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9.1: Viruses - Biology

9.1: Viruses - Biology


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Learning Objectives

  • Describe the general characteristics of viruses as pathogens
  • Describe viral genomes
  • Describe the general characteristics of viral life cycles
  • Differentiate among bacteriophages, plant viruses, and animal viruses
  • Describe the characteristics used to identify viruses as obligate intracellular parasites

Clinical Focus - part 1

David, a 45-year-old journalist, has just returned to the U.S. from travels in Russia, China, and Africa. He is not feeling well, so he goes to his general practitioner complaining of weakness in his arms and legs, fever, headache, noticeable agitation, and minor discomfort. He thinks it may be related to a dog bite he suffered while interviewing a Chinese farmer. He is experiencing some prickling and itching sensations at the site of the bite wound, but he tells the doctor that the dog seemed healthy and that he had not been concerned until now. The doctor ordered a culture and sensitivity test to rule out bacterial infection of the wound, and the results came back negative for any possible pathogenic bacteria.

Exercise (PageIndex{1})

  1. Based on this information, what additional tests should be performed on the patient?
  2. What type of treatment should the doctor recommend?

Despite their small size, which prevented them from being seen with light microscopes, the discovery of a filterable component smaller than a bacterium that causes tobacco mosaic disease (TMD) dates back to 1892.1 At that time, Dmitri Ivanovski, a Russian botanist, discovered the source of TMD by using a porcelain filtering device first invented by Charles Chamberland and Louis Pasteur in Paris in 1884. Porcelain Chamberland filters have a pore size of 0.1 µm, which is small enough to remove all bacteria ≥0.2 µm from any liquids passed through the device. An extract obtained from TMD-infected tobacco plants was made to determine the cause of the disease. Initially, the source of the disease was thought to be bacterial. It was surprising to everyone when Ivanovski, using a Chamberland filter, found that the cause of TMD was not removed after passing the extract through the porcelain filter. So if a bacterium was not the cause of TMD, what could be causing the disease? Ivanovski concluded the cause of TMD must be an extremely small bacterium or bacterial spore. Other scientists, including Martinus Beijerinck, continued investigating the cause of TMD. It was Beijerinck, in 1899, who eventually concluded the causative agent was not a bacterium but, instead, possibly a chemical, like a biological poison we would describe today as a toxin. As a result, the word virus, Latin for poison, was used to describe the cause of TMD a few years after Ivanovski’s initial discovery. Even though he was not able to see the virus that caused TMD, and did not realize the cause was not a bacterium, Ivanovski is credited as the original discoverer of viruses and a founder of the field of virology.

Today, we can see viruses using electron microscopes (Figure (PageIndex{1})) and we know much more about them. Viruses are distinct biological entities; however, their evolutionary origin is still a matter of speculation. In terms of taxonomy, they are not included in the tree of life because they are acellular (not consisting of cells). In order to survive and reproduce, viruses must infect a cellular host, making them obligate intracellular parasites. The genome of a virus enters a host cell and directs the production of the viral components, proteins and nucleic acids, needed to form new virus particles called virions. New virions are made in the host cell by assembly of viral components. The new virions transport the viral genome to another host cell to carry out another round of infection. Table (PageIndex{1}) summarizes the properties of viruses.

Table (PageIndex{1}):Properties of viruses.

Characteristics of Viruses
Infectious, acellular pathogens
Obligate intracellular parasites with host and cell-type specificity
DNA or RNA genome (never both)
Genome is surrounded by a protein capsid and, in some cases, a phospholipid membrane studded with viral glycoproteins
Lack genes for many products needed for successful reproduction, requiring exploitation of host-cell genomes to reproduce

Exercise (PageIndex{2})

Why was the first virus investigated mistaken for a toxin?

Hosts and Viral Transmission

Various viruses have been known infect every type of host cell, including those of plants, animals, fungi, protists, bacteria, and archaea. Each type of virus will only be able to infect the cells of one or a few species of living organism. This is called the host range. However, having a wide host range is not common and viruses will typically only infect specific hosts and only specific cell types within those hosts. The viruses that infect bacteria are called bacteriophages, or simply phages. The word phage comes from the Greek word for devour. Other viruses are just identified by their host group, such as animal or plant viruses. Once a cell is infected, the effects of the virus can vary depending on the type of virus. Viruses may cause abnormal growth of the cell or cell death, alter the cell’s genome, or cause little noticeable effect in the cell.

Viruses can be transmitted through direct contact, indirect contact with fomites (inanimate objects such as handles), or through a vector: an animal that transmits a pathogen from one host to another. Arthropods such as mosquitoes, ticks, and flies, are typical vectors for viral diseases, and they may act as mechanical vectors or biological vectors. Mechanical transmission occurs when the arthropod carries a viral pathogen on the outside of its body and transmits it to a new host by physical contact. Biological transmission occurs when the arthropod carries the viral pathogen inside its body and transmits it to the new host through biting or similar behavior.

In humans, a wide variety of viruses are capable of causing various infections and diseases. Some of the deadliest emerging pathogens in humans are viruses, yet we have few treatments or drugs to deal with viral infections, making them difficult to eradicate. Viruses that can be transmitted from an animal host to a human host can cause zoonoses. For example, the avian influenza virus originates in birds, but can cause disease in humans. Reverse zoonoses are caused by infection of an animal by a virus that originated in a human.

Fighting Bacteria with Viruses

The emergence of superbugs, or multidrug resistant bacteria, has become a major challenge for pharmaceutical companies and a serious health-care problem. According to a 2013 report by the US Centers for Disease Control and Prevention (CDC), more than 2 million people are infected with drug-resistant bacteria in the US annually, resulting in at least 23,000 deaths.2 The continued use and overuse of antibiotics will likely lead to the evolution of even more drug-resistant strains.

One potential solution is the use of phage therapy, a procedure that uses bacteria-killing viruses (bacteriophages) to treat bacterial infections. Phage therapy is not a new idea. The discovery of bacteriophages dates back to the early 20th century, and phage therapy was first used in Europe in 1915 by the English bacteriologist Frederick Twort.3 However, the subsequent discovery of penicillin and other antibiotics led to the near abandonment of this form of therapy, except in the former Soviet Union and a few countries in Eastern Europe. Interest in phage therapy outside of the countries of the former Soviet Union is only recently re-emerging because of the rise in antibiotic-resistant bacteria.4

Phage therapy has some advantages over antibiotics in that phages kill only one specific bacterium, whereas antibiotics kill not only the pathogen but also beneficial bacteria of the normal microbiota. Development of new antibiotics is also expensive for drug companies and for patients, especially for those who live in countries with high poverty rates.

