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Does soap kill human cells?

Does soap kill human cells?


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I see many products, particularly hand soap and cleaning products, that claim to kill 99.9% or more of bacteria.

This makes me wonder, if the chemicals are potent enough to break down bacterial cell membranes, can they also break down human cells? If not, why not?


salamander is right about triclosan being the active ingredient in antibacterial soap, but the reason why it doesn't kill human cells doesn't have anything to do with the skin. From salamander's same source:

Once they are in microbes cells, triclosan poisons a specific enzyme (enzymes are proteins that have particular functions, think of them as cellular machinery) that is used in making microbes cell membranes. Humans dont have this enzyme, so triclosan doesnt poison us.

The enzyme in question is called Enoyl-acyl carrier protein reductase (ENR), and is used by bacteria as part of their fatty acid synthesis. Eukaryotes use a different set of enzymes for fatty acid synthesis, so we aren't effected by this activity of triclosan.

For some more specifics about the interaction of triclosan and ENR, we can turn a study about the antibacterial mechanism of triclosan that was done soon after triclosan was first crystalized in situ with its target enzyme.

From Heath, et al (1999):

Triclosan is a broad-spectrum antibacterial agent that inhibits bacterial fatty acid synthesis at the enoyl-acyl carrier protein reductase (FabI) step… The ubiquitous occurrence of type II fatty acid synthase systems in bacteria and the essential nature of the FabI reaction make this enzyme an attractive target for antibacterial drugs. Accordingly, triclosan is effective against a broad spectrum of bacteria, including multi-drug-resistant Staphylococcus aureus.


Antibacterial soap commonly uses triclosan, which can pass through the phospholipid bilayer of bacteria and disrupt the production of essential enzymes, killing the bacteria (source). This triclosan would kill human body cells in the same way as it does bacteria, however we have a 1-1.5mm thick layer of dead skin cells(called the Stratum corneum) that exists to protect our epidermis from chemicals like antibacterial soap.

EDIT: I was absolutely wrong about triclosan killing human cells. In fact, it is impossible for triclosan to kill human cells, because the enzyme that is destroyed in bacteria by the triclosan does not exist in the human body.


What the coronavirus does to your body that makes it so deadly

Benjamin Neuman does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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The Conversation UK receives funding from these organisations

COVID-19 is caused by a coronavirus called SARS-CoV-2. Coronaviruses belong to a group of viruses that infect animals, from peacocks to whales. They’re named for the bulb-tipped spikes that project from the virus’s surface and give the appearance of a corona surrounding it.

A coronavirus infection usually plays out one of two ways: as an infection in the lungs that includes some cases of what people would call the common cold, or as an infection in the gut that causes diarrhea. COVID-19 starts out in the lungs like the common cold coronaviruses, but then causes havoc with the immune system that can lead to long-term lung damage or death.

SARS-CoV-2 is genetically very similar to other human respiratory coronaviruses, including SARS-CoV and MERS-CoV. However, the subtle genetic differences translate to significant differences in how readily a coronavirus infects people and how it makes them sick.

SARS-CoV-2 has all the same genetic equipment as the original SARS-CoV, which caused a global outbreak in 2003, but with around 6,000 mutations sprinkled around in the usual places where coronaviruses change. Think whole milk versus skim milk.

Compared to other human coronaviruses like MERS-CoV, which emerged in the Middle East in 2012, the new virus has customized versions of the same general equipment for invading cells and copying itself. However, SARS-CoV-2 has a totally different set of genes called accessories, which give this new virus a little advantage in specific situations. For example, MERS has a particular protein that shuts down a cell’s ability to sound the alarm about a viral intruder. SARS-CoV-2 has an unrelated gene with an as-yet unknown function in that position in its genome. Think cow milk versus almond milk.


Biology 171

By the end of this section, you will be able to do the following:

  • Explain the need for nitrogen fixation and how it is accomplished
  • Describe the beneficial effects of bacteria that colonize our skin and digestive tracts
  • Identify prokaryotes used during the processing of food
  • Describe the use of prokaryotes in bioremediation

Fortunately, only a few species of prokaryotes are pathogenic! Prokaryotes also interact with humans and other organisms in a number of ways that are beneficial. For example, prokaryotes are major participants in the carbon and nitrogen cycles. They produce or process nutrients in the digestive tracts of humans and other animals. Prokaryotes are used in the production of some human foods, and also have been recruited for the degradation of hazardous materials. In fact, our life would not be possible without prokaryotes!

Cooperation between Bacteria and Eukaryotes: Nitrogen Fixation

Nitrogen is a very important element to living things, because it is part of nucleotides and amino acids that are the building blocks of nucleic acids and proteins, respectively. Nitrogen is usually the most limiting element in terrestrial ecosystems, with atmospheric nitrogen, N2, providing the largest pool of available nitrogen. However, eukaryotes cannot use atmospheric, gaseous nitrogen to synthesize macromolecules. Fortunately, nitrogen can be “fixed,” meaning it is converted into a more accessible form—ammonia (NH3)—either biologically or abiotically.

Abiotic nitrogen fixation occurs as a result of physical processes such as lightning or by industrial processes. Biological nitrogen fixation (BNF) is exclusively carried out by prokaryotes: soil bacteria, cyanobacteria, and Frankia spp. (filamentous bacteria interacting with actinorhizal plants such as alder, bayberry, and sweet fern). After photosynthesis, BNF is the most important biological process on Earth. The overall nitrogen fixation equation below represents a series of redox reactions (Pi stands for inorganic phosphate).

The total fixed nitrogen through BNF is about 100 to 180 million metric tons per year, which contributes about 65 percent of the nitrogen used in agriculture.

Cyanobacteria are the most important nitrogen fixers in aquatic environments. In soil, members of the genera Clostridium and Azotobacter are examples of free-living, nitrogen-fixing bacteria. Other bacteria live symbiotically with legume plants, providing the most important source of fixed nitrogen. Symbionts may fix more nitrogen in soils than free-living organisms by a factor of 10. Soil bacteria, collectively called rhizobia, are able to symbiotically interact with legumes to form nodules , specialized structures where nitrogen fixation occurs ((Figure)). Nitrogenase, the enzyme that fixes nitrogen, is inactivated by oxygen, so the nodule provides an oxygen-free area for nitrogen fixation to take place. The oxygen is sequestered by a form of plant hemoglobin called leghemoglobin, which protects the nitrogenase, but releases enough oxygen to support respiratory activity.

Symbiotic nitrogen fixation provides a natural and inexpensive plant fertilizer: It reduces atmospheric nitrogen to ammonia, which is easily usable by plants. The use of legumes is an excellent alternative to chemical fertilization and is of special interest to sustainable agriculture, which seeks to minimize the use of chemicals and conserve natural resources. Through symbiotic nitrogen fixation, the plant benefits from using an endless source of nitrogen: the atmosphere. The bacteria benefit from using photosynthates (carbohydrates produced during photosynthesis) from the plant and having a protected niche. In addition, the soil benefits from being naturally fertilized. Therefore, the use of rhizobia as biofertilizers is a sustainable practice.

Why are legumes so important? Some, like soybeans, are key sources of agricultural protein. Some of the most important legumes consumed by humans are soybeans, peanuts, peas, chickpeas, and beans. Other legumes, such as alfalfa, are used to feed cattle.

The commensal bacteria that inhabit our skin and gastrointestinal tract do a host of good things for us. They protect us from pathogens, help us digest our food, and produce some of our vitamins and other nutrients. These activities have been known for a long time. More recently, scientists have gathered evidence that these bacteria may also help regulate our moods, influence our activity levels, and even help control weight by affecting our food choices and absorption patterns. The Human Microbiome Project has begun the process of cataloging our normal bacteria (and archaea) so we can better understand these functions.

A particularly fascinating example of our normal flora relates to our digestive systems. People who take high doses of antibiotics tend to lose many of their normal gut bacteria, allowing a naturally antibiotic-resistant species called Clostridium difficile to overgrow and cause severe gastric problems, especially chronic diarrhea ((Figure)). Obviously, trying to treat this problem with antibiotics only makes it worse. However, it has been successfully treated by giving the patients fecal transplants from healthy donors to reestablish the normal intestinal microbial community. Clinical trials are underway to ensure the safety and effectiveness of this technique.

