Vertebrates such as mice and men have evolved additional ways of recognizing invaders. These mechanisms use antibody molecules on blood cells called B cells and ab (alpha beta) or gd (gamma delta) receptors on blood cells called T cells. These receptors are created by a rearrangement of genes during the development of T and B cells.
For example, the a chain of the ab T cell receptor is a single polypeptide made up of three different segments: Va, Ja and Ca. There is only one Ca gene, but there are about 50 Va and 50 Ja genes. As a T cell develops, it randomly chooses one of the 50 Va genes and moves it next to one of the 50 Ja genes. Often random nucleotides (bits of DNA) are subtracted or added to the point at which the Va gene lies next to the Ja gene.
Hence T cells can create at least 50 2 , or 2,500, different genes on the DNA "a" chain, and in fact, because of the random nucleotides, the number is probably much larger. Similar processes lead to the rearranged genes which code for T cell receptor "b" chain genes, and also to T cell receptor g and d genes and antibody genes.
Because of these rearrangements, each of the approximately 10 12 B cells and 10 12 T cells in a human being has a different receptor on its surface. These B and T cells exist within the blood and lymphatic system of the body in what is called a resting state--that is, they are not doing anything detectable. However, when a B or T cell encounters an invader that can bind to its receptor, the cell divides many times and so creates lots of daughter cells. Each bears receptors that are the same as, or very similar to, those of the parent. Hence, contact with the invader creates from a few B and T cells many more that can react with the invader.
During this division the T and B cells also create so-called effector and memory cells. Effector cells act to get rid of the invader. For example, effector B cells, called plasma cells, secrete antibody molecules that bind to invading bacteria and viruses and help eliminate them from the body. One type of effector T cell, called a cytotoxic T cell, kills virus infected cells and thus prevents its spread. The memory cells survive to protect their host against further infections by the same invader.
B cells bearing antibodies and T cells bearing ab or gd receptors recognize the appearance of an invader in the body in different ways. B cell antibodies bind to the invading particle, such as a bacterium, in the form in which it enters the body. The ab receptor-bearing T cells do not bind the invader directly. Instead, they bind to peptide fragments made from the invader's proteins. These fragments are created inside other cells. For example, viruses must invade host cells to increase in number. There, they produce their own proteins and copies of their genes.
Some of the viral proteins, however, are chewed up into peptides by the invaded cells. These peptides bind to proteins called major histocompatibility complex (MHC) proteins. It is this combination of viral peptide and MHC protein that the ab T cell receptors recognize.
It is still not certain how gd receptor bearing T cells recognize invaders. One hypothesis is that they react with damaged cells, that is, rather than recognizing the invader directly, they recognize the damage that the invader has done to the host.
These different ways of homing in on something foreign that has arrived in the body are thought to act as backups for each other. The old systems react with chemicals that are very different between bacteria and mammals. B cells and their antibodies react directly with invading organisms and help rid the body of them. The ab T cells react only with fragments of invading organisms associated with cells. These cells therefore help the body reject organisms, such as viruses or tuberculosis bacteria, that exist inside cells. The ab T cells are also good at reacting with other cells of the immune system, such as B cells. And the gd T cells react with damaged host cells.
Although an invading organism may evolve so that it can avoid one of these methods of recognition, it is almost impossible for an invader to avoid all types of immunity. Therefore, higher vertebrates are well protected against most organisms.
Device used in physics/chemistry reveals dynamics of pervasive pathogen
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If you have it, you probably don’t know it.
Cytomegalovirus, or CMV, is perhaps one of the biggest pathogens you’ve never heard of—big, both proportionately and epidemiologically. It contains approximately 200 genes, compared to HIV’s paltry 18, and it’s everywhere. You can catch it as a preschooler salivating over blocks, or as a teenager experiencing your first kiss. Once you have it, you have it for life.
Good news: If you’re healthy, it’s harmless. Your T cells keep it in check, and you’ll be none the wiser.
Bad news: If you have any medical condition that dampens your immune system, such as HIV infection or a recent organ transplant, the virus can assert itself with a vengeance. The results, sometimes, are life-threatening.
Researchers in the lab of Steven Gygi, professor of cell biology at Harvard Medical School, report that they have discovered a menu of tactical secrets CMV employs.
Using a technological platform commonly used in physics and chemistry called mass spectrometry, the researchers were able to describe the dynamics of a CMV infection in a fibroblast, or connective tissue cell, over a three-day course of infection. As a result, the researchers discovered ways CMV evades the immune system, and were able to show how certain viral proteins target and destroy human proteins that defend against infection.
“This is an entirely new way of studying the behavior and tactics of viruses,” said Gygi.
These results are published June 5 in Cell .
Mass spectrometry has existed for more than a century, used primarily by physicists and chemists to describe and measure small molecules. Inside the mass spectrometer, or mass spec tool, molecules are shattered by an electric charge and then brought through a magnetic field where they are characterized one by one.
