burst out of the cell.
  • The lysogenic cycle involves the incorporation of the viral genome into the host cell genome, infecting it from within.

Key Terms

  • latency: The ability of a pathogenic virus to lie dormant within a cell.
  • bacteriophage: A virus that specifically infects bacteria.
  • lytic cycle: The normal process of viral reproduction involving penetration of the cell membrane, nucleic acid synthesis, and lysis of the host cell.
  • lysogenic cycle: A form of viral reproduction involving the fusion of the nucleic acid of a bacteriophage with that of a host, followed by proliferation of the resulting prophage.

Different Hosts and Their Viruses

Viruses are often very specific as to which hosts and which cells within the host they will infect. This feature of a virus makes it specific to one or a few species of life on earth. So many different types of viruses exist that nearly every living organism has its own set of viruses that try to infect its cells. Even the smallest and simplest of cells, prokaryotic bacteria, may be attacked by specific types of viruses.

Bacteriophage: This transmission electron micrograph shows bacteriophages attached to a bacterial cell.


Bacteriophages are viruses that infect bacteria. Bacteriophages may have a lytic cycle or a lysogenic cycle, and a few viruses are capable of carrying out both. When infection of a cell by a bacteriophage results in the production of new virions, the infection is said to be productive.

Lytic versus lysogenic cycle: A temperate bacteriophage has both lytic and lysogenic cycles. In the lytic cycle, the phage replicates and lyses the host cell. In the lysogenic cycle, phage DNA is incorporated into the host genome, where it is passed on to subsequent generations. Environmental stressors such as starvation or exposure to toxic chemicals may cause the prophage to excise and enter the lytic cycle.

Lytic Cycle

With lytic phages, bacterial cells are broken open (lysed) and destroyed after immediate replication of the virion. As soon as the cell is destroyed, the phage progeny can find new hosts to infect. An example of a lytic bacteriophage is T4, which infects E. coli found in the human intestinal tract. Lytic phages are more suitable for phage therapy.

Some lytic phages undergo a phenomenon known as lysis inhibition, where completed phage progeny will not immediately lyse out of the cell if extracellular phage concentrations are high.

Lysogenic Cycle

In contrast, the lysogenic cycle does not result in immediate lysing of the host cell. Those phages able to undergo lysogeny are known as temperate phages. Their viral genome will integrate with host DNA and replicate along with it fairly harmlessly, or may even become established as a plasmid. The virus remains dormant until host conditions deteriorate, perhaps due to depletion of nutrients then, the endogenous phages (known as prophages) become active. At this point they initiate the reproductive cycle, resulting in lysis of the host cell. As the lysogenic cycle allows the host cell to continue to survive and reproduce, the virus is reproduced in all of the cell’s offspring. An example of a bacteriophage known to follow the lysogenic cycle and the lytic cycle is the phage lambda of E. coli.

Latency Period

Viruses that infect plant or animal cells may also undergo infections where they are not producing virions for long periods. An example is the animal herpes viruses, including herpes simplex viruses, which cause oral and genital herpes in humans. In a process called latency, these viruses can exist in nervous tissue for long periods of time without producing new virions, only to leave latency periodically and cause lesions in the skin where the virus replicates. Even though there are similarities between lysogeny and latency, the term lysogenic cycle is usually reserved to describe bacteriophages.

How do viruses work?

Viruses can’t make new viruses on their own. Instead, they take over cells, and trick the cell into making new viruses. To enter the cell, a virus floats up to, or lands on a cell, then attaches to a receptor. Receptors are proteins on the surface of cells that act like locks. They will only fit a specific key. The sneaky virus has a copy of that key. Proteins on the virus’ surface are shaped just like the keys, and fit into a receptor. This starts a process that leads to the virus either entering the cell whole, or injecting its DNA or RNA into the cell.