Phages have also been used to prevent food spoilage. In 2006, the US Food and Drug Administration approved the use of a solution containing six bacteriophages that can be sprayed on lunch meats such as bologna, ham, and turkey to kill Listeria monocytogenes, a bacterium responsible for listeriosis, a form of food poisoning. Some consumers have concerns about the use of phages on foods, however, especially given the rising popularity of organic products. Foods that have been treated with phages must declare “bacteriophage preparation” in the list of ingredients or include a label declaring that the meat has been “treated with antimicrobial solution to reduce microorganisms.”5

Exercise (PageIndex{3})

  1. Why do humans not have to be concerned about the presence of bacteriophages in their food?
  2. What are three ways that viruses can be transmitted between hosts?

Viral Structures

In general, virions (viral particles) are small and cannot be observed using a regular light microscope. They are much smaller than prokaryotic and eukaryotic cells; this is an adaptation allowing viruses to infect these larger cells (see Figure (PageIndex{2})). The size of a virion can range from 20 nm for small viruses up to 900 nm for typical, large viruses (see Figure (PageIndex{3})). Recent discoveries, however, have identified new giant viral species, such as Pandoravirus salinus and Pithovirus sibericum, with sizes approaching that of a bacterial cell.6

In 1935, after the development of the electron microscope, Wendell Stanley was the first scientist to crystallize the structure of the tobacco mosaic virus and discovered that it is composed of RNA and protein. In 1943, he isolated Influenza B virus, which contributed to the development of an influenza (flu) vaccine. Stanley’s discoveries unlocked the mystery of the nature of viruses that had been puzzling scientists for over 40 years and his contributions to the field of virology led to him being awarded the Nobel Prize in 1946.

As a result of continuing research into the nature of viruses, we now know they consist of a nucleic acid (either RNA or DNA, but never both) surrounded by a protein coat called a capsid (see Figure (PageIndex{4})). The interior of the capsid is not filled with cytosol, as in a cell, but instead it contains the bare necessities in terms of genome and enzymes needed to direct the synthesis of new virions. Each capsid is composed of protein subunits called capsomeres made of one or more different types of capsomere proteins that interlock to form the closely packed capsid.

There are two categories of viruses based on general composition. Viruses formed from only a nucleic acid and capsid are called naked viruses or nonenveloped viruses. Viruses formed with a nucleic-acid packed capsid surrounded by a lipid layer are called enveloped viruses (see Figure (PageIndex{4})). The viral envelope is a small portion of phospholipid membrane obtained as the virion buds from a host cell. The viral envelope may either be intracellular or cytoplasmic in origin.

Extending outward and away from the capsid on naked viruses and enveloped viruses are protein structures called spikes. At the tips of these spikes are structures that allow the virus to attach and enter a cell, like the influenza virus hemagglutinin spikes (H) or enzymes like the neuraminidase (N) influenza virus spikes that allow the virus to detach from the cell surface during release of new virions. Influenza viruses are often identified by their H and N spikes. For example, H1N1 influenza viruses were responsible for the pandemics in 1918 and 2009,7 H2N2 for the pandemic in 1957, and H3N2 for the pandemic in 1968.

Viruses vary in the shape of their capsids, which can be either helical, polyhedral, or complex. A helical capsid forms the shape of tobacco mosaic virus (TMV), a naked helical virus, and Ebola virus, an enveloped helical virus. The capsid is cylindrical or rod shaped, with the genome fitting just inside the length of the capsid. Polyhedral capsids form the shapes of poliovirus and rhinovirus, and consist of a nucleic acid surrounded by a polyhedral (many-sided) capsid in the form of an icosahedron. An icosahedral capsid is a three-dimensional, 20-sided structure with 12 vertices. These capsids somewhat resemble a soccer ball. Both helical and polyhedral viruses can have envelopes. Viral shapes seen in certain types of bacteriophages, such as T4 phage, and poxviruses, like vaccinia virus, may have features of both polyhedral and helical viruses so they are described as a complex viral shape (see Figure (PageIndex{5})). In the bacteriophage complex form, the genome is located within the polyhedral head and the sheath connects the head to the tail fibers and tail pins that help the virus attach to receptors on the host cell’s surface. Poxviruses that have complex shapes are often brick shaped, with intricate surface characteristics not seen in the other categories of capsid.

Exercise (PageIndex{4})

Which types of viruses have spikes?

Classification and Taxonomy of Viruses

Although viruses are not classified in the three domains of life, their numbers are great enough to require classification. Since 1971, the International Union of Microbiological Societies Virology Division has given the task of developing, refining, and maintaining a universal virus taxonomy to the International Committee on Taxonomy of Viruses (ICTV). Since viruses can mutate so quickly, it can be difficult to classify them into a genus and a species epithet using the binomial nomenclature system. Thus, the ICTV’s viral nomenclature system classifies viruses into families and genera based on viral genetics, chemistry, morphology, and mechanism of multiplication. To date, the ICTV has classified known viruses in seven orders, 96 families, and 350 genera. Viral family names end in -viridae (e.g, Parvoviridae) and genus names end in −virus (e.g., Parvovirus). The names of viral orders, families, and genera are all italicized. When referring to a viral species, we often use a genus and species epithet such as Pandoravirus dulcis or Pandoravirus salinus. Explore the latest virus taxonomy at the ICTV website.

The Baltimore classification system is an alternative to ICTV nomenclature. The Baltimore system classifies viruses according to their genomes (DNA or RNA, single versus double stranded) and mode of replication. This system thus creates seven groups of viruses that have common genetics and biology.

Aside from formal systems of nomenclature, viruses are often informally grouped into categories based on chemistry, morphology, or other characteristics they share in common. Categories may include naked or enveloped structure, single-stranded (ss) or double-stranded (ds) DNA or ss or ds RNA genomes, segmented or nonsegmented genomes, and positive-strand (+) or negative-strand (−) RNA. For example, herpes viruses can be classified as a dsDNA enveloped virus; human immunodeficiency virus (HIV) is a +ssRNA enveloped virus, and tobacco mosaic virus is a +ssRNA virus. Other characteristics such as host specificity, tissue specificity, capsid shape, and special genes or enzymes may also be used to describe groups of similar viruses. Table (PageIndex{2}) lists some of the most common viruses that are human pathogens by genome type.