Traditionally, this approach has not been relevant for the life sciences since biomolecules such as proteins are too large for this process. But over the last 15 years, Gygi has been innovating ways to incorporate mass spec into biology.
In one approach, “electrospray,” subunits of proteins called peptides are vaporized and then sprayed into a chamber where they are broken apart by helium. The mass spec then sequences the amino acids of each peptide. The molecules are “reassembled” through an algorithm that matches them to a protein database.
Michael Weekes, a postdoctoral researcher in the Gygi lab and an expert in infectious disease, decided to use mass spec for virology. He chose CMV because, for a virus that is so widespread, we actually know very little about it.
“Many scientists are interested in CMV, but few if any have tried to tackle it in a comprehensive way before,” he said.
Weekes took a sample of fibroblasts newly infected with CMV, harvested the proteins from both the virus and the cell, and sprayed them into the mass spec at different times over three days in order to construct a thorough trajectory of infection. The first three days of infection are particularly important since they mark a covert stage in which the virus hijacks, but hasn’t yet destroyed, the cell.
The researchers were able to study approximately 8,000 total proteins, not only identifying ways that CMV evades the immune system, but also discovering a number of new therapeutic targets.
Most notably, they were able to look closely at proteins that live on the cell surface. This is especially crucial since most drugs target cell surface proteins, yet these proteins are harder to study than proteins inside the cell due to their low numbers.
Weekes and his colleagues found 29 viral proteins living on the cell surface, 23 of which had not previously been discovered. Many of these CMV surface proteins deter immune cells.
Others block cellular proteins that activate immunity. In other words, CMV wards off rescuers while disabling a cell’s ability to defend itself.
“So much of this viral genome is dedicated to simply evading the immune system,” said Weekes.
The next step, according to the researchers, would be to identify antibodies against many of these viral proteins, ideally destroying infected cells before they replicate and spread the pathogen.
“This would be an entirely new way to combat CMV,” said Weekes.
This study was funded by the Wellcome Trust Fellowship and National Institute of Health grant (GM067945).
October 10, 2019
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T he human genome is not entirely human.
Some 8% of our DNA, in fact, originated in viruses, remnants of ancients invasions dating back millions of years. By infecting sperm and eggs, viral DNA found its way into germline DNA — the genetic information passed down to future generations — and stuck around.
Researchers can find these fragments and study what they do. But because the pieces burrowed their way into our DNA so long ago, scientists haven’t been able to watch the process unfold in nature — and see how the genome puts up a fight against such an infiltration.
“It’s a rare event, so basically, it’s never been directly studied, certainly not in a mammal,” said William Theurkauf, a geneticist at University of Massachusetts Medical School.
“And that’s where the koala comes in.”
A koala retrovirus, or KoRV, has been rolling through koala populations in Australia from the north to south. It’s passed among the animals like other types of viruses — what’s called horizontal transmission — but it has also started to wriggle its way into the germline. Koalas are now being born with the virus already integrated into their genomes — vertical transmission.
The virus has left koalas susceptible to infections and types of cancer. But it’s also extended scientists an opportunity to research the transition as a virus goes from exogenous (external) to endogenous (built into the genome), a process that hasn’t played out in humans in hundreds of thousands of years. It’s like a marsupial-enabled time machine.
“The koala provided this ideal system because it is quite a spectacular invasion in the wild, in nature,” said Cedric Feschotte, a professor of molecular biology and genetics at Cornell University. “There are relatively few examples of this.”
In a new paper, Theurkauf and colleagues report what appears to be an initial immune-like response that cells deploy to recognize viruses as foreign and to try to stop them from proliferating. It’s not always effective, given that viruses do make it into the genome. But the system that the researchers described works by distinguishing something foreign as different from the self, and tries to block it.
“We think we’ve stumbled on this innate recognition response,” Theurkauf said.
The study, which was published Thursday in the journal Cell, relied on samples — testis, liver, and brain — from two wild koalas that had KoRV.
Researchers who were not involved with the study said it highlighted an important hypothesis, but that the system described doesn’t fully explain how a cell can differentiate between genes from a virus and genes from itself.
“They brought a new piece to the puzzle,” Feschotte said. “The puzzle is not done yet.”
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Retroviruses like KoRV replicate by inserting their genome into the DNA of an infected cell. (HIV is the most well-known example of a retrovirus.) If they infect germ cells, the DNA they’re embedding into is the germline, and the viral DNA can potentially catch a ride into future generations.
Generally, once viral DNA gets settled into an animal’s genome, it develops mutations over time and loses its infectious capabilities.
“It’s almost like carbon dating,” said Zhiping Weng, a computational biologist at UMass Medical School and, along with Theurkauf, a senior author on the paper. “You can tell the sequences are old because they pick up a lot of defective pieces, so they don’t work.”