Once a virus enters the cell, it can use the cell to make more viruses. The virus can do this because viruses and cells have an important thing in common: they both use DNA and RNA. DNA and RNA are molecules that act like instructions. Viruses bring their DNA and RNA instructions to the cell, and trick the cell into following them. The cells follow the virus’ directions and make all the necessary parts for the virus. Cells even use their own tools and raw martials for the virus parts. New copies of viruses can then be put together inside the cell. Eventually, the new virus particles escape the cell, often killing it. These new viruses go on to find more cells to infect.

Martinus Beijerinck was the scientist who gave these infectious particles the name “virus”. He wasn’t sure yet what viruses looked like, just that they were much smaller than bacteria, so he thought a virus was some sort of toxin.

In humans, viruses that cause disease like cold and flu are spread through bodily fluids, like spit or snot. The virus is so small that it leaves our bodies in these fluids, and can even float through the air in droplets from a sneeze or cough. The virus can enter the body through the eyes, nose, or mouth. It can also land somewhere and wait. When someone else touches it, then rubs their face, the virus can be passed on to the new person.

How Viruses Work

Once inside the cell, the viral enzymes take over those enzymes of the host cell and begin making copies of the viral genetic instructions and new viral proteins using the virus's genetic instructions and the cell's enzyme machinery (see How Cells Work for details on the machinery). The new copies of the viral genetic instructions are packaged inside the new protein coats to make new viruses.

Once the new viruses are made, they leave the host cell in one of two ways:

  1. They break the host cell open (lysis) and destroy the host cell.
  2. They pinch out from the cell membrane and break away (budding) with a piece of the cell membrane surrounding them. This is how enveloped viruses leave the cell. In this way, the host cell is not destroyed.

Once free from the host cell, the new viruses can attack other cells. Because one virus can reproduce thousands of new viruses, viral infections can spread quickly throughout the body.

The sequence of events that occurs when you come down with the flu or a cold is a good demonstration of how a virus works:

  1. An infected person sneezes near you.
  2. You inhale the virus particle, and it attaches to cells lining the sinuses in your nose.
  3. The virus attacks the cells lining the sinuses and rapidly reproduces new viruses.
  4. The host cells break, and new viruses spread into your bloodstream and also into your lungs. Because you have lost cells lining your sinuses, fluid can flow into your nasal passages and give you a runny nose.
  5. Viruses in the fluid that drips down your throat attack the cells lining your throat and give you a sore throat.
  6. Viruses in your bloodstream can attack muscle cells and cause you to have muscle aches.

Your immune system responds to the infection, and in the process of fighting, it produces chemicals called pyrogens that cause your body temperature to increase. This fever actually helps you to fight the infection by slowing down the rate of viral reproduction, because most of your body's chemical reactions have an optimal temperature of 98.6 degrees Fahrenheit (37 degrees Celsius). If your temperature rises slightly above this, the reactions slow down. This immune response continues until the viruses are eliminated from your body. However, if you sneeze, you can spread thousands of new viruses into the environment to await another host.

Fungal and Protozoan Parasites Have Complex Life Cycles with Multiple Forms

Pathogenic fungi and protozoan parasites are eucaryotes. It is therefore more difficult to find drugs that will kill them without killing the host. Consequently, antifungal and antiparasitic drugs are often less effective and more toxic than antibiotics. A second characteristic of fungal and parasitic infections that makes them difficult to treat is the tendency of the infecting organisms to switch among several different forms during their life cycles. A drug that is effective at killing one form is often ineffective at killing another form, which therefore survives the treatment.

The fungal branch of the eucaryotic kingdom includes both unicellular yeasts (such as Saccharomyces cerevisiae and Schizosaccharomyces pombe) and filamentous, multicellular molds (like those found on moldy fruit or bread). Most of the important pathogenic fungi exhibit dimorphism—the ability to grow in either yeast or mold form. The yeast-to-mold or mold-to-yeast transition is frequently associated with infection. Histoplasma capsulatum, for example, grows as a mold at low temperature in the soil, but it switches to a yeast form when inhaled into the lung, where it can cause the disease histoplasmosis (Figure 25-9).