Table (PageIndex{2}): Common Pathogenic Viruses
GenomeFamilyExample VirusClinical Features
dsDNA, envelopedPoxviridaeOrthopoxvirusSkin papules, pustules, lesions
PoxviridaeParapoxvirusSkin lesions
HerpesviridaeSimplexvirusCold sores, genital herpes, sexually transmitted disease
dsDNA, nakedAdenoviridaeAtadenovirusRespiratory infection (common cold)
PapillomaviridaePapillomavirusGenital warts, cervical, vulvar, or vaginal cancer
ReoviridaeReovirusGastroenteritis severe diarrhea (stomach flu)
ssDNA, nakedParvoviridaeAdeno-associated dependoparvovirus ARespiratory tract infection
ParvoviridaeAdeno-associated dependoparvovirus BRespiratory tract infection
dsRNA, nakedReoviridaeRotavirusGastroenteritis
+ssRNA, nakedPicornaviridaeEnterovirus CPoliomyelitis
PicornaviridaeRhinovirusUpper respiratory tract infection (common cold)
PicornaviridaeHepatovirusHepatitis
+ssRNA, envelopedTogaviridaeAlphavirusEncephalitis, hemorrhagic fever
TogaviridaeRubivirusRubella
RetroviridaeLentivirusAcquired immune deficiency syndrome (AIDS)
−ssRNA, envelopedFiloviridaeZaire EbolavirusHemorrhagic fever
OrthomyxoviridaeInfluenzavirus A, B, CFlu
RhabdoviridaeLyssavirusRabies

Exercise (PageIndex{5})

What are the types of virus genomes?

Classification of Viral Diseases

While the ICTV has been tasked with the biological classification of viruses, it has also played an important role in the classification of diseases caused by viruses. To facilitate the tracking of virus-related human diseases, the ICTV has created classifications that link to the International Classification of Diseases (ICD), the standard taxonomy of disease that is maintained and updated by the World Health Organization (WHO). The ICD assigns an alphanumeric code of up to six characters to every type of viral infection, as well as all other types of diseases, medical conditions, and causes of death. This ICD code is used in conjunction with two other coding systems (the Current Procedural Terminology, and the Healthcare Common Procedure Coding System) to categorize patient conditions for treatment and insurance reimbursement.

For example, when a patient seeks treatment for a viral infection, ICD codes are routinely used by clinicians to order laboratory tests and prescribe treatments specific to the virus suspected of causing the illness. This ICD code is then used by medical laboratories to identify tests that must be performed to confirm the diagnosis. The ICD code is used by the health-care management system to verify that all treatments and laboratory work performed are appropriate for the given virus. Medical coders use ICD codes to assign the proper code for procedures performed, and medical billers, in turn, use this information to process claims for reimbursement by insurance companies. Vital-records keepers use ICD codes to record cause of death on death certificates, and epidemiologists used ICD codes to calculate morbidity and mortality statistics.

Exercise (PageIndex{6})

Identify two locations where you would likely find an ICD code.

Summary

  • Viruses are generally ultramicroscopic, typically from 20 nm to 900 nm in length. Some large viruses have been found.
  • Virions are acellular and consist of a nucleic acid, DNA or RNA, but not both, surrounded by a protein capsid. There may also be a phospholipid membrane surrounding the capsid.
  • Viruses are obligate intracellular parasites.
  • Viruses are known to infect various types of cells found in plants, animals, fungi, protists, bacteria, and archaea. Viruses typically have limited host ranges and infect specific cell types.
  • Viruses may have helical, polyhedral, or complex shapes.
  • Classification of viruses is based on morphology, type of nucleic acid, host range, cell specificity, and enzymes carried within the virion.
  • Like other diseases, viral diseases are classified using ICD codes.

Footnotes

  1. H. Lecoq. “[Discovery of the First Virus, the Tobacco Mosaic Virus: 1892 or 1898?].” Comptes Rendus de l’Academie des Sciences – Serie III – Sciences de la Vie 324, no. 10 (2001): 929–933.
  2. US Department of Health and Human Services, Centers for Disease Control and Prevention. “Antibiotic Resistance Threats in the United States, 2013.” www.cdc.gov/drugresistance/pd...s-2013-508.pdf (accessed September 22, 2015).
  3. M. Clokie et al. “Phages in Nature.” Bacteriophage 1, no. 1 (2011): 31–45.
  4. A. Sulakvelidze et al. “Bacteriophage Therapy.” Antimicrobial Agents and Chemotherapy 45, no. 3 (2001): 649–659.
  5. US Food and Drug Administration. “FDA Approval of Listeria-specific Bacteriophage Preparation on Ready-to-Eat (RTE) Meat and Poultry Products.” www.fda.gov/food/ingredientsp.../ucm083572.htm (accessed September 22, 2015).
  6. N. Philippe et al. “Pandoraviruses: Amoeba Viruses with Genomes up to 2.5 Mb Reaching that of Parasitic Eukaryotes.” Science 341, no. 6143 (2013): 281–286.
  7. J. Cohen. “What’s Old Is New: 1918 Virus Matches 2009 H1N1 Strain. Science 327, no. 5973 (2010): 1563–1564.

Contributor

  • Nina Parker, (Shenandoah University), Mark Schneegurt (Wichita State University), Anh-Hue Thi Tu (Georgia Southwestern State University), Philip Lister (Central New Mexico Community College), and Brian M. Forster (Saint Joseph’s University) with many contributing authors. Original content via Openstax (CC BY 4.0; Access for free at https://openstax.org/books/microbiology/pages/1-introduction)


9.1: Viruses - Biology

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9.1 Signalling Molecules and Cellular Receptors

In this section, you will explore the following questions:

  • What are the four types of signaling that are found in multicellular organisms?
  • What are the differences between internal receptors and cell-surface receptors?
  • What is the relationship between a ligand’s structure and its mechanism of action?