Scientists are also discovering that the absence of certain key microbes from our intestinal tract may set us up for a variety of problems. This seems to be particularly true regarding the appropriate functioning of the immune system. There are intriguing findings that suggest that the absence of these microbes is an important contributor to the development of allergies and some autoimmune disorders. Research is currently underway to test whether adding certain microbes to our internal ecosystem may help in the treatment of these problems, as well as in treating some forms of autism.

Early Biotechnology: Cheese, Bread, Wine, Beer, and Yogurt

According to the United Nations Convention on Biological Diversity, biotechnology is “any technological application that uses biological systems, living organisms, or derivatives thereof, to make or modify products or processes for specific use.” 1 The concept of “specific use” involves some sort of commercial application. Genetic engineering, artificial selection, antibiotic production, and cell culture are current topics of study in biotechnology and will be described in later chapters. However, humans were using prokaryotes before the term biotechnology was even coined. Some of the products of this early biotechnology are as familiar as cheese, bread, wine, beer, and yogurt, which employ both bacteria and other microbes, such as yeast, a fungus ((Figure)).

Cheese production began around 4,000 to 7,000 years ago when humans began to breed animals and process their milk. Fermentation in this case preserves nutrients: Milk will spoil relatively quickly, but when processed as cheese, it is more stable. As for beer, the oldest records of brewing are about 6,000 years old and were an integral part of the Sumerian culture. Evidence indicates that the Sumerians discovered fermentation by chance. Wine has been produced for about 4,500 years, and evidence suggests that cultured milk products, like yogurt, have existed for at least 4,000 years.

Using Prokaryotes to Clean up Our Planet: Bioremediation

Microbial bioremediation is the use of prokaryotes (or microbial metabolism) to remove pollutants. Bioremediation has been used to remove agricultural chemicals (e.g., pesticides, fertilizers) that leach from soil into groundwater and the subsurface. Certain toxic metals and oxides, such as selenium and arsenic compounds, can also be removed from water by bioremediation. The reduction of SeO4 -2 to SeO3 -2 and to Se 0 (metallic selenium) is a method used to remove selenium ions from water. Mercury (Hg) is an example of a toxic metal that can be removed from an environment by bioremediation. As an active ingredient of some pesticides, mercury is used in industry and is also a by-product of certain processes, such as battery production. Methyl mercury is usually present in very low concentrations in natural environments, but it is highly toxic because it accumulates in living tissues. Several species of bacteria can carry out the biotransformation of toxic mercury into nontoxic forms. These bacteria, such as Pseudomonas aeruginosa, can convert Hg +2 into Hg 0 , which is nontoxic to humans.

One of the most useful and interesting examples of the use of prokaryotes for bioremediation purposes is the cleanup of oil spills. The significance of prokaryotes to petroleum bioremediation has been demonstrated in several oil spills in recent years, such as the Exxon Valdez spill in Alaska (1989) ((Figure)), the Prestige oil spill in Spain (2002), the spill into the Mediterranean from a Lebanon power plant (2006), and more recently, the BP oil spill in the Gulf of Mexico (2010). In the case of oil spills in the ocean, ongoing natural bioremediation tends to occur, since there are oil-consuming bacteria in the ocean prior to the spill. In addition to these naturally occurring oil-degrading bacteria, humans select and engineer bacteria that possess the same capability with increased efficacy and spectrum of hydrocarbon compounds that can be processed. Bioremediation is enhanced by the addition of inorganic nutrients that help bacteria to grow.

Some hydrocarbon-degrading bacteria feed on hydrocarbons in the oil droplet, breaking down the hydrocarbons into smaller subunits. Some species, such as Alcanivorax borkumensis, produce surfactants that solubilize the oil (making it soluble in water), whereas other bacteria degrade the oil into carbon dioxide. Under ideal conditions, it has been reported that up to 80 percent of the nonvolatile components in oil can be degraded within one year of the spill. Other oil fractions containing aromatic and highly branched hydrocarbon chains are more difficult to remove and remain in the environment for longer periods of time.

Section Summary

Pathogens are only a small percentage of all prokaryotes. In fact, prokaryotes provide essential services to humans and other organisms. Nitrogen, which is not usable by eukaryotes in its plentiful atmospheric form, can be “fixed,” or converted into ammonia (NH3) either biologically or abiotically. Biological nitrogen fixation (BNF) is exclusively carried out by prokaryotes, and constitutes the second most important biological process on Earth. Although some terrestrial nitrogen is fixed by free-living bacteria, most BNF comes from the symbiotic interaction between soil rhizobia and the roots of legume plants.

Human life is only possible due to the action of microbes, both those in the environment and those species that call us home. Internally, they help us digest our food, produce vital nutrients for us, protect us from pathogenic microbes, and help train our immune systems to function properly.

Microbial bioremediation is the use of microbial metabolism to remove pollutants. Bioremediation has been used to remove agricultural chemicals that leach from soil into groundwater and the subsurface. Toxic metals and oxides, such as selenium and arsenic compounds, can also be removed by bioremediation. Probably one of the most useful and interesting examples of the use of prokaryotes for bioremediation purposes is the cleanup of oil spills.

Free Response

Your friend believes that prokaryotes are always detrimental and pathogenic. How would you explain to them that they are wrong?

Remind them of the important roles prokaryotes play in decomposition and freeing up nutrients in biogeochemical cycles remind them of the many prokaryotes that are not human pathogens and that fill very specialized niches. Furthermore, our normal bacterial symbionts are crucial for our digestion and in protecting us from pathogens.

Many people use antimicrobial soap to kill bacteria on their hands. However, overuse may actually increase the risk of infection. How could this occur?

Soap indiscriminately kills bacteria on skin. This kills harmful bacteria, but can also eliminate “good” bacteria from the skin. When the non-pathogenic bacteria are eliminated, pathogenic bacteria can colonize the empty surface.

Footnotes

Glossary


Topical Agent Found To Kill Papillomavirus

HERSHEY, PA--A common surfactant and detergent found in many shampoos and toothpastes is the first topical microbicidal agent shown to kill animal and human papillomavirus, according to a Penn State researcher. Sodium dodecyl sulfate (SDS) was found in cell culture and animal testing to inactivate sexually transmitted viruses including human immunodeficiency virus (HIV), herpes simplex virus type 2 (HSV-2) and human papillomaviruses (HPVs). These viruses cause AIDS, genital herpes and genital warts, respectively.

"This is a major step toward our goal of producing a practical, non-toxic, inexpensive, discreet product which women can apply topically to the vagina prior to intercourse -- a product which would protect them from HPV infection even during encounters with infected partners," explains Mary K. Howett, Ph.D., professor of microbiology and immunology at Penn State's College of Medicine. "In the case of previously infected women, this agent could prevent them from transmitting the virus to their partners. In addition, this agent could be used alone or with other currently available microbicides or spermicides to prevent HSV-2 and HIV transmission."

Howett and her colleagues' work titled, "A Broad-Spectrum Microbicide with Virucidal Activity against Sexually Transmitted Viruses," is published in the February issue of the journal Antimicrobial Agents and Chemotherapy.

Howett says it will take at least several years before such products will be produced for use in humans. However, she adds that such products could greatly reduce cervical cancer.

Protection from genital wart viruses is important to public health because lesions caused by these viruses can progress to cancer, most notably cancer of the uterine cervix. This cancer causes 5,000 deaths per year in women in the U.S. In the developing world, cervical cancer is the number one cause of cancer related deaths in women. Worldwide, 250,000 women die annually from this form of cancer. Prevention of HPV infection could prevent most of these cancers. HPV infection may also lead to other cancers in the ano-genital tracts of women and men. HPV is frequently associated with vulvar and anal cancers. Prevention from transmission could also protect men and women from development of these cancers.

It is thought that about one in four women are infected by these viruses in the genital tract, with 1 to 3 percent of women showing overt signs of clinical infection upon gynecologic examination. Although most infected people do not develop cancer, individuals with HPV worry about infecting their partners, suffer from physical repercussions including possible loss of fertility and fear the development of cancer. Many people with HPV infection are unaware that they are infected. HPV infections occur commonly in adolescents and in people during their reproductive years. Lesions caused by these viruses are worse in immunocompromised people such as those with AIDS.