Figure 25-9

Dimorphism in the pathogenic fungus Histoplasma capsulatum. (A) At low temperature in the soil, Histoplasma grows as a filamentous fungus. (B) After being inhaled into the lung of a mammal, Histoplasma undergoes a morphological switch triggered by the (more. )

Protozoan parasites have more elaborate life cycles than do fungi. These cycles frequently require the services of more than one host. Malaria is the most common protozoal disease, infecting 200� million people every year and killing 1𠄳 million of them. It is caused by four species of Plasmodium, which are transmitted to humans by the bite of the female of any of 60 species of Anopheles mosquito. Plasmodium falciparum—the most intensively studied of the malaria-causing parasites𠅎xists in no fewer than eight distinct forms, and it requires both the human and mosquito hosts to complete its sexual cycle (Figure 25-10). Gametes are formed in the bloodstream of infected humans, but they can only fuse to form a zygote in the gut of the mosquito. Three of the Plasmodium forms are highly specialized to invade and replicate in specific tissues—the insect gut lining, the human liver, and the human red blood cell.

Figure 25-10

The complex life cycle of malaria. (A) The sexual cycle of Plasmodium falciparum requires passage between a human host and an insect host. (B)-(D) Blood smears from people infected with malaria, showing three different forms of the parasite that appear (more. )

Because malaria is so widespread and devastating, it has acted as a strong selective pressure on human populations in areas of the world that harbor the Anopheles mosquito. Sickle cell anemia, for example, is a recessive genetic disorder caused by a point mutation in the gene that encodes the hemoglobin β chain, and it is common in areas of Africa with a high incidence of the most serious form of malaria (caused by Plasmodium falciparum). The malarial parasites grow poorly in red blood cells from either homozygous sickle cell patients or healthy heterozygous carriers, and, as a result, malaria is seldom found among carriers of this mutation. For this reason, malaria has maintained the sickle cell mutation at high frequency in these regions of Africa.

How does a virus take control over the host cell? - Biology

Over the past twenty years, Professor Hyeryun Choe from The Scripps Research Institute in Florida, has focused on understanding the fundamental processes that enable enveloped viruses to enter and exploit healthy cells. Professor Choe and her team have shown that particular cellular proteins are required for infection of specific viruses. For example, the presence of certain host receptors that bind to viral glycoproteins, is essential for successful infection of viruses. By identifying these cellular receptors, Professor Choe aims to develop a range of therapies that inhibit viral infection.
Viruses can cause some of the most fatal diseases on Earth. The infectious nature of viruses enables them to spread rapidly throughout populations and cause global epidemics. For example, one of the most prevalent viral diseases are caused by dengue viruses, which originated in Africa and South Asia. This mosquito-transmitted viral infection has increased in incidence over the last 50 years and spread to over 100 countries. Alarmingly, around 390 million infections occur per year, of which over 90 million manifest clinical symptoms, and approximately half of the global population are at risk.
Viruses hijack healthy host cells, exploiting resources and reproductive machinery for rapid replication. However, a major consequence of speedy reproduction is the increased risk of random genetic mutation, which can result in a myriad of unique viral strains. Therefore, viruses are very difficult to treat. Vaccines that target a specific viral strain could become ineffective in the long-term. This is because viruses could genetically alter to become resistant to the antibodies raised by a vaccine. Ultimately, a conflict exists between humans and viruses, with each side battling to overcome obstacles created by the opposition. HIV binds to cell-surface CD4, and CD4-induced conformational change in the glycoprotein exposes coreceptor binding site, which brings about further changes in the glycoprotein that leads to the fusion between the cell and virus. We urgently need more effective therapies to treat viral infections. In order to accomplish this goal, we need to further our understanding of the specific mechanisms that enable viruses to enter cells. The research of Professor Choe and her team has taken us one step further to achieving this goal. The team has conducted exciting studies that highlight the importance of both host and viral elements needed for infection of specific viruses. This means that in the future we can design more targeted, virus-specific treatments.
How do viruses enter cells?
Essentially, viruses consist of two key elements – a nucleic acid molecule and a protein coat. Some of the these proteins, glycoproteins, are used to gain entry into healthy cells by binding to its specific receptor, found on the cell membrane. Additionally, interactions with coreceptors and various attachment factors enhance infection. When the viral glycoprotein binds to its receptor, a process is triggered in which the host and viral membranes fuse and the genetic material of the virus is delivered into the cell. Professor Choe has investigated these viral glycoproteins and cellular receptors for a range of different viruses.
Chemokine receptors are needed for HIV infection
Professor Choe started her journey of virus research by studying Human Immunodeficiency Virus (HIV). HIV is one of the most severe global health issues having claimed approximately 35 million lives. This devastating virus infects healthy cells including T lymphocytes, dendritic cells and macrophages (cells of the immune system), and the cells in the central nervous system. These diverse range of cells have one factor in common – they all express the protein, CD4, on the cellular membrane. CD4 acts as a receptor for the HIV, and upon binding a virus, it helps internalising the virus into the cell. Professor Choe identified two key chemokine receptors, CCR3 and CCR5, which are also required to facilitate HIV infection. These chemokine receptors are expressed on immune cells and help the cells to migrate to infection sites. HIV then infects these immune cells, gathered at the infection sites, utilising chemokine receptors expressed on them. The team showed this by manipulating HIV-resistant cells to become susceptible to HIV infection by expressing CCR5 or CCR3 coreceptor as well as CD4 receptor.