Connection for AP ® Courses

Just like you communicate with your classmates face-to-face, using your phone, or via e-mail, cells communicate with each other by both inter’and intracellular signaling. Cells detect and respond to changes in the environment using signaling pathways. Signaling pathways enable organisms to coordinate cellular activities and metabolic processes. Errors in these pathways can cause disease. Signaling cells secrete molecules called ligands that bind to target cells and initiate a chain of events within the target cell. For example, when epinephrine is released, binding to target cells, those cells respond by converting glycogen to glucose. Cell communication can happen over short distances. For example, neurotransmitters are released across a synapse to transfer messages between neurons (Figure 26.15). Gap junctions and plasmodesmata allow small molecules, including signaling molecules, to flow between neighboring cells. Cell communication can also happen over long distances using. For example, hormones released from endocrine cells travel to target cells in multiple body systems. How does a ligand such as a hormone traveling through the bloodstream “know” when it has reached its target organ to initiate a cellular response? Nearly all cell signaling pathways involve three stages: reception, signal transduction, and cellular response.

Cell signaling pathways begin when the ligand binds to a receptor, a protein that is embedded in the plasma membrane of the target cell or found in the cell cytoplasm. The receptors are very specific, and each ligand is recognized by a different one. This stage of the pathway is called reception. Molecules that are nonpolar, such as steroids, diffuse across the cell membrane and bind to internal receptors. In turn, the receptor-ligand complex moves to the nucleus and interacts with cellular DNA. This changes how a gene is expressed. Polar ligands, on the other hand, interact with membrane receptor protein. Some membrane receptors work by changing conformation so that certain ions, such as Na + and K + , can pass through the plasma membrane. Other membrane receptors interact with a G-protein on the cytoplasmic side of the plasma membrane, which causes a series of reactions inside the cell. Disruptions to this process are linked to several diseases, including cholera.

It is important to keep in mind that each cell has a variety of receptors, allowing it to respond to a variety of stimuli. Some receptors can bind several different ligands for example, odorant molecules/receptors associated with the sense of smell in animals. Once the signaling molecule and receptor interact, a cascade of events called signal transduction usually amplifies the signal inside the cell.

The content presented in this section supports the Learning Objectives outlined in Big Idea 3 of the AP ® Biology Curriculum Framework listed. The AP ® Learning Objectives merge Essential knowledge content with one or more of the seven Science Practices. These objectives provide a transparent foundation for the AP ® Biology course, along with inquiry-based laboratory experiences, instructional activities, and AP ® Exam questions.

Big Idea 3 Living systems store, retrieve, transmit and respond to information essential to life processes.
Enduring Understanding 3.D Cells communicate by generating, transmitting and receiving chemical signals.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with cellular response.
Science Practice 6.2 The student can construct explanations of phenomena based on evidence produced through scientific practices.
Learning Objective 3.34 The student is able to construct explanations of cell communication through cell-to-cell direct contact or through chemical signaling.
Essential Knowledge 3.D.3 Signal transduction pathways link signal reception with cellular response.
Science Practice 1.1 The student can create representations and models of natural or man-made phenomena and systems in the domain.
Learning Objective 3.35 The student is able to create representations that depict how cell-to-cell communication occurs by direct contact or from a distance through chemical signaling.

The Science Practice Challenge Questions contain contains additional test questions for this section that will help you prepare for the AP exam. These questions address the following standards:
[APLO 3.33][APLO 3.36]

There are two kinds of communication in the world of living cells. Communication between cells is called intercellular signaling , and communication within a cell is called intracellular signaling . An easy way to remember the distinction is by understanding the Latin origin of the prefixes: inter- means "between" (for example, intersecting lines are those that cross each other) and intra- means "inside" (like intravenous).

Chemical signals are released by signaling cells in the form of small, usually volatile or soluble molecules called ligands. A ligand is a molecule that binds another specific molecule, in some cases, delivering a signal in the process. Ligands can thus be thought of as signaling molecules. Ligands interact with proteins in target cells , which are cells that are affected by chemical signals these proteins are also called receptors . Ligands and receptors exist in several varieties however, a specific ligand will have a specific receptor that typically binds only that ligand.

Forms of Signaling

There are four categories of chemical signaling found in multicellular organisms: paracrine signaling, endocrine signaling, autocrine signaling, and direct signaling across gap junctions (Figure 9.2). The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell. Not all cells are affected by the same signals.

Paracrine Signaling

Signals that act locally between cells that are close together are called paracrine signals . Paracrine signals move by diffusion through the extracellular matrix. These types of signals usually elicit quick responses that last only a short amount of time. In order to keep the response localized, paracrine ligand molecules are normally quickly degraded by enzymes or removed by neighboring cells. Removing the signals will reestablish the concentration gradient for the signal, allowing them to quickly diffuse through the intracellular space if released again.

One example of paracrine signaling is the transfer of signals across synapses between nerve cells. A nerve cell consists of a cell body, several short, branched extensions called dendrites that receive stimuli, and a long extension called an axon, which transmits signals to other nerve cells or muscle cells. The junction between nerve cells where signal transmission occurs is called a synapse. A synaptic signal is a chemical signal that travels between nerve cells. Signals within the nerve cells are propagated by fast-moving electrical impulses. When these impulses reach the end of the axon, the signal continues on to a dendrite of the next cell by the release of chemical ligands called neurotransmitters by the presynaptic cell (the cell emitting the signal). The neurotransmitters are transported across the very small distances between nerve cells, which are called chemical synapses (Figure 9.3). The small distance between nerve cells allows the signal to travel quickly this enables an immediate response, such as, Take your hand off the stove!

When the neurotransmitter binds the receptor on the surface of the postsynaptic cell, the electrochemical potential of the target cell changes, and the next electrical impulse is launched. The neurotransmitters that are released into the chemical synapse are degraded quickly or get reabsorbed by the presynaptic cell so that the recipient nerve cell can recover quickly and be prepared to respond rapidly to the next synaptic signal.

Endocrine Signaling

Signals from distant cells are called endocrine signals , and they originate from endocrine cells . (In the body, many endocrine cells are located in endocrine glands, such as the thyroid gland, the hypothalamus, and the pituitary gland.) These types of signals usually produce a slower response but have a longer-lasting effect. The ligands released in endocrine signaling are called hormones, signaling molecules that are produced in one part of the body but affect other body regions some distance away.

Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, which is a relatively slow way to move throughout the body. Because of their form of transport, hormones get diluted and are present in low concentrations when they act on their target cells. This is different from paracrine signaling, in which local concentrations of ligands can be very high.