Howett and her colleagues are searching for partners to develop products that incorporate these anti-papillomavirus agents, alone or in combination with other microbicides. One such partnership has been established with Dan Malamud, Ph.D., and investigators at Biosyn, Inc. in Philadelphia to include SDS in products containing C31G, another potent microbicide under development by Biosyn.

The findings presented in this paper result from joint research efforts by investigators in the Departments of Microbiology and Immunology and Pathology and the Jake Gittlen Cancer Research Institute at The Milton S. Hershey Medical Center of the Penn State College of Medicine in Hershey, Pa. and investigators in the Department of Biochemistry at the University of Pennsylvania School of Dental Medicine, and at Biosyn, Inc. in Philadelphia, Pa.

The work was performed through funding provided by a Program Project Grant that was awarded to Penn State, the University of Pennsylvania, Biosyn, Inc. and the University of North Carolina by the National Institute of Allergy and Infectious Diseases, and from support provided by the Jake Gittlen Cancer Research Institute.

Story Source:

Materials provided by Penn State. Note: Content may be edited for style and length.


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Blue Animals Are Different From All the Rest

Paola Picotti, the biophysicist who led the study, explained that the experiments sprang from an old, thorny question: Why do some cells survive at high temperatures while others die? The bacterium Thermus thermophilus lives happily in hot springs and even in household hot water heaters, while E. coli withers above 40 degrees Celsius (104 degrees Fahrenheit). Strong evidence implies that differences in the stability of each organism’s proteins are involved. But looking at a protein’s behavior while it is still sitting in its living cell—the ideal way to understand it—is not easy. And isolating a protein in a test tube gives only partial answers, because within the organism, proteins nestle together, altering each other’s chemistry or holding each other in the right shape. To understand what is falling apart and why, you need to look at the proteins while they are still influencing each other.


(Lucy Reading-Ikkanda / Quanta Magazine)

To address this problem, the team devised a sprawling automated workflow in which they split open cells and heated up their contents in stages, unleashing protein-slicing enzymes on the mixtures at every stage. These enzymes are particularly good at slicing up proteins that have unfolded, so the researchers could tell by looking at the fragments which proteins fell apart at each temperature hike. In this way, they graphed an unfolding, or denaturing, curve for each of the thousands of proteins they studied, showing its arc as it moved from an intact structure at comfortable temperatures to a denatured state as the degrees ticked up. To see how these curves differed across species, they performed the process on cells from four species—humans, E. coli, T. thermophilus and yeast. “This is a beautiful study,” said Allan Drummond, a biologist at the University of Chicago, emphasizing both the scale and the delicacy of the process.

One of the clearest observations was that in each species, the proteins did not unfold en masse with a temperature boost. Instead, “we saw that only a small subset of proteins collapses very early,” Picotti said, “and these are key proteins.” In a network-style diagram of proteins’ interrelations, these fragile few are often highly connected, meaning that they influence numerous processes in the cell. “Without these the cell cannot function,” Picotti said. “When these are gone, the whole network most likely collapses.” And with it, evidently, the life of the cell.

This paradox—that some of the most important proteins seem to be the most delicate—may reflect how evolution has shaped them to do their jobs. If a protein has many roles to play, it might gain an advantage from being somewhat unstable and prone to unfolding and refolding, since this could allow it to assume various shapes appropriate to whatever its next target might be. “Many of these [key] proteins have high flexibility, which makes them more unstable,” but it may give them the versatility to bind to a variety of target molecules in the cell, Picotti explained. “That’s how they can perform their function, most likely. … It’s a trade-off.”

Looking more closely at E. coli, for which they had the cleanest data, the researchers also found a relationship between a protein’s abundance—how many copies of it are floating around the cell—and its stability. The more copies the cell made, they reported, the more heat it took to break a protein down. (Abundance, it should be noted, doesn’t necessarily correlate with being essential for life: some rare proteins are crucial.) This connection between abundance and sturdiness supports an idea that Drummond put forward a decade or so ago, concerning the cellular protein-making machinery’s tendency to make occasional errors. A mistake usually destabilizes a protein. If that protein happens to be a common one, produced by the hundreds or thousands in a cell daily, then misfolded copies made in large numbers could fatally clog the cell. It would behoove an organism to evolve versions of common proteins with extra stability built in, and the Picotti team’s data seem to reflect this.

To explore what qualities make a protein heat stable, the researchers compared the data from E. coli and T. thermophilus. E. coli proteins began to fall apart at 40 degrees Celsius and had mostly degraded by 70 degrees Celsius. But at that temperature, T. thermophilus proteins were just starting to get uncomfortable: Some of them continued to hold their shape up to at least 90 degrees Celsius. The team found that the T. thermophilus proteins tended to be shorter, and certain kinds of shapes and components cropped up more often in the most stable proteins.


Lucy Reading-Ikkanda / Quanta Magazine

These findings could help researchers design proteins with stabilities carefully tuned to their needs. In many industrial processes that involve bacteria, for instance, raising the temperature increases yield—but before too long the bacteria die from the trauma of heat. It will be interesting to see if we can stabilize a bacterium by making those few proteins that disintegrate early more resistant to temperature, Picotti said.

Beyond all these observations, however, the group’s wealth of information about how easily each protein unfolds has some biologists especially excited. A protein’s stability is a direct measure of how likely it is to form aggregates: clumps of unfolded proteins that stick to each other. Aggregates, often a nightmare for the cell, can interfere with essential tasks. For instance, they are implicated in some serious neurological conditions, such as Alzheimer’s disease, in which plaques of denatured proteins gum up the brain.

Paola Picotti, a biophysicist at ETH Zurich, found that cells die when heat unravels just a small number of proteins.
(Katrien Nowak)

But that doesn’t mean aggregation occurs only in individuals suffering from these conditions. On the contrary, investigators are realizing that it may be happening all the time, without obvious stressors, and that a healthy cell has ways of dealing with it. “I think this is increasingly recognized as a very common phenomenon,” said Michele Vendruscolo, a biochemist at the University of Cambridge. “Most proteins actually misfold and aggregate in the cellular environment. The most fundamental information obtained by Picotti is about the fraction of time in which any given protein is in its unfolded state. This fraction determines the degree to which it will aggregate.” Some proteins almost never unfold and aggregate, others do it only in certain situations, and still others do it constantly. The new paper’s detailed information will make it much easier to study why these differences exist and what they mean, he said. Some of the denaturing curves even show patterns that suggest the proteins were aggregating after they unfolded. “They’ve been able to monitor both steps—both the unfolding and the subsequent aggregations,” Vendruscolo said. “That’s the excitement of this study.”

While many scientists are interested in aggregates because of the damage they cause, some are thinking about the phenomenon from another angle. Drummond said it has become clear that some aggregates are not just wads of trash floating around the cell rather, they contain active proteins that continue to do their jobs.

Imagine that from a distance, you see smoke billowing out of a building, he said. All around it are forms that you take to be bodies, dragged from the wreckage. But if you get closer, you may find that they’re actually living people, who escaped from the burning building and are waiting for the emergency to pass. That’s what’s happening in the study of aggregates, Drummond said: Researchers are finding that instead of being casualties, proteins in aggregates may sometimes be survivors. “In fact, there is a whole field that is now exploding,” he said.

Rather than being just a sign of damage, the clumping may serve as a way for proteins to preserve their function when the going gets tough. It might help protect them from the surrounding environment, for instance. And when conditions improve, the proteins could leave the aggregates and refold themselves. “They have temperature-sensitive [shape] changes that, if you don’t look too closely, look like misfolding,” Drummond said. “But there’s something else going on.” In a 2015 Cell paper, he and collaborators identified 177 yeast proteins that seem to regain function after being cloistered in aggregates. In a paper that appeared this past March, his team found that altering one of these proteins so that it couldn’t aggregate actually caused serious problems for the cell.