Professor Choe identified two key chemokine receptors, CCR3 and CCR5, facilitate HIV infection as coreceptors.

Angiotensin converting enzyme 2 supports SARS virus entry into cells
When Severe Acute Respiratory Syndrome (SARS) virus broke out and wreaked the havoc in 2003, Professor Choe together with long-term collaborator Professor Michael Fazan joined the SARS crusade, and identified the SARS virus receptor, angiotensin converting enzyme 2 (ACE2), at a lightning speed. SARS was first detected in February 2003, and the Farzan and Choe laboratories identified ACE2 by the summer of the same year. The identification of ACE2 is very important not only for its own sake but also for the scientific confirmation of palm civets as the immediate source of SARS virus. The same Choe/Farzan team discovered that the deadly stain of SARS virus derived from 2003 outbreak could utilise both civet and human ACE2 molecules to efficiently infect cells, but the mild strain isolated from the subdued outbreak in the following year efficiently used civet ACE but not human ACE. This discovery is crucial, because it explains at a molecular level why and how 2003 strains of SARS virus could easily jump to humans while 2004 strains could not, and helps to predict which animals could or could not be the carrier for SARS viruses. Later, together with other precautionary measures, eliminating all palm civet trading in animal markets contributed to bringing an end to SARS outbreaks. Infection of human fetal endothelial cells. New world arenaviruses use transferrin receptor 1 to invade cells
This ground-breaking research inspired Professor Choe to investigate the processes by which other viruses enter and manipulate cells, for example New World arenaviruses including Machupo, Guanarito, Junin and Sabia viruses. These viruses cause actue haemorrhagic fever in humans with mortality rates as high as 30%. Research conducted by the team showed that transferrin receptor 1 (TfR1) had a high affinity for the entry glycoprotein of Machupo virus. The team manipulated hamster cells, which are not susceptible to Machupo virus, to express human TfR1, and found that these cells became infected by Machupo virus. This phenomenon was observed by human TfR1, but not by a closely-related protein, TfR2. The team also found that human TfR1 was used by all other deadly New World arenaviruses to invade cells. Furthermore, the team investigated various strategies that could be used to inhibit arenavirus infection. Iron depletion is known to enhance synthesis of the TfR1 protein. Therefore, Professor Choe showed that iron supplementation decreased the efficiency of infection of hemorrhagic-fever New World arenaviruses such as Junin and Machupo. Additionally, the team showed that use of TfR1 antibodies can effectively block the virus-receptor interaction, meaning that the viral glycoprotein cannot bind to this receptor and therefore cannot enter the cells.
Apoptotic mimicry
More recently, the Choe laboratory was involved in several significant studies that focus on the so-called ‘phosphatidylserine (PS) receptors’. PS plays a key role in the process of apoptosis (programmed cell death). In healthy cells the enzymes, called flippases, activey ensure that PS is confined to the inner-side of the cellular membrane. However, during apoptosis, flippases are inactivated and the enzymes scramblases act upon PS, causing this phospholipid to be exposed on the outer-side of the cellular membrane. This exposed PS on apoptotic cells acts as an ‘eat-me’ signal it binds to PS receptors expressed on macrophages (a type of immune cells) and induces them to engulf apoptotic cells.
The Choe laboratory have shown that many enveloped viruses utilise these PS receptors to enter cells. This phenomenon is described as ‘apoptotic mimicry’, because viruses expose PS on their membrane surface, mimicking apoptotic cells. The membrane of enveloped viruses is derived from the cellular membrane, and because viruses do not contain flippases, PS located on the inner side of the virus membrane flops to outer side with time. These viruses, ‘disguised’ as apoptotic bodies, are engulfed by macrophages and other cells that express PS receptors, resulting in the infection of those cells. Zika virus’ ability to use AXL allows it to efficiently infect fetal endothelial cells, which helps Zika virus to easily cross the placental barrier and access the fetus. On the other hand, West Nile and dengue viruses do not efficiently use AXL, and thus cannot easily cross the placental barrier. Of various PS receptors, one that is most frequently and efficiently used by a wide range of enveloped viruses is TIM1. TIM1 is expressed on immune cells and helps infection of these cells by many dangerous viruses. Therefore, although the role of the PS receptors is to facilitate immune cells to engulf apoptotic cells dying of pathogen invasion, they end up promoting virus infection of those cells. As these PS receptors are not specific for certain viruses, they are not virus ‘receptors’ but described as ‘attachment factors’. Nonetheless, they are not less important than virus-specific receptors in helping viruses to gain entry into target cells. Many enveloped viruses take advantage of PS receptors to infect target cells. These include, but not limited to, ebola, dengue, and West Nile viruses.