Autocrine Signaling

Autocrine signals are produced by signaling cells that can also bind to the ligand that is released. This means the signaling cell and the target cell can be the same or a similar cell (the prefix auto- means self, a reminder that the signaling cell sends a signal to itself). This type of signaling often occurs during the early development of an organism to ensure that cells develop into the correct tissues and take on the proper function. Autocrine signaling also regulates pain sensation and inflammatory responses. Further, if a cell is infected with a virus, the cell can signal itself to undergo programmed cell death, killing the virus in the process. In some cases, neighboring cells of the same type are also influenced by the released ligand. In embryological development, this process of stimulating a group of neighboring cells may help to direct the differentiation of identical cells into the same cell type, thus ensuring the proper developmental outcome.

Direct Signaling Across Gap Junctions

Gap junctions in animals and plasmodesmata in plants are connections between the plasma membranes of neighboring cells. These fluid-filled channels allow small signaling molecules, called intracellular mediators , to diffuse between the two cells. Small molecules, such as calcium ions (Ca 2+ ), are able to move between cells, but large molecules like proteins and DNA cannot fit through the channels. The specificity of the channels ensures that the cells remain independent but can quickly and easily transmit signals. The transfer of signaling molecules communicates the current state of the cell that is directly next to the target cell this allows a group of cells to coordinate their response to a signal that only one of them may have received. In plants, plasmodesmata are ubiquitous, making the entire plant into a giant communication network.

Types of Receptors

Receptors are protein molecules in the target cell or on its surface that bind ligand. There are two types of receptors, internal receptors and cell-surface receptors.

Internal receptors

Internal receptors , also known as intracellular or cytoplasmic receptors, are found in the cytoplasm of the cell and respond to hydrophobic ligand molecules that are able to travel across the plasma membrane. Once inside the cell, many of these molecules bind to proteins that act as regulators of mRNA synthesis (transcription) to mediate gene expression. Gene expression is the cellular process of transforming the information in a cell's DNA into a sequence of amino acids, which ultimately forms a protein. When the ligand binds to the internal receptor, a conformational change is triggered that exposes a DNA-binding site on the protein. The ligand-receptor complex moves into the nucleus, then binds to specific regulatory regions of the chromosomal DNA and promotes the initiation of transcription (Figure 9.4). Transcription is the process of copying the information in a cells DNA into a special form of RNA called messenger RNA (mRNA) the cell uses information in the mRNA (which moves out into the cytoplasm and associates with ribosomes) to link specific amino acids in the correct order, producing a protein. Internal receptors can directly influence gene expression without having to pass the signal on to other receptors or messengers.

Cell-Surface Receptors

Cell-surface receptors , also known as transmembrane receptors, are cell surface, membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, in which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types.

Because cell-surface receptor proteins are fundamental to normal cell functioning, it should come as no surprise that a malfunction in any one of these proteins could have severe consequences. Errors in the protein structures of certain receptor molecules have been shown to play a role in hypertension (high blood pressure), asthma, heart disease, and cancer.

Each cell-surface receptor has three main components: an external ligand-binding domain, a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The ligand-binding domain is also called the extracellular domain . The size and extent of each of these domains vary widely, depending on the type of receptor.

EVOLUTION CONNECTION

How Viruses Recognize a Host

Unlike living cells, many viruses do not have a plasma membrane or any of the structures necessary to sustain life. Some viruses are simply composed of an inert protein shell containing DNA or RNA. To reproduce, viruses must invade a living cell, which serves as a host, and then take over the hosts cellular apparatus. But how does a virus recognize its host?

Viruses often bind to cell-surface receptors on the host cell. For example, the virus that causes human influenza (flu) binds specifically to receptors on membranes of cells of the respiratory system. Chemical differences in the cell-surface receptors among hosts mean that a virus that infects a specific species (for example, humans) cannot infect another species (for example, chickens).

However, viruses have very small amounts of DNA or RNA compared to humans, and, as a result, viral reproduction can occur rapidly. Viral reproduction invariably produces errors that can lead to changes in newly produced viruses these changes mean that the viral proteins that interact with cell-surface receptors may evolve in such a way that they can bind to receptors in a new host. Such changes happen randomly and quite often in the reproductive cycle of a virus, but the changes only matter if a virus with new binding properties comes into contact with a suitable host. In the case of influenza, this situation can occur in settings where animals and people are in close contact, such as poultry and swine farms. 1 Once a virus jumps to a new host, it can spread quickly. Scientists watch newly appearing viruses (called emerging viruses) closely in the hope that such monitoring can reduce the likelihood of global viral epidemics.

  1. The virus must infect at least two different animals before infecting humans.
  2. The virus must come into contact with a new host so mutations will occur which allow the virus to bind to that host.
  3. A mutation must occur in the host allowing the virus to bind to the host.
  4. A mutation must occur in the virus allowing the virus to infect a new host, and the virus must come into contact with this host.

Cell-surface receptors are involved in most of the signaling in multicellular organisms. There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. In order to interact with the phospholipid fatty acid tails that form the center of the plasma membrane, many of the amino acids in the membrane-spanning region are hydrophobic in nature. Conversely, the amino acids that line the inside of the channel are hydrophilic to allow for the passage of water or ions. When a ligand binds to the extracellular region of the channel, there is a conformational change in the proteins structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through (Figure 9.5).

G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane (Figure 9.6). All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.

Cell signaling using G-protein-linked receptors occurs as a cyclic series of events. Before the ligand binds, the inactive G-protein can bind to a newly revealed site on the receptor specific for its binding. Once the G-protein binds to the receptor, the resultant shape change activates the G-protein, which releases GDP and picks up GTP. The subunits of the G-protein then split into the α subunit and the βγ subunit. One or both of these G-protein fragments may be able to activate other proteins as a result. After awhile, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and the βγ subunit is deactivated. The subunits reassociate to form the inactive G-protein and the cycle begins anew.

G-protein-linked receptors have been extensively studied and much has been learned about their roles in maintaining health. Bacteria that are pathogenic to humans can release poisons that interrupt specific G-protein-linked receptor function, leading to illnesses such as pertussis, botulism, and cholera. In cholera (Figure 9.7), for example, the water-borne bacterium Vibrio cholerae produces a toxin, choleragen, that binds to cells lining the small intestine. The toxin then enters these intestinal cells, where it modifies a G-protein that controls the opening of a chloride channel and causes it to remain continuously active, resulting in large losses of fluids from the body and potentially fatal dehydration as a result.

Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. The enzyme-linked receptors normally have large extracellular and intracellular domains, but the membrane-spanning region consists of a single alpha-helical region of the peptide strand. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response. One example of this type of enzyme-linked receptor is the tyrosine kinase receptor (Figure 9.8). A kinase is an enzyme that transfers phosphate groups from ATP to another protein. The tyrosine kinase receptor transfers phosphate groups to tyrosine molecules (tyrosine residues). First, signaling molecules bind to the extracellular domain of two nearby tyrosine kinase receptors. The two neighboring receptors then bond together, or dimerize. Phosphates are then added to tyrosine residues on the intracellular domain of the receptors (phosphorylation). The phosphorylated residues can then transmit the signal to the next messenger within the cytoplasm.

VISUAL CONNECTION

  1. dimerization and the downstream cellular response
  2. phosphatase activity, dimerization, and the downstream cellular response
  3. signaling molecule binding, dimerization, and the downstream cellular response
  4. the downstream cellular response

Produced by signaling cells and the subsequent binding to receptors in target cells, ligands act as chemical signals that travel to the target cells to coordinate responses. The types of molecules that serve as ligands are incredibly varied and range from small proteins to small ions like calcium (Ca 2+ ).

Small Hydrophobic Ligands

Small hydrophobic ligands can directly diffuse through the plasma membrane and interact with internal receptors. Important members of this class of ligands are the steroid hormones. Steroids are lipids that have a hydrocarbon skeleton with four fused rings different steroids have different functional groups attached to the carbon skeleton. Steroid hormones include the female sex hormone, estradiol, which is a type of estrogen the male sex hormone, testosterone and cholesterol, which is an important structural component of biological membranes and a precursor of steriod hormones (Figure 9.9). Other hydrophobic hormones include thyroid hormones and vitamin D. In order to be soluble in blood, hydrophobic ligands must bind to carrier proteins while they are being transported through the bloodstream.

Water-Soluble Ligands

Water-soluble ligands are polar and therefore cannot pass through the plasma membrane unaided sometimes, they are too large to pass through the membrane at all. Instead, most water-soluble ligands bind to the extracellular domain of cell-surface receptors. This group of ligands is quite diverse and includes small molecules, peptides, and proteins.

Other Ligands

Nitric oxide (NO) is a gas that also acts as a ligand. It is able to diffuse directly across the plasma membrane, and one of its roles is to interact with receptors in smooth muscle and induce relaxation of the tissue. NO has a very short half-life and therefore only functions over short distances. Nitroglycerin, a treatment for heart disease, acts by triggering the release of NO, which causes blood vessels to dilate (expand), thus restoring blood flow to the heart.


9.1: Viruses - Biology

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Web Links

This site provides some information on Evaluation and Synthesis.

Part of the University of Leicester Microbiology and Immunology website, this article describes the prevention and treatment of viral diseases. It also describes the different types of vaccines available for disease prevention.

From the Center for Disease Control, this website describes four of the most common viral diseases. These include, Measles, Rubella as well as Hepatitis B. Vaccines and vaccination programs are discussed.

An FDA website discussing the rise of antibiotic resistance and proposing possible methods to deal with the problem. The paper also discusses how this may have happened.

An Access Excellence page describing drug resistant bacterial outbreaks. The article includes links to other online resources. It also reviews a few of the major studies that have been conducted in the hopes of better understanding antibiotics.

An article on the Australian Academy of Science website discussing the cause and effect relationship between algal blooms and the health/age of a water body. Clicking the tabs on the page leads to other useful sites and information.

This site from a University of Guelph student goes into great detail about eutrophication and provides a number of links to other sites on this topic.

This page contains the original press release announcing the results of the Iron fertilization project by the Woods Hole Oceanographic Institution. The release provides contact information and email addresses of individuals that may be contacted for more about the topic.

This page is a Reuters News Article mirrored on the Environmental News Network website. The article reports on the premise of the research conducted in the Iron/Algae experiment to begin with. It briefly explains the affect that the algae will have on the excess carbon dioxide in the environment.

This site from the National Centers for Coastal Ocean Science provides details on harmful algal blooms (HAB's), including types of HAB's, causes, and research.

A page from the website of the Nova Scotia Museum, the article briefly describes the reproduction cycles of infected algae blooms as well as the organisms that are contaminated by eating them.

A page displaying a fact sheet from the Rhode Island Sea Grant. The page describes the health risks involved as well as safety precautions that should be taken into consideration to prevent harmful health effects that are brought on by red tides. It also gives a brief description of the origin of red tides.


IGCSE Biology 9-1 - 5c Genetic modification (genetic engineering)

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New Edexcel IGCSE 9-1 4BI1 syllabus for 2017 first examined in 2019

This is a PowerPoint presentation for the topic - Section 5c Genetic modification (genetic engineering)

5.12 understand how restriction enzymes are used to cut DNA at specific sites and ligase enzymes are used to join pieces of DNA together
5.13 understand how plasmids and viruses can act as vectors, which take up pieces of DNA, and then insert this recombinant DNA into other cells
5.14 understand how large amounts of human insulin can be manufactured from genetically modified bacteria that are grown in a fermenter
5.15 understand how genetically modified plants can be used to improve food production
5.16 understand that the term transgenic means the transfer of genetic material from one species to a different species

The file is fully editable, has plenty of original diagrams and animations along with true false concept check questions at the end of the presentation and an exam style question.

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A close look at the biology of SARS-CoV-2, and the potential influence of weather conditions and seasons on COVID-19 case spread

Background: There is sufficient epidemiological and biological evidence of increased human susceptibility to viral pathogens such as Middle East respiratory syndrome coronavirus, respiratory syncytial virus, human metapneumovirus and influenza virus, in cold weather. The pattern of outbreak of the coronavirus disease 2019 (COVID-19) in China during the flu season is further proof that meteorological conditions may potentially influence the susceptibility of human populations to coronaviruses, a situation that may become increasingly evident as the current global pandemic of COVID-19 unfolds.

Main body: A very rapid spread and high mortality rates have characterized the COVID-19 pandemic in countries north of the equator where air temperatures have been seasonally low. It is unclear if the currently high rates of COVID-19 infections in countries of the northern hemisphere will wane during the summer months, or if fewer people overall will become infected with COVID-19 in countries south of the equator where warmer weather conditions prevail through most of the year. However, apart from the influence of seasons, evidence based on the structural biology and biochemical properties of many enveloped viruses similar to the novel severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 (aetiology of COVID-19), support the higher likelihood of the latter of the two outcomes. Other factors that may potentially impact the rate of virus spread include the effectiveness of infection control practices, individual and herd immunity, and emergency preparedness levels of countries.