Even after stretches of viral DNA get passed along and mutate over millions of years, they can sometimes still be expressed and make proteins. They have occasionally played a key role in evolution: Endogenous retroviruses helped drive the development of the placenta in mammals, for example.
Generally, though, the animal genome has tools to suppress the expression of viral genes. If this is a secondary immune response to a viral DNA invasion — one that specifically tamps down certain genes — then the system described in the new paper is like a primary, broader defense, Theurkauf said.
Theurkauf likened it to how the immune system responds when you are infected by a virus — like, say, flu. The body identifies the strain of flu that is making you sick and starts making antibodies designed to wipe out that specific virus — what’s called adaptive immunity.
But there’s an initial, innate response in which the immune system recognizes the virus as something generally foreign — different from the host — and tries to fend it off. It’s not as powerful or precise, but it can help buy time as the adaptive response classifies the particular invader and fortifies the antibodies.
“It turns out the genome basically has the same two-phase system” as a general immune response, Theurkauf said.
This innate genome system kicks in when the virus gives away its presence in a cell, according to the new research. When a gene is expressed, a piece of RNA is made with protein-manufacturing instructions. During this process, genetic pieces that are not required for putting together the protein are cut out, or spliced. A virus, however, makes a piece of unspliced RNA. The new paper suggests it’s like a phone ringing in a game of hide-and-seek: the unspliced sequence alerts the cell to the presence of a target. The cell in turn tries to block the virus from replicating.
John Coffin, a virologist at Tufts University, who was not involved with the study, said he wondered if the germ cells’ response was part of the body’s broader immune reaction to recognizing a pathogen — that the genetic battle was one arm of the body’s effort to fend off infection. That would make more sense from an evolutionary perspective, he said.
And Feschotte noted that some host genes are also left unspliced, or get spliced in alternative ways. This means that the system described in the paper has to have other ways of distinguishing host genes from foreign genes.
“The splicing alone is not enough — there’s got to be something else going on,” he said, adding that the paper “brings us one step closer to figuring out” the full process.
For their future research, Theurkauf and Weng are hoping to learn how cells recognize viral DNA in a more detailed way. They’re also trying to get a better sense of how a virus can evade the immune defenses, and find a new home in our genomes.
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If it doesn’t make sense to you that a person can have enough virus in his or her body to be able to spread the infection, but not enough to feel ill, you’re not alone. It doesn’t make sense, but there is an explanation.
The explanation begins and ends with our immune system — our internal defense against foreign invaders. Those invaders are typically viruses and bacteria, but occasionally it’s the wood sliver off your patio deck, or the nickel in a piece of cheap jewelry.
Our immune system offers us two lines of defense: innate and adaptive immunity. Innate immunity includes physical barriers like our skin, as well as a number of different kinds of white blood cells that are hostile to invaders. Innate immunity acts like a security team, providing a routine vigilance that can get an early jump on an infection.
Adaptive immunity is more like a SWAT team, composed of two types of white blood cells (with special weapons and tactics) called B-lymphocytes and T-lymphocytes. B-lymphocytes create antibodies, which are like those arrows you had as a kid with the pink rubber suction cup on the end. Except the rubber cup of an antibody is designed to stick to a very specific molecule found only on the invader (rather than the fridge, or your sister’s bare legs).
Otherwise, these antibodies might stick to our own cells, and that would be bad. Because when an antibody sticks to its target (either the outside of a bacteria or virus, or the outside of a cell that’s infected with a virus), it triggers a cascade of biochemical and immunological assaults. These attacks can blow a hole in the bacteria’s cell wall, an ultimately lethal injury. Alarm signals are broadcast that call in reserve unit white blood cells from other sites in the body (some have been sitting around waiting, and others will be newly manufactured for the event). T-lymphocytes begin physically attacking and demolishing anything tagged with an antibody.
It’s war, and as in the wars we humans wage, there is a lot of collateral damage. Instead of smoke, dust, debris and rubble, an infection war zone creates inflammation, swelling, pain, and lots of cellular debris. Our most intimate experience with this battleground is a bad cold. For a day or so, the nose is open but it’s red-hot and it hurts to inhale. Then, as the battle peaks, it gets plugged up until you can hardly breathe. Finally your body is ready to start clearing debris, and the “gunk” that you blow from your nose goes from green/yellow to white and then clear. You might feel recovered in terms of energy etc., and the virus might be gone, but you’ll be blowing your nose for days until the cleanup in aisle four is over.
Our SWAT-team adaptive immunity is also in charge of our “immunologic memory”: It keeps a log of prior offenders, so that we are “immune” to infections we have seen before. Vaccines allow our cells to create an immunological response and memory without actually having had the infection.