The Choe laboratory have shown that many enveloped viruses utilise these PS receptors to enter cells.

AXL and Zika virus interaction
Currently, Professor Choe and her colleagues are investigating another PS receptor, AXL, which specifically aids Zika virus infection, a flavivirus, although all flaviviruses are very similar in their genetic material and shape. Interestingly, the team found that AXL does not support the entry of other flaviviruses. AXL is found on fetal endothelial cells, therefore the Zika virus can interact with AXL and infect fetal endothelial cells, whereas other flaviviruses such as West Nile and dengue viruses cannot. This observation is of great importance because it explains how Zika virus can breach the placental barrier and spread via fetal circulation to the brain. The infection of the fetal brain with Zika virus can be life-threatening and cause the devastating condition, microcephaly, characterised by a smaller than normal head size, potentially resulting in physical and/or mental retardation of the babies born with it.
Future research
Overall, the research of Professor Choe and her team has greatly helped our understanding of how different viruses infect healthy cells by using a range of host and viral proteins and exploiting a wide range of biochemical, biophysical and virological techniques. However, there are many questions that remain unanswered that the Choe laboratory aims to explore: I) Do flaviviruses, including Zika virus, actively enhance PS incorporation into the virion membrane, thereby ensuring efficient infection of neighbouring cells? ii) Why Zika virus, but not other flaviviruse, uses AXL and cross the placental barrier?, and iii) How does the use of the PS receptors help the transmission from the vector to the host? Investigating these essential questions will take the team one step further to developing effective treatments to fight against these devastating viruses.