All in all, this work suggests that proteins are curiously dynamic structures. At first they might look like rigid machines, at work on fixed tasks for which one specific shape suits them. But in fact, proteins may morph into several different forms in the course of their normal duty. And in times of need, their shapes may alter so radically that they look as though they are expiring, when they are really fortifying themselves. At the molecular level, life may consist of constantly coming together and falling apart.


How Heat Kills Cells

Above a certain temperature, a cell will collapse and die. One of the most straightforward explanations for this lack of heat hardiness is that the proteins essential to life — the ones that extract energy from food or sunlight, fend off invaders, destroy waste products and so on — often have beautifully precise shapes. They start as long strands, then fold into helixes, hairpins and other configurations, as dictated by the sequence of their components. These shapes play a huge role in what they do. Yet when things start to heat up, the bonds that keep protein structures together break: first the weaker ones, and then, as the temperature mounts, the stronger ones. It makes sense that a pervasive loss of protein structure would be lethal, but until recently, the details of how, or if, this kills overheated cells were unknown.

Now, however, in a true tour de force, biophysicists at ETH Zurich in Switzerland have examined the behavior of every protein in cells from four different organisms as heat increases. This study and its rich deposit of data, published recently in Science, reveal that at the temperature at which a cell dies — whether it’s a human cell or one from Escherichia coli — only a handful of key proteins fall apart. Moreover, a protein’s abundance in a cell seems to show an intriguing relationship to the protein’s stability. The studies offer a glimpse into the fundamental rules that govern the order and disorder of proteins — rules that, researchers are realizing, have implications far beyond the question of why heat kills.

Paola Picotti, the biophysicist who led the study, explained that the experiments sprang from an old, thorny question: Why do some cells survive at high temperatures while others die? The bacterium Thermus thermophilus lives happily in hot springs and even in household hot water heaters, while E. coli withers above 40 degrees Celsius (104 degrees Fahrenheit). Strong evidence implies that differences in the stability of each organism’s proteins are involved. But looking at a protein’s behavior while it is still sitting in its living cell — the ideal way to understand it — is not easy. And isolating a protein in a test tube gives only partial answers, because within the organism, proteins nestle together, altering each other’s chemistry or holding each other in the right shape. To understand what is falling apart and why, you need to look at the proteins while they are still influencing each other.

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Lucy Reading-Ikkanda/Quanta Magazine

To address this problem, the team devised a sprawling automated workflow in which they split open cells and heated up their contents in stages, unleashing protein-slicing enzymes on the mixtures at every stage. These enzymes are particularly good at slicing up proteins that have unfolded, so the researchers could tell by looking at the fragments which proteins fell apart at each temperature hike. In this way, they graphed an unfolding, or denaturing, curve for each of the thousands of proteins they studied, showing its arc as it moved from an intact structure at comfortable temperatures to a denatured state as the degrees ticked up. To see how these curves differed across species, they performed the process on cells from four species — humans, E. coli, T. thermophilus and yeast. “This is a beautiful study,” said Allan Drummond, a biologist at the University of Chicago, emphasizing both the scale and the delicacy of the process.

One of the clearest observations was that in each species, the proteins did not unfold en masse with a temperature boost. Instead, “we saw that only a small subset of proteins collapses very early,” Picotti said, “and these are key proteins.” In a network-style diagram of proteins’ interrelations, these fragile few are often highly connected, meaning that they influence numerous processes in the cell. “Without these the cell cannot function,” Picotti said. “When these are gone, the whole network most likely collapses.” And with it, evidently, the life of the cell.

This paradox — that some of the most important proteins seem to be the most delicate — may reflect how evolution has shaped them to do their jobs. If a protein has many roles to play, it might gain an advantage from being somewhat unstable and prone to unfolding and refolding, since this could allow it to assume various shapes appropriate to whatever its next target might be. “Many of these [key] proteins have high flexibility, which makes them more unstable,” but it may give them the versatility to bind to a variety of target molecules in the cell, Picotti explained. “That’s how they can perform their function, most likely. … It’s a trade-off.”

Looking more closely at E. coli, for which they had the cleanest data, the researchers also found a relationship between a protein’s abundance — how many copies of it are floating around the cell — and its stability. The more copies the cell made, they reported, the more heat it took to break a protein down. (Abundance, it should be noted, doesn’t necessarily correlate with being essential for life: some rare proteins are crucial.) This connection between abundance and sturdiness supports an idea that Drummond put forward a decade or so ago, concerning the cellular protein-making machinery’s tendency to make occasional errors. A mistake usually destabilizes a protein. If that protein happens to be a common one, produced by the hundreds or thousands in a cell daily, then misfolded copies made in large numbers could fatally clog the cell. It would behoove an organism to evolve versions of common proteins with extra stability built in, and the Picotti team’s data seem to reflect this.

To explore what qualities make a protein heat stable, the researchers compared the data from E. coli and T. thermophilus. E. coli proteins began to fall apart at 40 degrees Celsius and had mostly degraded by 70 degrees Celsius. But at that temperature, T. thermophilus proteins were just starting to get uncomfortable: Some of them continued to hold their shape up to at least 90 degrees Celsius. The team found that the T. thermophilus proteins tended to be shorter, and certain kinds of shapes and components cropped up more often in the stablest proteins.

Lucy Reading-Ikkanda/Quanta Magazine

These findings could help researchers design proteins with stabilities carefully tuned to their needs. In many industrial processes that involve bacteria, for instance, raising the temperature increases yield — but before too long the bacteria die from the trauma of heat. It will be interesting to see if we can stabilize a bacterium by making those few proteins that disintegrate early more resistant to temperature, Picotti said.

Beyond all these observations, however, the group’s wealth of information about how easily each protein unfolds has some biologists especially excited. A protein’s stability is a direct measure of how likely it is to form aggregates: clumps of unfolded proteins that stick to each other. Aggregates, often a nightmare for the cell, can interfere with essential tasks. For instance, they are implicated in some serious neurological conditions, such as Alzheimer’s disease, in which plaques of denatured proteins gum up the brain.

But that doesn’t mean aggregation occurs only in individuals suffering from these conditions. On the contrary, investigators are realizing that it may be happening all the time, without obvious stressors, and that a healthy cell has ways of dealing with it. “I think this is increasingly recognized as a very common phenomenon,” said Michele Vendruscolo, a biochemist at the University of Cambridge. “Most proteins actually misfold and aggregate in the cellular environment. The most fundamental information obtained by Picotti is about the fraction of time in which any given protein is in its unfolded state. This fraction determines the degree to which it will aggregate.” Some proteins almost never unfold and aggregate, others do it only in certain situations, and still others do it constantly. The new paper’s detailed information will make it much easier to study why these differences exist and what they mean, he said. Some of the denaturing curves even show patterns that suggest the proteins were aggregating after they unfolded. “They’ve been able to monitor both steps — both the unfolding and the subsequent aggregations,” Vendruscolo said. “That’s the excitement of this study.”

While many scientists are interested in aggregates because of the damage they cause, some are thinking about the phenomenon from another angle. Drummond said it has become clear that some aggregates are not just wads of trash floating around the cell rather, they contain active proteins that continue to do their jobs.

Imagine that from a distance, you see smoke billowing out of a building, he said. All around it are forms that you take to be bodies, dragged from the wreckage. But if you get closer, you may find that they’re actually living people, who escaped from the burning building and are waiting for the emergency to pass. That’s what’s happening in the study of aggregates, Drummond said: Researchers are finding that instead of being casualties, proteins in aggregates may sometimes be survivors. “In fact, there is a whole field that is now exploding,” he said.

Rather than being just a sign of damage, the clumping may serve as a way for proteins to preserve their function when the going gets tough. It might help protect them from the surrounding environment, for instance. And when conditions improve, the proteins could leave the aggregates and refold themselves. “They have temperature-sensitive [shape] changes that, if you don’t look too closely, look like misfolding,” Drummond said. “But there’s something else going on.” In a 2015 Cell paper, he and collaborators identified 177 yeast proteins that seem to regain function after being cloistered in aggregates. In a paper that appeared this past March, his team found that altering one of these proteins so that it couldn’t aggregate actually caused serious problems for the cell.