Conclusion: This report highlights the potential influence of weather conditions, seasons and non-climatological factors on the geographical spread of cases of COVID-19 across the globe.

Keywords: COVID-19 Case spread Emergency preparedness Human immunity Infection control SARS-CoV-2 Season.


Edexcel Biology (9-1) Virus Life Cycles Topic SB5f

A lesson geared towards the Edexcel (9-1) single Biology syllabus.

Includes activities but specific pg numbers and question numbers are for The Pearson Biology (9-1) text book.

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Contents

Reverse transcriptases were discovered by Howard Temin at the University of Wisconsin–Madison in Rous sarcoma virions [5] and independently isolated by David Baltimore in 1970 at MIT from two RNA tumour viruses: murine leukemia virus and again Rous sarcoma virus. [6] For their achievements, they shared the 1975 Nobel Prize in Physiology or Medicine (with Renato Dulbecco).

Well-studied reverse transcriptases include:

  • HIV-1 reverse transcriptase from human immunodeficiency virus type 1 ( PDB: 1HMV ​) has two subunits, which have respective molecular weights of 66 and 51 kDas. [7]
  • M-MLV reverse transcriptase from the Moloney murine leukemia virus is a single 75 kDa monomer. [8]
  • AMV reverse transcriptase from the avian myeloblastosis virus also has two subunits, a 63 kDa subunit and a 95 kDa subunit. [8] that maintains the telomeres of eukaryoticchromosomes. [9]

The enzymes are encoded and used by viruses that use reverse transcription as a step in the process of replication. Reverse-transcribing RNA viruses, such as retroviruses, use the enzyme to reverse-transcribe their RNA genomes into DNA, which is then integrated into the host genome and replicated along with it. Reverse-transcribing DNA viruses, such as the hepadnaviruses, can allow RNA to serve as a template in assembling and making DNA strands. HIV infects humans with the use of this enzyme. Without reverse transcriptase, the viral genome would not be able to incorporate into the host cell, resulting in failure to replicate.

Process of reverse transcription or retrotranscription Edit

Reverse transcriptase creates double-stranded DNA from an RNA template.

In virus species with reverse transcriptase lacking DNA-dependent DNA polymerase activity, creation of double-stranded DNA can possibly be done by host-encoded DNA polymerase δ, mistaking the viral DNA-RNA for a primer and synthesizing a double-stranded DNA by similar mechanism as in primer removal, where the newly synthesized DNA displaces the original RNA template.

The process of reverse transcription, also called retrotranscription or retrotras, is extremely error-prone, and it is during this step that mutations may occur. Such mutations may cause drug resistance.

Retroviral reverse transcription Edit

Retroviruses, also referred to as class VI ssRNA-RT viruses, are RNA reverse-transcribing viruses with a DNA intermediate. Their genomes consist of two molecules of positive-sense single-stranded RNA with a 5' cap and 3' polyadenylated tail. Examples of retroviruses include the human immunodeficiency virus (HIV) and the human T-lymphotropic virus (HTLV). Creation of double-stranded DNA occurs in the cytosol [10] as a series of these steps:

    tRNA acts as a primer and hybridizes to a complementary part of the virus RNA genome called the primer binding site or PBS.
  1. Reverse transcriptase then adds DNA nucleotides onto the 3' end of the primer, synthesizing DNA complementary to the U5 (non-coding region) and R region (a direct repeat found at both ends of the RNA molecule) of the viral RNA.
  2. A domain on the reverse transcriptase enzyme called RNAse H degrades the U5 and R regions on the 5’ end of the RNA.
  3. The tRNA primer then "jumps" to the 3’ end of the viral genome, and the newly synthesised DNA strands hybridizes to the complementary R region on the RNA.
  4. The complementary DNA (cDNA) added in (2) is further extended.
  5. The majority of viral RNA is degraded by RNAse H, leaving only the PP sequence.
  6. Synthesis of the second DNA strand begins, using the remaining PP fragment of viral RNA as a primer.
  7. The tRNA primer leaves and a "jump" happens. The PBS from the second strand hybridizes with the complementary PBS on the first strand.
  8. Both strands are extended to form a complete double-stranded DNA copy of the original viral RNA genome, which can then be incorporated into the host's genome by the enzyme integrase.

Creation of double-stranded DNA also involves strand transfer, in which there is a translocation of short DNA product from initial RNA-dependent DNA synthesis to acceptor template regions at the other end of the genome, which are later reached and processed by the reverse transcriptase for its DNA-dependent DNA activity. [11]

Retroviral RNA is arranged in 5’ terminus to 3’ terminus. The site where the primer is annealed to viral RNA is called the primer-binding site (PBS). The RNA 5’end to the PBS site is called U5, and the RNA 3’ end to the PBS is called the leader. The tRNA primer is unwound between 14 and 22 nucleotides and forms a base-paired duplex with the viral RNA at PBS. The fact that the PBS is located near the 5’ terminus of viral RNA is unusual because reverse transcriptase synthesize DNA from 3’ end of the primer in the 5’ to 3’ direction (with respect to the newly synthesized DNA strand). Therefore, the primer and reverse transcriptase must be relocated to 3’ end of viral RNA. In order to accomplish this reposition, multiple steps and various enzymes including DNA polymerase, ribonuclease H(RNase H) and polynucleotide unwinding are needed. [12] [13]

The HIV reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that copies the sense cDNA strand into an antisense DNA to form a double-stranded viral DNA intermediate (vDNA). [14]

Self-replicating stretches of eukaryotic genomes known as retrotransposons utilize reverse transcriptase to move from one position in the genome to another via an RNA intermediate. They are found abundantly in the genomes of plants and animals. Telomerase is another reverse transcriptase found in many eukaryotes, including humans, which carries its own RNA template this RNA is used as a template for DNA replication. [15]

Initial reports of reverse transcriptase in prokaryotes came as far back as 1971 in France (Beljanski et al., 1971a, 1972) and a few years later in the USSR (Romashchenko 1977 [16] ). These have since been broadly described as part of bacterial Retrons, distinct sequences that code for reverse transcriptase, and are used in the synthesis of msDNA. In order to initiate synthesis of DNA, a primer is needed. In bacteria, the primer is synthesized during replication. [17]

Valerian Dolja of Oregon State argues that viruses, due to their diversity, have played an evolutionary role in the development of cellular life, with reverse transcriptase playing a central role. [18]