  • Choe, H., Farzan, M., Sun, Y., Sullivan, N., Rollins, B., Ponath, P.D., Wu, L., Mackay, C.R., LaRosa, G., Newman, W. and Gerard, N., Sodroski J. 1996. The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell, 85(7), pp.1135-1148.
  • Li, W., Moore, M.J., Vasilieva, N., Sui, J., Wong, S.K., Berne, M.A., Somasundaran, M., Sullivan, J.L., Luzuriaga, K., Greenough, T.C. and Choe, H., Farzan M. 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 426(6965), p.450.
  • Radoshitzky, S.R., Abraham, J., Spiropoulou, C.F., Kuhn, J.H., Nguyen, D., Li, W., Nagel, J., Schmidt, P.J., Nunberg, J.H., Andrews, N.C. and Farzan, M., Choe. H. 2007. Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature, 446(7131), p.92.
  • Jemielity, S., Wang, J.J., Chan, Y.K., Ahmed, A.A., Li, W., Monahan, S., Bu, X., Farzan, M., Freeman, G.J., Umetsu, D.T. and DeKruyff, R.H., Choe H. 2013. TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine. PLoS pathogens, 9(3), p.e1003232.
  • Richard, A.S., Zhang, A., Park, S.J., Farzan, M., Zong, M. and Choe, H. 2015. Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses. Proceedings of the National Academy of Sciences, 112(47), pp.14682-14687.
Research Objectives
Professor Choe and her team study how the TIM family of phosphatidylserine receptors promote infections of a wide range of enveloped viruses including filoviruses and flaviviruses such as West Nile, dengue and Zika viruses. They are continuing with their efforts to identify and characterise host factors, which modulate virus infection, and use their insight to develop strategies to inhibit viral replication.
Hyeryun Choe, Professor in the Department of Immunology and Microbiology at Scripps-FL received her PhD degree from Pennsylvania State University. Since then, she identified or involved in identifying receptors for three important viruses: HIV-1, SARS virus and New World hemorrhagic fever viruses. Before joining Scripps-FL, she was Associate Professor at Harvard Medical School, Boston, MA, USA.
Audrey Stephanie Richard studied molecular and cellular biology at University of Lille 2, Lille, France, where she received her PhD degree. She is currently working with Prof Choe as Staff Scientist at Scripps-FL, and played an essential role in discovering the crucial difference between Zika virus and other closely-related flaviviruses.
Hyeryun Choe , PhD
Department of Immunology and Microbiology
The Scripps Research Institute
130 Scripps Way
Jupiter, Florida 33458, USA
E: [email protected]
T: +1 561 228 2440

Influenza Viruses

Influenza viruses are simple entities belonging to one of three types: A, B, or C. They consist of no more than seven or eight RNA segments enclosed within an envelope of proteins. Mutations in viral RNA and recombinations of RNA from different sources lead to viral evolution.

Antigenic Drift

Influenza viruses can evolve in a gradual way through mutations in the genes that relate to the viral surface proteins hemagglutinin and neuraminidase (HA and NA in shorthand). These mutations may cause the virus’s outer surface to appear different to a host previously infected with the ancestor strain of the virus. In such a case, antibodies produced by previous infection with the ancestor strain cannot effectively fight the mutated virus, and disease results. (Hemagglutinin and neuraminidase lend their first initials to flu subtypes. For example, the 2009 influenza pandemic was caused by an influenza A H1N1 virus.) As mutations accumulate in future generations of the virus, the virus “drifts” away from its ancestor strain.

Antigenic drift is one reason that new flu vaccines often need to be created for each flu season. Scientists try to predict which changes are likely to occur to currently circulating flu viruses. They create a vaccine designed to fight the predicted virus. Sometimes the prediction is accurate, and the flu vaccine is effective. Other times the prediction misses the mark, and the vaccine won’t prevent disease.

Antigenic Shift

Antigenic shift is a process by which two or more different types of influenza A combine to form a virus radically different from the ancestor strains. The virus that results has a new HA or NA subtype. Antigenic shift may result in global disease spread, or pandemic, because humans will have few or no antibodies to block infection. However, if the new influenza A subtype does not easily pass from person to person, the disease outbreak will be limited.