All in all, this work suggests that proteins are curiously dynamic structures. At first they might look like rigid machines, at work on fixed tasks for which one specific shape suits them. But in fact, proteins may morph into several different forms in the course of their normal duty. And in times of need, their shapes may alter so radically that they look as though they are expiring, when they are really fortifying themselves. At the molecular level, life may consist of constantly coming together and falling apart.


Contents

In early experiments on cell-mediated cytotoxicity against tumor target cells, both in cancer patients and animal models, investigators consistently observed what was termed a "natural" reactivity that is, a certain population of cells seemed to be able to lyse tumor cells without having been previously sensitized to them. The first published study to assert that untreated lymphoid cells were able to confer a natural immunity to tumors was performed by Dr. Henry Smith at the University of Leeds School of Medicine in 1966, [10] leading to the conclusion that the "phenomenon appear[ed] to be an expression of defense mechanisms to tumor growth present in normal mice." Other researchers had also made similar observations, but as these discoveries were inconsistent with the established model at the time, many initially considered these observations to be artifacts. [11]

By 1973, 'natural killing' activity was established across a wide variety of species, and the existence of a separate lineage of cells possessing this ability was postulated. The discovery that a unique type of lymphocyte was responsible for "natural" or spontaneous cytotoxicity was made in the early 1970s by doctoral student Rolf Kiessling and postdoctoral fellow Hugh Pross, in the mouse, [12] and by Hugh Pross and doctoral student Mikael Jondal in the human. [13] [14] The mouse and human work was carried out under the supervision of professors Eva Klein and Hans Wigzell, respectively, of the Karolinska Institute, Stockholm. Kiessling's research involved the well-characterized ability of T lymphocytes to lyse tumor cells against which they had been previously immunized. Pross and Jondal were studying cell-mediated cytotoxicity in normal human blood and the effect of the removal of various receptor-bearing cells on this cytotoxicity. Later that same year, Ronald Herberman published similar data with respect to the unique nature of the mouse effector cell. [15] The human data were confirmed, for the most part, by West et al. [16] using similar techniques and the same erythroleukemic target cell line, K562. K562 is highly sensitive to lysis by human NK cells and, over the decades, the K562 51 chromium-release assay has become the most commonly used assay to detect human NK functional activity. [17] Its almost universal use has meant that experimental data can be compared easily by different laboratories around the world.

Using discontinuous density centrifugation, and later monoclonal antibodies, natural killing ability was mapped to the subset of large, granular lymphocytes known today as NK cells. The demonstration that density gradient-isolated large granular lymphocytes were responsible for human NK activity, made by Timonen and Saksela in 1980, [18] was the first time that NK cells had been visualized microscopically, and was a major breakthrough in the field.

NK cells can be classified as CD56 bright or CD56 dim . [19] [20] [3] CD56 bright NK cells are similar to T helper cells in exerting their influence by releasing cytokines. [20] CD56 bright NK cells constitute the majority of NK cells, being found in bone marrow, secondary lymphoid tissue, liver, and skin. [3] CD56 dim NK cells are primarily found in the peripheral blood, [3] and are characterized by their cell killing ability. [20] CD56 dim NK cells are always CD16 positive (CD16 is the key mediator of antibody-dependent cellular cytotoxicity (ADCC). [20] CD56 bright can transition into CD56 dim by acquiring CD16. [3]

NK cells can eliminate virus-infected cells via CD16-mediated ADCC. [21] All coronavirus disease 2019 (COVID-19) patients show depleted CD56 bright NK cells, but CD56 dim is only depleted in patients with severe COVID-19. [21]

NK cell receptors can also be differentiated based on function. Natural cytotoxicity receptors directly induce apoptosis (cell death) after binding to Fas ligand that directly indicate infection of a cell. The MHC-independent receptors (described above) use an alternate pathway to induce apoptosis in infected cells. Natural killer cell activation is determined by the balance of inhibitory and activating receptor stimulation. For example, if the inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited similarly, if the activating signal is dominant, then NK cell activation will result. [22]

NK cell receptor types (with inhibitory, as well as some activating members) are differentiated by structure, with a few examples to follow:

Activating receptors Edit

  • Ly49(homodimers), relatively ancient, C-type lectin family receptors, are of multigenic presence in mice, while humans have only one pseudogenic Ly49, the receptor for classical (polymorphic) MHC I molecules.
  • NCR (natural cytotoxicity receptors), type 1 transmembrane proteins of the immunoglobulin superfamily, upon stimulation mediate NK killing and release of IFNγ. They bind viral ligands such as hemagglutinins and hemagglutinin neuraminidases, some bacterial ligands and cellular ligands related to tumour growth such as PCNA.
  • CD16 (FcγIIIA) plays a role in antibody-dependent cell-mediated cytotoxicity in particular, they bind Immunoglobulin G.

Inhibitory receptors Edit

    (KIRs) belong to a multigene family of more recently evolved Ig-like extracellular domain receptors they are present in nonhuman primates, and are the main receptors for both classical MHC I (HLA-A, HLA-B, HLA-C) and nonclassical Mamu-G (HLA-G) in primates. Some KIRs are specific for certain HLA subtypes. Most KIRs are inhibitory and dominant. Regular cells express MHC class 1, so are recognised by KIR receptors and NK cell killing is inhibited. [5]
  • CD94/NKG2 (heterodimers), a C-type lectin family receptor, is conserved in both rodents and primates and identifies nonclassical (also nonpolymorphic) MHC I molecules such as HLA-E. Expression of HLA-E at the cell surface is dependent on the presence of nonamer peptide epitope derived from the signal sequence of classical MHC class I molecules, which is generated by the sequential action of signal peptide peptidase and the proteasome. Though indirect, this is a way to survey the levels of classical (polymorphic) HLA molecules.
  • ILT or LIR (immunoglobulin-like receptor) — are recently discovered members of the Ig receptor family.
  • Ly49 (homodimers) have both activating and inhibitory isoforms. They are highly polymorphic on the population level though they are structurally unrelated to KIRs, they are the functional homologues of KIRs in mice, including the expression pattern. Ly49s are receptor for classical (polymorphic) MHC I molecules.

Cytolytic granule mediated cell apoptosis Edit

NK cells are cytotoxic small granules in their cytoplasm contain proteins such as perforin and proteases known as granzymes. Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through which the granzymes and associated molecules can enter, inducing either apoptosis or osmotic cell lysis. The distinction between apoptosis and cell lysis is important in immunology: lysing a virus-infected cell could potentially release the virions, whereas apoptosis leads to destruction of the virus inside. α-defensins, antimicrobial molecules, are also secreted by NK cells, and directly kill bacteria by disrupting their cell walls in a manner analogous to that of neutrophils. [5]

Antibody-dependent cell-mediated cytotoxicity (ADCC) Edit

Infected cells are routinely opsonized with antibodies for detection by immune cells. Antibodies that bind to antigens can be recognised by FcγRIII (CD16) receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis. This is a major killing mechanism of some monoclonal antibodies like rituximab (Rituxan), ofatumumab (Azzera), and others. The contribution of antibody-dependent cell-mediated cytotoxicity to tumor cell killing can be measured with a specific test that uses NK-92, an immortal line of NK-like cells licensed to NantKwest, Inc.: the response of NK-92 cells that have been transfected with a high-affinity Fc receptor are compared to that of the "wild type" NK-92 which does not express the Fc receptor. [23]

Cytokine-induced NK and Cytotoxic T lymphocyte (CTL) activation Edit

Cytokines play a crucial role in NK cell activation. As these are stress molecules released by cells upon viral infection, they serve to signal to the NK cell the presence of viral pathogens in the affected area. Cytokines involved in NK activation include IL-12, IL-15, IL-18, IL-2, and CCL5. NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response generates antigen-specific cytotoxic T cells that can clear the infection. NK cells work to control viral infections by secreting IFNγ and TNFα. IFNγ activates macrophages for phagocytosis and lysis, and TNFα acts to promote direct NK tumor cell killing. Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection.