Sometimes our immune system gives us “partial immunity”: We recognize the invader, sort of, and have some antibodies at hand that will loosely attach to the virus. It’s enough to keep the infection under check, mild perhaps, until we can manufacture some more specific antibodies and polish the invader off.
So how can a person be infected enough to spread the virus, but not enough to feel ill? We tend to think that the sicker one appears, the more infectious one is, but that may not be the case with a novel virus like COVID-19, where no one’s immune system recognizes it. This allows the virus to enter the cells of our respiratory tract without being recognized for a while. It sets up shop, and immediately begins reproducing millions of new viruses that fall out into our respiratory tract. With no immunological fire alarms triggered, the not yet symptomatic host feels fine, but a simple throat-clearing cough (and we do this fairly often) or an unwitting sneeze (‘must have been some dust off the keyboard’) can send millions of highly infectious viral particles into a shared office space.
It’s hard to discover how (or if) an infection is being spread by asymptomatic-yet-infected individuals. First, even in a pandemic, most people aren’t infected, so you have to screen a lot of individuals. Second, when you do find a person who tests positive for COVID-19, the screening test only checks for traces of viral RNA — not fully intact, fully infective viral particles. It’s proof of infection, but it doesn’t indicate how infective one is. Particularly late in the recovery phase, respiratory secretions might still contain viral debris, but not active, intact viruses.
Although the data is limited, here are a few examples that suggest COVID-19 is both highly infective, and people can spread the disease before they feel ill.
When Germany flew 126 of its citizens home from Hubei on Feb. 1, only two of the passengers on the flight tested positive for COVID-19. They were both asymptomatic. In both cases, officials were able to grow (culture) the virus out of their respiratory tract. That suggests that these two were infective, even though they remained asymptomatic as they were monitored in isolation. [One ultimately had a slight redness of the throat and a faint rash].
A study by Chinese researchers looked at the first 425 confirmed COVID-19 cases in China. Early on, a large majority of infected persons reported they had either been to the ground-zero Huanan Seafood Market, or had direct contact with someone with a respiratory infection (often, a family member). Once the virus began making sustained, person-to-person transmission outside the seafood market, the majority of infected persons reported they had no exposure to the seafood market or contact with anyone who was ill. Despite being armed with information about the infection and with a heightened vigilance for avoiding symptomatic individuals, the infection still spread.
A Chinese businesswoman from Shanghai felt well as she traveled to Munich for two days of meetings in late January. While there, she had a few, very mild symptoms that she attributed to jet lag and business pressures. On the evening of her return to China she began to feel ill, and was confirmed to have COVID-19 five days after leaving Munich. At that point she notified the German company, who then referred her primary business contact there (Pt #1) to the health department. He tested positive for COVID, as did three more employees, one of whom had contact with the Chinese woman, but two of whom only had contact with Pt. #1 — who at that time was completely asymptomatic.
So why do most people get a mild case of COVID-19 (80% were reported as mild in China), and others more severe? There are a variety of explanations.
Influenza typically has a “U-shaped” mortality curve, where the very young and the very old have the highest mortality rates. We can thank our lucky stars that COVID-19 has a J-curve that leaves the young mostly untouched. There’s speculation that COVID-19 is sparing children and young adults because they might have partial immunity from having dealt with other less virulent corona strains that can cause colds. Or it may be that they don’t have a high number of the receptors in the lung – “ACE-2 receptors” — that COVID-19 uses to get a foothold.
The reason(s) COVID-19 hits older patients and those with chronic medical conditions harder is because our immune system weakens as we age, and chronic medical conditions make it even more difficult for the body to marshal a potent immune response.
For the 80% who work through their COVID-19 infection without too much difficulty, presumably their immune system gears up appropriately, clears the virus, and goes back to standby position. It’s not yet fully well understood, but sometimes it appears that our sickest infected patients suffer less from the primary infection than from an over-zealous immune response — aka “cytokine storm.” Particularly in respiratory infections, an overexuberant immune response can so damage the delicate tissue of the lungs that even a ventilator machine cannot improve breathing.
This brings us to an odd paradox: Our immune system can make us feel sick. Patients who are on medications to suppress their immune system — for example to keep their immune system from rejecting a donated kidney — are at increased risk of infection. When they do get infected, they often show few signs or symptoms until the virus or bacteria is beginning to overwhelm them.
The “flatten the curve” graphs that are going — forgive me — viral are an excellent visual dramatization of why we need to hunker down, spread out, and starve COVID-19 of any fresh fuel. Evidence that infected patients can spread the virus around before they even feel ill just supports that plan of action. If we can’t tell whom to avoid (based on symptoms), we should avoid everyone for a time. If we do, we may be able to turn a tsunami into a long slow swell. For an infection like this, our communal actions are the best — and only — treatment we have.
Dr. Craig Bowron is a Twin Cities internist and writer.
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