Antigenic shift occurs in two ways. First, antigenic shift can occur through genetic recombination, or reassortment, when two or more different influenza A viruses infect the same host cell and combine their genetic material. Influenza A viruses can infect birds, pigs, and humans, and major antigenic shifts can occur when these virus types combine. For example, a pig flu virus and a human flu virus could combine in a bird, resulting in a radically different flu type. If the virus infects humans and is efficiently transmitted among them, a pandemic may occur.

Second, an influenza A virus can jump from one type of organism, usually a bird, to another type of organism, such as a human, without undergoing major genetic change. If the virus mutates in the human host so that it is easily spread among people, a pandemic may result.

In all cases, antigenic shift produces a virus with a new HA or NA subtype to which humans have no, or very few, preexisting antibodies. Once scientists are able to identify the new subtype, a vaccine can generally be created that will provide protection from the virus.

Why does antigenic shift occur only with influenza A, and not influenza B and C? Influenza A is the only influenza type that can infect a wide variety of animals: humans, waterfowl, other birds, pigs, dogs, and horses. Recombination possibilities, therefore, are very low or nonexistent with influenza B and C.

A pandemic had the potential to occur in the bird flu outbreaks in 2003 in Asia. An H5N1 influenza A virus spread from infected birds to humans, resulting in serious human disease. But the virus has not evolved to be easily spread among humans, and an H5N1 pandemic has not occurred.

When a virus enters a cell it relies on the molecular machinery of its host to help it replicate. In particular, the virus relies on the ribosomes in the host cell to translate viral messenger RNA (mRNA) into polypeptides. Many viruses also impair the translation of cellular mRNA, via a process termed “host shutoff”, in order to prevent the production of anti-viral, host defense proteins. For example, poliovirus does this by inactivating a translation factor that is required to load ribosomes onto host mRNAs, all of which have a type of "cap" called an "m 7 G cap". Moreover, while the translation of these mRNAs is being suppressed, host ribosomes are involved in the translation of poliovirus mRNA, which does not have a cap: this is possible without the translation factor because poliovirus mRNA has an internal entry site for ribosomes (Jan et al., 2016). However, the mechanisms responsible for host shutoff in viruses that have mRNAs with m 7 G-caps, such as influenza A virus, have remained enigmatic.

Numerous mechanisms have been proposed to explain host shutoff by influenza A virus (IAV). One of these involves the viral mRNAs “stealing” capped fragments originally thought to be derived from cellular pre-mRNAs, followed by extension into mRNA (Koppstein et al., 2015). Other mechanisms put forward include the preferential translation of viral mRNA (Park and Katze, 1995), the degradation of cellular mRNA (Beloso et al., 1992), inhibiting the formation of cellular pre-mRNA (Nemeroff et al., 1998), the degradation of cellular RNA polymerase II (Rodriguez et al., 2007), and the retention of host mRNA in the cell nucleus (Fortes et al., 1994).

Now, in eLife, Noam Stern-Ginossar of the Weizmann Institute of Science and colleagues – including Adi Bercovich-Kinori and Julie Tai as joint first authors – report how they have combined RNA sequencing (which measures the abundance of different mRNAs) with ribosome profiling (which gives a measure of mRNA translation or protein synthesis (Ingolia, 2016)) to produce a genome-wide map that illustrates changes in the abundance and translation of both host and viral mRNA across the IAV replication cycle (Bercovich-Kinori et al., 2016). Unexpectedly they found that host and viral mRNAs were both translated with similar efficiencies, indicating that viral mRNAs were not preferentially translated relative to host mRNAs. Instead, IAV-induced host shutoff primarily originates from a reduced abundance of cellular mRNA and from the high levels of viral mRNA in both the nucleus and cytoplasm. Fluorescence-based measurements confirmed these findings and revealed that the reduced abundance of cellular mRNA has its origins in the nucleus. This likely involves an RNA endoribonuclease called PA-X, which is encoded in the genome of IAV, stimulating the decay of cellular mRNA (Khaperskyy et al., 2016).