Missing 'self' hypothesis Edit

For NK cells to defend the body against viruses and other pathogens, they require mechanisms that enable the determination of whether a cell is infected or not. The exact mechanisms remain the subject of current investigation, but recognition of an "altered self" state is thought to be involved. To control their cytotoxic activity, NK cells possess two types of surface receptors: activating receptors and inhibitory receptors, including killer-cell immunoglobulin-like receptors. Most of these receptors are not unique to NK cells and can be present in some T cell subsets, as well.

The inhibitory receptors recognize MHC class I alleles, which could explain why NK cells preferentially kill cells that possess low levels of MHC class I molecules. This mode of NK cell target interaction is known as "missing-self recognition", a term coined by Klas Kärre and co-workers in the late 90s. MHC class I molecules are the main mechanism by which cells display viral or tumor antigens to cytotoxic T cells. A common evolutionary adaptation to this is seen in both intracellular microbes and tumors: the chronic down-regulation of MHC I molecules, which makes affected cells invisible to T cells, allowing them to evade T cell-mediated immunity. NK cells apparently evolved as an evolutionary response to this adaptation (the loss of the MHC eliminates CD4/CD8 action, so another immune cell evolved to fulfill the function). [24]

Tumor cell surveillance Edit

Natural killer cells often lack antigen-specific cell surface receptors, so are part of innate immunity, i.e. able to react immediately with no prior exposure to the pathogen. In both mice and humans, NKs can be seen to play a role in tumor immunosurveillance by directly inducing the death of tumor cells (NKs act as cytolytic effector lymphocytes), even in the absence of surface adhesion molecules and antigenic peptides. This role of NK cells is critical to immune success particularly because T cells are unable to recognize pathogens in the absence of surface antigens. [2] Tumor cell detection results in activation of NK cells and consequent cytokine production and release.

If tumor cells do not cause inflammation, they will also be regarded as self and will not induce a T cell response. A number of cytokines are produced by NKs, including tumor necrosis factor α (TNFα), IFNγ, and interleukin (IL-10). TNFα and IL-10 act as proinflammatory and immunosuppressors, respectively. The activation of NK cells and subsequent production of cytolytic effector cells impacts macrophages, dendritic cells, and neutrophils, which subsequently enables antigen-specific T and B cell responses. Instead of acting via antigen-specific receptors, lysis of tumor cells by NK cells is mediated by alternative receptors, including NKG2D, NKp44, NKp46, NKp30, and DNAM. [22] NKG2D is a disulfide-linked homodimer which recognizes a number of ligands, including ULBP and MICA, which are typically expressed on tumor cells. The role of dendritic cell—NK cell interface in immunobiology have been studied and defined as critical for the comprehension of the complex immune system. [ citation needed ]

NK cells, along with macrophages and several other cell types, express the Fc receptor (FcR) molecule (FC-gamma-RIII = CD16), an activating biochemical receptor that binds the Fc portion of IgG class antibodies. This allows NK cells to target cells against which a humoral response has been gone through and to lyse cells through antibody-dependant cytotoxicity (ADCC). This response depends on the affinity of the Fc receptor expressed on NK cells, which can have high, intermediate, and low affinity for the Fc portion of the antibody. This affinity is determined by the amino acid in position 158 of the protein, which can be phenylalanine (F allele) or valine (V allele). Individuals with high-affinity FcRgammRIII (158 V/V allele) respond better to antibody therapy. This has been shown for lymphoma patients who received the antibody Rituxan. Patients who express the 158 V/V allele had a better antitumor response. Only 15–25% of the population expresses the 158 V/V allele. To determine the ADCC contribution of monoclonal antibodies, NK-92 cells (a "pure" NK cell line) has been transfected with the gene for the high-affinity FcR.

Clearance of senescent cells Edit

Natural killer cells (NK cells) and macrophages play a major role in clearance of senescent cells. [25] Natural killer cells directly kill senescent cells, and produce cytokines which activate macrophages which remove senescent cells. [25]

Natural killer cells can use NKG2D receptors to detect senescent cells, and kill those cells using perforin pore-forming cytolytic protein. [26] CD8+ cytotoxic T-lymphocytes also use NKG2D receptors to detect senescent cells, and promote killing similar to NK cells. [26]

Adaptive features of NK cells—"memory-like", "adaptive" and memory NK cells Edit

The ability to generate memory cells following a primary infection and the consequent rapid immune activation and response to succeeding infections by the same antigen is fundamental to the role that T and B cells play in the adaptive immune response. For many years, NK cells have been considered to be a part of the innate immune system. However, recently increasing evidence suggests that NK cells can display several features that are usually attributed to adaptive immune cells (e.g. T cell responses) such as dynamic expansion and contraction of subsets, increased longevity and a form of immunological memory, characterized by a more potent response upon secondary challenge with the same antigen. [27] [28] In mice, the majority of research was carried out with murine cytomegalovirus (MCMV) and in models of hapten-hypersensitivity reactions. Especially, in the MCMV model, protective memory functions of MCMV-induced NK cells were discovered [29] and direct recognition of the MCMV-ligand m157 by the receptor Ly49 was demonstrated to be crucial for the generation of adaptive NK cell responses. [29] In humans, most studies have focused on the expansion of an NK cell subset carrying the activating receptor NKG2C (KLRC2). Such expansions were observed primarily in response to human cytomegalovirus (HCMV), [30] but also in other infections including Hantavirus, Chikungunya virus, HIV, or viral hepatitis. However, whether these virus infections trigger the expansion of adaptive NKG2C+ NK cells or whether other infections result in re-activation of latent HCMV (as suggested for hepatitis [31] ), remains a field of study. Notably, recent research suggests that adaptive NK cells can use the activating receptor NKG2C (KLRC2) to directly bind to human cytomegalovirus-derived peptide antigens and respond to peptide recognition with activation, expansion, and differentiation, [32] a mechanism of responding to virus infections that was previously only known for T cells of the adaptive immune system.

NK cell function in pregnancy Edit

As the majority of pregnancies involve two parents who are not tissue-matched, successful pregnancy requires the mother's immune system to be suppressed. NK cells are thought to be an important cell type in this process. [33] These cells are known as "uterine NK cells" (uNK cells) and they differ from peripheral NK cells. They are in the CD56 bright NK cell subset, potent at cytokine secretion, but with low cytotoxic ability and relatively similar to peripheral CD56 bright NK cells, with a slightly different receptor profile. [33] These uNK cells are the most abundant leukocytes present in utero in early pregnancy, representing about 70% of leukocytes here, but from where they originate remains controversial. [34]

These NK cells have the ability to elicit cell cytotoxicity in vitro, but at a lower level than peripheral NK cells, despite containing perforin. [35] Lack of cytotoxicity in vivo may be due to the presence of ligands for their inhibitory receptors. Trophoblast cells downregulate HLA-A and HLA-B to defend against cytotoxic T cell-mediated death. This would normally trigger NK cells by missing self recognition however, these cells survive. The selective retention of HLA-E (which is a ligand for NK cell inhibitory receptor NKG2A) and HLA-G (which is a ligand for NK cell inhibitory receptor KIR2DL4) by the trophoblast is thought to defend it against NK cell-mediated death. [33]

Uterine NK cells have shown no significant difference in women with recurrent miscarriage compared with controls. However, higher peripheral NK cell percentages occur in women with recurrent miscarriages than in control groups. [36]

NK cells secrete a high level of cytokines which help mediate their function. NK cells interact with HLA-C to produce cytokines necessary for trophoblastic proliferation. Some important cytokines they secrete include TNF-α, IL-10, IFN-γ, GM-CSF and TGF-β, among others. [33] For example, IFN-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. [37]

NK cell evasion by tumor cells Edit

By shedding decoy NKG2D soluble ligands, tumor cells may avoid immune responses. These soluble NKG2D ligands bind to NK cell NKG2D receptors, activating a false NK response and consequently creating competition for the receptor site. [2] This method of evasion occurs in prostate cancer. In addition, prostate cancer tumors can evade CD8 cell recognition due to their ability to downregulate expression of MHC class 1 molecules. This example of immune evasion actually highlights NK cells' importance in tumor surveillance and response, as CD8 cells can consequently only act on tumor cells in response to NK-initiated cytokine production (adaptive immune response). [38]

Excessive NK cells Edit

Experimental treatments with NK cells have resulted in excessive cytokine production, and even septic shock. Depletion of the inflammatory cytokine interferon gamma reversed the effect. [ citation needed ]