The reverse transcriptase employs a "right hand" structure similar to that found in other viral nucleic acid polymerases. [19] [20] In addition to the transcription function, retroviral reverse transcriptases have a domain belonging to the RNase H family, which is vital to their replication. By degrading the RNA template, it allows the other strand of DNA to be synthesized. [21] Some fragments from the digestion also serve as the primer for the DNA polymerase (either the same enzyme or a host protein), responsible for making the other (plus) strand. [19]

There are three different replication systems during the life cycle of a retrovirus. The first process is the reverse transcriptase synthesis of viral DNA from viral RNA, which then forms newly made complementary DNA strands. The second replication process occurs when host cellular DNA polymerase replicates the integrated viral DNA. Lastly, RNA polymerase II transcribes the proviral DNA into RNA, which will be packed into virions. Mutation can occur during one or all of these replication steps. [22]

Reverse transcriptase has a high error rate when transcribing RNA into DNA since, unlike most other DNA polymerases, it has no proofreading ability. This high error rate allows mutations to accumulate at an accelerated rate relative to proofread forms of replication. The commercially available reverse transcriptases produced by Promega are quoted by their manuals as having error rates in the range of 1 in 17,000 bases for AMV and 1 in 30,000 bases for M-MLV. [23]

Other than creating single-nucleotide polymorphisms, reverse transcriptases have also been shown to be involved in processes such as transcript fusions, exon shuffling and creating artificial antisense transcripts. [24] [25] It has been speculated that this template switching activity of reverse transcriptase, which can be demonstrated completely in vivo, may have been one of the causes for finding several thousand unannotated transcripts in the genomes of model organisms. [26]

Template switching Edit

Two RNA genomes are packaged into each retrovirus particle, but, after an infection, each virus generates only one provirus. [27] After infection, reverse transcription is accompanied by template switching between the two genome copies (copy choice recombination). [27] There are two models that suggest why RNA transcriptase switches templates. The first, the forced copy-choice model, proposes that reverse transcriptase changes the RNA template when it encounters a nick, implying that recombination is obligatory to maintaining virus genome integrity. The second, the dynamic choice model, suggests that reverse transcriptase changes templates when the RNAse function and the polymerase function are not in sync rate-wise, implying that recombination occurs at random and is not in response to genomic damage. A study by Rawson et al. supported both models of recombination. [27] From 5 to 14 recombination events per genome occur at each replication cycle. [28] Template switching (recombination) appears to be necessary for maintaining genome integrity and as a repair mechanism for salvaging damaged genomes. [29] [27]

Antiviral drugs Edit

As HIV uses reverse transcriptase to copy its genetic material and generate new viruses (part of a retrovirus proliferation circle), specific drugs have been designed to disrupt the process and thereby suppress its growth. Collectively, these drugs are known as reverse-transcriptase inhibitors and include the nucleoside and nucleotide analogues zidovudine (trade name Retrovir), lamivudine (Epivir) and tenofovir (Viread), as well as non-nucleoside inhibitors, such as nevirapine (Viramune).

Molecular biology Edit

Reverse transcriptase is commonly used in research to apply the polymerase chain reaction technique to RNA in a technique called reverse transcription polymerase chain reaction (RT-PCR). The classical PCR technique can be applied only to DNA strands, but, with the help of reverse transcriptase, RNA can be transcribed into DNA, thus making PCR analysis of RNA molecules possible. Reverse transcriptase is used also to create cDNA libraries from mRNA. The commercial availability of reverse transcriptase greatly improved knowledge in the area of molecular biology, as, along with other enzymes, it allowed scientists to clone, sequence, and characterise RNA.

Reverse transcriptase has also been employed in insulin production. By inserting eukaryotic mRNA for insulin production along with reverse transcriptase into bacteria, the mRNA could be inserted into the prokaryote's genome. Large amounts of insulin can then be created, sidestepping the need to harvest pig pancreas and other such traditional sources. Directly inserting eukaryotic DNA into bacteria would not work because it carries introns, so would not translate successfully using the bacterial ribosomes. Processing in the eukaryotic cell during mRNA production removes these introns to provide a suitable template. Reverse transcriptase converts this edited RNA back into DNA so it could be incorporated in the genome.


Secondary structure of the segment 5 genomic RNA of influenza A virus and its application for designing antisense oligonucleotides

Influenza virus causes seasonal epidemics and dangerous pandemic outbreaks. It is a single stranded (-)RNA virus with a segmented genome. Eight segments of genomic viral RNA (vRNA) form the virion, which are then transcribed and replicated in host cells. The secondary structure of vRNA is an important regulator of virus biology and can be a target for finding new therapeutics. In this paper, the secondary structure of segment 5 vRNA is determined based on chemical mapping data, free energy minimization and structure-sequence conservation analysis for type A influenza. The revealed secondary structure has circular folding with a previously reported panhandle motif and distinct novel domains. Conservations of base pairs is 87% on average with many structural motifs that are highly conserved. Isoenergetic microarray mapping was used to additionally validate secondary structure and to discover regions that easy bind short oligonucleotides. Antisense oligonucleotides, which were designed based on modeled secondary structure and microarray mapping, inhibit influenza A virus proliferation in MDCK cells. The most potent oligonucleotides lowered virus titer by

90%. These results define universal for type A structured regions that could be important for virus function, as well as new targets for antisense therapeutics.

Conflict of interest statement

The authors declare no competing interests.

Figures

The influenza A virus vRNA5…

The influenza A virus vRNA5 nucleotides reactivity diagrams. The vRNA5 chemical mapping experiments…

Secondary structure of influenza A…

Secondary structure of influenza A vRNA5 predicted by RNAstructure 5.7 using experimental data…

Microarrays mapping results for vRNA5.…

Microarrays mapping results for vRNA5. Sites that strongly bind complementary probes and sites…

The probability of forming base…

The probability of forming base pairs and single-stranded regions in vRNA5. The probability…

Conservation of vRNA5 secondary structure…

Conservation of vRNA5 secondary structure in type A of influenza viruses. Colors indicate…

Binding sites of antisense oligonucleotides…

Binding sites of antisense oligonucleotides marked on vRNA5 secondary structure. Complementary regions for…

Antiviral activity of ASOs in…

Antiviral activity of ASOs in MDCK cells against A/California/04/2009. Antiviral activity was analyzed…

Antiviral activity of ASOs in…

Antiviral activity of ASOs in MDCK cells against A/California/04/2009. Antiviral activity was analyzed…


Watch the video: Viruses Updated (October 2022).