Significantly, Bercovich-Kinori et al. – who are based at the Weizmann Institute, the Chaim Sheba Medical Center and Tel-Aviv University – found that the sensitivity of host mRNAs to IAV-induced host shutoff was not uniform, and that certain host mRNAs resisted IAV-induced decay. For example, shorter and more GC-rich host mRNAs were less impacted by IAV-induced decay. Furthermore, host mRNAs encoding proteins that maintain vital cellular processes (such as the proteins that maintain oxidative phosphorylation) were less perturbed by IAV because such processes support the replication of the virus. Thus, IAV infection effectively sculpts the total pool of mRNA in virus-infected cells, allowing select host mRNAs that are important for virus replication to persist and be translated.

Exploring further Bercovich-Kinori et al. noticed that a number of host mRNAs – those that are translated when eIF2α, a subunit of eukaryotic initiation factor 2, is phosphorylated – were enriched on ribosomes in IAV-infected cells. The phosphorylation of eIF2α is a response to physiological stress, including viral infection, that restricts overall protein synthesis (Jan et al., 2016), while stimulating the translation of select mRNAs that are required for stress responses. The researchers found evidence for increased levels of eIF2α phosphorylation at 4 hours post infection, and for much reduced levels at 8 hours post infection. Thus, while eIF2α phosphorylation is traditionally antiviral, the changes observed during IAV infection illustrate how a virus might benefit from this stress-response program. It is conceivable, therefore, that other stress-responsive host mRNAs that encode antiviral functions might restrict the replication of IAV, albeit incompletely. We do not know how viral mRNAs are translated when the levels of eIF2α phosphorylation transiently increase, but the overwhelming abundance of viral mRNAs may simply enhance the likelihood of capturing ribosomes carrying unphosphorylated eIF2α.

The study by Bercovich-Kinori et al. has broad implications in infection biology. Host shutoff enforced by viral domination of the mRNA pool has the advantage of preserving the cellular machinery needed for the translation of mRNAs with m 7 G caps. Instead of inactivating cellular translation factors, or relying on the preferential translation of viral mRNA, the mRNA pool can be remodeled via mRNA decay. This could allow the virus to better take advantage of critical host processes. Strikingly, the genomes of herpesviruses, poxviruses and coronaviruses, which all produce m 7 G-capped mRNAs, also encode proteins that can stimulate mRNA decay and, therefore remodel the mRNA pool inside cells (Abernathy and Glaunsinger, 2015 Jan et al., 2016). The extent to which the domination of the mRNA pool by viral mRNA drives host shutoff, or if similar host mRNAs resist virus-induced mRNA decay in cells infected with these different viruses, remains to be explored. Likewise, the latest work also illustrates how remodeling of the mRNA pool by mRNA decay, coupled with new transcription, might rapidly reprogram gene expression, and therefore potentially impact the stress responses of uninfected cells to a range of physiological stimuli.

How influenza virus A drives virus-induced host shutoff.

Top left: Pools of host mRNAs (green lines) in the nucleus (blue) and cytoplasm (grey) in uninfected cells. The 5' end of each mRNA has an m 7 G cap (light green filled). Lower right: Influenza virus A (IAV) mRNAs (salmon lines) dominate the mRNA pool in virus-infected cells. The 5’-end of viral mRNAs contain m 7 G-caps and 5’-proximal sequences derived from host RNAs. The abundance of host mRNAs within the nucleus is reduced by IAV: this is probably caused by an RNA endonuclease called PA-X. Some of the host mRNAs resistant to IAV-induced decay are shown within the cytoplasm (inside the dotted box): besides being shorter and more GC-rich than host mRNAs that are not resistant to IAV-induced decay, some of these mRNAs are stress-responsive and are translated when eIF2α is phosphorylated (see text). m 7 G: methyl-7-guanosine.