Anticancer therapy Edit

Since NK cells recognize target cells when they express nonself HLA antigens (but not self), autologous (patients' own) NK cell infusions have not shown any antitumor effects. Instead, investigators are working on using allogeneic cells from peripheral blood, which requires that all T cells be removed before infusion into the patients to remove the risk of graft versus host disease, which can be fatal. This can be achieved using an immunomagnetic column (CliniMACS). In addition, because of the limited number of NK cells in blood (only 10% of lymphocytes are NK cells), their number needs to be expanded in culture. This can take a few weeks and the yield is donor-dependent. A simpler way to obtain high numbers of pure NK cells is to expand NK-92 cells whose cells continuously grow in culture and can be expanded to clinical grade numbers in bags or bioreactors. [39] Clinical studies have shown it to be well tolerated and some antitumor responses have been seen in patients with lung cancer, melanoma, and lymphoma. [40] [41] However, there are significant limitations associated with NK-92 immunotherapy, as the cell line was derived from a patient with non-Hodgkin lymphoma and thus must be irradiated prior to infusion, thus limiting persistence in vivo. Furthermore, NK-92 cells lack CD-16, making them unable to perform ADCC, preventing this therapy from being used in combination with monoclonal antibody therapies. [42] They can, however, be engineered to include CD16 thus enabling ADCC function and expanding their potential therapeutic utility.

Infusions of T cells engineered to express a chimeric antigen receptor (CAR) that recognizes an antigen molecule on leukemia cells could induce remissions in patients with advanced leukemia. Logistical challenges are present for expanding T cells and investigators are working on applying the same technology to peripheral blood NK cells and NK-92. NK-92 cells can be engineered to include both CD16 and CARs to allow them to perform both ADCC mediated killing via IgG1 antibodies and CAR mediated killing from the same cell. One such NK-92 derived cell line called t-haNK has been engineered with both CD16 and an anti-PD-L1 CAR and is currently in clinical development for oncology indications. NK-92.

In a study at Boston Children's Hospital, in coordination with Dana-Farber Cancer Institute, in which immunocompromised mice had contracted lymphomas from EBV infection, an NK-activating receptor called NKG2D was fused with a stimulatory Fc portion of the EBV antibody. The NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients. In a transplantation model of LMP1-fueled lymphomas, the NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients.

In Hodgkin lymphoma, in which the malignant Hodgkin Reed-Sternberg cells are typically HLA class I deficient, immune evasion is in part mediated by skewing towards an exhausted PD-1hi NK cell phenotype, and re-activation of these NK cells appears to be one mechanism of action induced by checkpoint-blockade. [43]

Innate resistance to HIV Edit

Recent research suggests specific KIR-MHC class I gene interactions might control innate genetic resistance to certain viral infections, including HIV and its consequent development of AIDS. [5] Certain HLA allotypes have been found to determine the progression of HIV to AIDS an example is the HLA-B57 and HLA-B27 alleles, which have been found to delay progression from HIV to AIDS. This is evident because patients expressing these HLA alleles are observed to have lower viral loads and a more gradual decline in CD4 + T cells numbers. Despite considerable research and data collected measuring the genetic correlation of HLA alleles and KIR allotypes, a firm conclusion has not yet been drawn as to what combination provides decreased HIV and AIDS susceptibility.

NK cells can impose immune pressure on HIV, which had previously been described only for T cells and antibodies. [44] HIV mutates to avoid NK cell detection. [44]

Tissue-resident NK cells Edit

Most of our current knowledge is derived from investigations of mouse splenic and human peripheral blood NK cells. However, in recent years tissue-resident NK cell populations have been described. [45] [46] These tissue-resident NK cells share transcriptional similarity to tissue-resident memory T cells described previously. However, tissue-resident NK cells are not necessarily of the memory phenotype, and in fact, majority of the tissue-resident NK cells functionally immature. [47] These specialized NK-cell subsets can play a role in organ homeostasis. For example, NK cells are enriched in the human liver with a specific phenotype and take part in the control of liver fibrosis. [48] [49] Tissue-resident NK cells have also been identified in sites like bone marrow, spleen and more recently, in lung, intestines and lymph nodes. In these sites, tissue-resident NK cells may act as reservoir for maintaining immature NK cells in humans throughout life. [47]


The coronavirus is no match for plain, old soap — here’s the science behind it

This is how soap removes dirt, and bacteria, from the skin.

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Why does soap work so well on the new coronavirus and, indeed, most viruses? Because it is a self-assembled nanoparticle in which the weakest link is the lipid (fatty) bilayer.

That sounds scientific. Let me explain.

Soap dissolves the fat membrane, and the virus falls apart like a house of cards and “dies,” or rather, it becomes inactive as viruses aren’t really alive. Viruses can be active outside the body for hours, even days.

Disinfectants, or liquids, wipes, gels and creams containing alcohol (and soap) have a similar effect but are not as good as regular soap. Apart from alcohol and soap, antibacterial agents in those products don’t affect the virus structure much. Consequently, many antibacterial products are basically just an expensive version of soap in how they act on viruses. Soap is the best, but alcohol wipes are good when soap is not practical or handy, for example in office reception areas.

&ldquo Soap outcompetes the interactions between the virus and the skin surface, and the virus gets detached and falls apart like a house of cards. &rdquo

Supramolecular chemistry

But why, exactly, is soap so good? To explain that, I will take you through a journey of supramolecular chemistry, nanoscience and virology. I will try to explain this in generic terms, which means leaving out special chemistry terms. (I must point out that, while I am an expert in supramolecular chemistry and the assembly of nanoparticles, I am not a virologist.)

I have always been fascinated by viruses, as I see them as one of them most spectacular examples of how supramolecular chemistry and nanoscience converge.

Most viruses consist of three key building blocks: RNA, proteins and lipids.The RNA is the viral genetic material — it is similar to DNA. The proteins have several roles, including breaking into the target cell, assisting with virus replication and basically being a key building block (like a brick in a house) in the virus structure.

The lipids then form a coat around the virus, both for protection and to assist with its spread and cellular invasion. The RNA, proteins and lipids self-assemble to form the virus. Critically, there are no strong “covalent” bonds holding these units together.

Instead, the viral self-assembly is based on weak “non-covalent” interactions between the proteins, RNA and lipids. Together, these act together like Velcro, so it is hard to break up the self-assembled viral particle. Still, we can do it — with soap!

Most viruses, including the coronavirus, are between 50-200 nanometers — so they truly are nanoparticles. Nanoparticles have complex interactions with surfaces they are on it’s the same with viruses. Skin, steel, timber, fabric, paint and porcelain are very different surfaces.

When a virus invades a cell, the RNA “hijacks” the cellular machinery like a computer virus and forces the cell to make fresh copies of its own RNA and the various proteins that make up the virus.

These new RNA and protein molecules self-assemble with lipids (readily present in the cell) to form new copies of the virus. That is, the virus does not photocopy itself it makes copies of the building blocks, which then self-assemble into new viruses.

All those new viruses eventually overwhelm the cell, and it dies or explodes, releasing viruses that then go on to infect more cells. In the lungs, viruses end up in the airways and mucous membranes.

When you cough, or especially when you sneeze, tiny droplets from the airways can fly up to 30 feet. The larger ones are thought to be main coronavirus carriers, and they can go at least 7 feet. So, cover your coughs and sneezes!

Skin is an ideal surface for viruses

These tiny droplets end up on surfaces and dry out quickly. But the viruses are still active. What happens next is all about supramolecular chemistry and how self-assembled nanoparticles (like the viruses) interact with their environment.

Now it is time to introduce a powerful supramolecular chemistry concept that effectively says: Similar molecules appear to interact more strongly with each other than dissimilar ones. Wood, fabric and skin interact fairly strongly with viruses.

Contrast this with steel, porcelain and at least some plastics, such as Teflon. The surface structure also matters. The flatter the surface, the less the virus will “stick” to the surface. Rougher surfaces can actually pull the virus apart.

So why are surfaces different? The virus is held together by a combination of hydrogen bonds (like those in water) and hydrophilic, or “fat-like,” interactions. The surface of fibers or wood, for instance, can form a lot of hydrogen bonds with the virus.

In contrast, steel, porcelain or Teflon do not form much of a hydrogen bond with the virus. So the virus is not strongly bound to those surfaces and is quite stable.

For how long does the virus stay active? It depends. The novel coronavirus is thought to stay active on favorable surfaces for hours, possibly a day. What makes the virus less stable? Moisture (“dissolves”), sunlight (UV light) and heat (molecular motions).

The skin is an ideal surface for a virus. It is organic, of course, and the proteins and fatty acids in the dead cells on the surface interact with the virus through both hydrogen bonds and the “fat-like” hydrophilic interactions.

So when you touch a steel surface with a virus particle on it, it will stick to your skin and, hence, get transferred on to your hands. But you are not (yet) infected. If you touch your face, though, the virus can get transferred.

And now the virus is dangerously close to the airways and the mucus-type membranes in and around your mouth and eyes. So the virus can get in and — voila! — you are infected. That is, unless your immune system kills the virus.

If the virus is on your hands, you can pass it on by shaking someone’s else hand. Kisses, well, that’s pretty obvious. It goes without saying that if someone sneezes in your face, you’re stuck.

So how often do you touch your face? It turns out most people touch the face once every two to five minutes. So you’re at high risk once the virus gets on your hands, unless you wash off the active virus.

So let’s try washing it off with plain water. It might just work. But water “only” competes with the strong “glue-like” interactions between the skin and virus via hydrogen bonds. The virus is sticky and may not budge. Water isn’t enough.

Soap dissolves a virus’ structure

Soapy water is totally different. Soap contains fat-like substances known as amphiphiles, some structurally similar to the lipids in the virus membrane. The soap molecules “compete” with the lipids in the virus membrane. That is more or less how soap also removes normal dirt of the skin (see graphic at the top of this article).

The soap molecules also compete with a lot other non-covalent bonds that help the proteins, RNA and the lipids to stick together. The soap is effectively “dissolving” the glue that holds the virus together. Add to that all the water.

The soap also outcompetes the interactions between the virus and the skin surface. Soon the virus gets detached and falls apart like a house of cards due to the combined action of the soap and water. Boom, the virus is gone!

The skin is rough and wrinkly, which is why you need a fair amount of rubbing and soaking to ensure the soap reaches every nook and cranny on the skin surface that could be hiding active viruses.

Alcohol-based products include all “disinfectants” and “antibacterial” products that contain a high share of alcohol solution, typically 60%-80% ethanol, sometimes with a bit of isopropanol, water and a bit of soap.

Ethanol and other types of alcohol do not only readily form hydrogen bonds with the virus material but, as a solvent, are more lipophilic than water. Hence, alcohol does dissolve the lipid membrane and disrupt other supramolecular interactions in the virus.

However, you need a fairly high concentration (maybe 60%-plus) of the alcohol to get a rapid dissolution of the virus. Vodka or whiskey (usually 40% ethanol) won’t dissolve the virus as quickly. Overall, alcohol is not as good as soap at this task.

Nearly all antibacterial products contain alcohol and some soap, and that does help kill viruses. But some also include “active” bacterial killing agents, such as triclosan. Those, however, do basically nothing to the virus.

Alcohol works — to a degree

To sum up, viruses are almost like grease-nanoparticles. They can stay active for many hours on surfaces and then get picked up by touch. Then they get to our face and infect us because most of us touch our face frequently.

Water is not effective alone in washing the virus off our hands. Alcohol-based products work better. But nothing beats soap — the virus detaches from the skin and falls apart readily in soapy water.

Supramolecular chemistry and nanoscience tell us not only a lot about how the virus self-assembles into a functional, active menace, but also how we can beat viruses with something as simple as soap.

Palli Thordarson is a professor at the School of Chemistry at the University of New South Wales, Sydney. Follow him on Twitter and Facebook.


How Do Cytotoxic Lymphocytes Kill Cancer Cells?

In the past few years, cancer immunotherapy has emerged as a safe and effective alternative for treatment of cancers that do not respond to classical treatments, including those types with high aggressiveness. New immune modulators, such as cytokines, blockers of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1(programmed cell death protein 1)/PD-L1 (programmed death-ligand 1), and interaction or adoptive cell therapy, have been developed and approved to treat solid and hematologic carcinomas. In these scenarios, cytotoxic lymphocytes (CL), mainly cytotoxic T cells (Tc) and natural killer (NK) cells, are ultimately responsible for killing the cancer cells and eradicating the tumor. Extensive studies have been conducted to assess how Tc and NK cells get activated and recognize the cancer cell. In contrast, few studies have focused on the effector molecules used by CLs to kill cancer cells during cancer immunosurveillance and immunotherapy. In this article, the two main pathways involved in CL-mediated tumor cell death, granule exocytosis (perforin and granzymes) and death ligands, are briefly introduced, followed by a critical discussion of the molecules involved in cell death during cancer immunosurveillance and immunotherapy. This discussion also covers unexpected consequences of proinflammatory and survival effects of granzymes and death ligands and recent experimental evidence indicating that perforin and granzymes of CLs can activate nonapoptotic pathways of cell death, overcoming apoptosis defects and chemoresistance. The consequences of apoptosis versus other modalities of cell death for an effective treatment of cancer by modulating the patient immune system are also briefly discussed. See all articles in this CCR Focus section, "Cell Death and Cancer Therapy."


Show/hide words to know

Antibody: a molecule made by B-cells to trap foreign particles and microbes. more

Antigen: a molecule that can be recognized by the immune system. more

Bacteria: one-celled, microscopic organisms that grow and multiply everywhere on Earth. They can be either useful or harmful to animals. more

Cytokine: a chemical released by cells in the immune system that helps coordinate an immune response by sending messages to specific cells. more

Immune system: all the cells, tissues, and organs involved in fighting infection or disease in the body. more

Microbe: a living thing so tiny that you would need a microscope to see it. more

Receptor: a molecule on the surface of a cell that responds to specific molecules and receives chemical signals sent by other cells.

Friend or foe? Identifying invaders and bandits

The human body has the ability to recognize millions of different enemies. Our built-in “defense force” is called the immune system. Different parts of the system can produce cells and powerful chemicals called cytokines. These cells and cytokines match up with and destroy bacteria and other invaders. Millions and millions of immune system cells are organized into sets and subsets. These groups of cells pass information back and forth.

The chemical substances produced by these cells function as an internal alarm system. Their message is simple: “Germs are here. Kill the germs.”

The immune system does much more than simply protect us from infection. It can tell the difference between the body's own cells and those belonging to invaders. Immune system cells can tell the difference between “self” and “non-self.”

Each and every cell in our body carries special marker molecules. These markers are also called antigens. They advertise “self.” Think of a typical cell as being an orange covered with knobby toothpicks and colorful little marker flags.

On a real cell, these toothpicks and flags are bits of protein and other special molecules. One or more of these bits of protein tell the immune system's hunter and killer cells that everything is fine. The alarm sounds when immune defenders come across a cell or microbe that has no “self” marker. The system swings into action to meet the threat of disease.

Long-term memory

Immune system cells can remember past fights with disease-causing viruses and bacteria. The system keeps a chemical record of how it recognized each invader. These special protein molecules are called antibodies. Antibodies are Y-shaped molecules. They fit a specific antigen much like a key fits into a lock. Any cell or organism that triggers the immune system into action is called an antigen (and is usually a non-self antigen). Antigens can be germs such as a virus or bacterium. Or they can be bits and pieces of those germs.

Antibodies lock onto an antigen. They serve as the flag that marks the invader for destruction. Later, when a similar microbe invades again, the body recognizes it as an invader. The immune system cranks into action. The goal is to destroy the invading antigen or microbe before it can develop into a new infection.

This is why most people get chicken pox or other childhood diseases only once. The immune system fought the fight once against these invading germs. Vaccines work the same way. They expose your body to pieces or weakened versions of the germs, and your body learns to fight them off. Vaccines for measles and mumps help children avoid getting the disease at all. Your body keeps a chemical record and protects you from contracting those illnesses.