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In our body we carry a lot of bacteria. Some of them are bad for our health, but others are beneficial. For example bacteria may protect us against other pathogenic bacteria.
But is our immune system reacting to all bacteria, i.e. the good and the bad, or does it selectively target the bad? If yes, how does it differentiate between beneficial and pathogenic bacteria?
The immune system is capable of recognizing pathogenic ("bad") bacteria, either by components of the innate (non-specific) or adaptive (specific) immune system. Pathogenic bacteria will have antigen on their surface that mark them as 'foreign', leading to an immune response targeted to the bacteria. In contrast, the immune system tolerates the normal flora of the body. The precise role that the human immune system takes in tolerating and regulating the populations of the normal flora is not known, it is currently a hot area of research.
Current research suggests that microbiota induces host immune tolerance to commensal bacteria directly via a microbe-associated molecular pattern (MAMP) and polysaccharide (PSA) signalling. The immune system continuously monitors the resident microbiota, and certain antimicrobial mechanisms are constitutively engaged to prevent overgrowth of the colonizing microbes: this maintains what is loosely called immune homeostasis. The mechanisms that control (intestinal) tolerance include those that:
1) minimize exposure to and 2) immune recognition of intestinal microbiota, and 3) those that down-regulate immune responses through intra-cellular and inter-cellular mechanisms.
Research has shown that he tolerance of the normal microbiota of the gut seems to require an extensive network of regulatory immune cells including Tregs and (tolerogenic) dendritic cells. Thymus-derived Tregs were discovered by Dr. Leszek Ignatowicz to be a crucial player involved in "educating" the immune system about the diverse bacterial colonies in the intestinal flora of mice. In response to the diversity of gut bacteria found in the gut, the Tregs express a 'repertoire T cell receptors' (TCR) that recognize the antigens characteristic of individual bacterial colonies in the gut. Upon engagement of these receptors, Tregs suppresses the adaptive immune response, specifically through the release of immune-modulatory cytokines such as interleukin-2. Moreover, it was found that gut bacteria can also be recognized and protected by a distinct innate lymphoid cell population (ILC) in the intestinal lining of mice. These cells behave like antigen presenting cells, and can recognize and present antigens from gut bacteria through the major histocompatibility complex class II (MHCII). But rather than activating CD4+ T lymphocytes through MHCII engagement, these ILC works by suppressing CD4+ T lymphocytes through MHCII engagement. CD4+ T lymphocytes are involved in clearing pathogen/bacteria, and thus the suppression of CD4+ T lymphocytes is involved in the immune-tolerance of normal flora.
How Lyme bacteria can outsmart the human immune system
A University of Maryland (UMD) researcher has uncovered a mechanism by which the bacteria that causes Lyme disease persists in the body and fights your early, innate immune responses.
Dr. Utpal Pal, Professor in Veterinary Medicine, has been studying the Borrelia burgdorferi bacteria throughout his twelve years with UMD, and his work has already produced the protein marker used to identify this bacterial infection in the body.
Now, Dr. Pal has isolated a protein produced by the bacteria that disables one of the body’s first immune responses, giving insight into mechanisms that are largely not understood. He has also observed a never-before-seen phenomena demonstrating that even without this protein and with the immune system responding perfectly, the bacteria can spring back in the body weeks later.
Understanding this bacteria, which is among only a few pathogens that can actually persist in the body for long periods of time, has major implications for the treatment of tick-borne diseases like Lyme disease, which is an increasingly chronic and consistently prevalent public health issue.
“Most people don’t realize that they actually are walking around with more bacterial cells in their bodies than their own cells, so we are really bags of bacteria,” explains Pal. “Most are good, but the second your body detects something that is a pathogen and can cause disease, your immune system starts to work.”
The body sends a first, nonspecific wave of attack to kill the bacteria detected that doesn’t belong. This happens within a few hours to days. If this doesn’t work, it takes seven to ten days to learn about the enemy and send a large second wave of reinforcements to kill what is left.
“Lyme disease is actually caused by your immune system,” explains Pal. “This bacteria wins the first battle, and your body overreacts so much that it causes intense inflammation in all the joints and areas that the bacteria spreads by sending so many reinforcements to kill it. Borrelia is then killed, but the inflammation remains and causes many of your symptoms for Lyme disease. That is why killing Borrelia in the first wave of immunity is so important.”
The Centers for Disease Control and Prevention estimate about 300,000 cases of Lyme disease annually in the United States. However, these cases are largely underestimated and underreported, due to the attention given to mosquito-transmitted diseases like malaria.
“The majority of all vector-borne diseases in the US are actually tick-borne, and 6 of the 15 distinct tick diseases are transmitted by the Ixodes tick we study in our lab,” says Pal. “The symptoms of these diseases present similarly to many other illnesses and are hard to pin down, so they are vastly underreported and an even bigger public health concern locally and globally than people realize.”
Now, chronic Lyme disease is a growing concern. Six to twelve months after traditional antibiotic therapy, many people have non-objective symptoms that return with varying intensity and no current treatment strategy, known as Post-Treatment Lyme Disease Syndrome.
Dr. Pal’s research has shed some light on this issue and paved the way for future research and treatment options by discovering that even without the protein used to beat the first wave of immune defense, infection can reoccur in the body weeks later.
“This means there is a second line of defense for Borrelia just like for our body’s immune system. This had never been observed before and gives us insight into what could be causing these chronic Lyme disease cases,” explains Pal.
Dr. Pal is frequently consulted for his expertise and has written books on this highly versatile bacteria. The federal government has recently put more emphasis on tick-borne disease research and a major public health issue with the passage of the 21st Century Cures Act.
As part of this, Dr. Pal was asked to serve on a Tick-Borne Disease Working Group Subcommittee for the U.S. Department of Health & Human Services, focused on vaccines and therapeutics for tick-borne diseases, driving future research in the field.
Dr. Pal currently holds two concurrent multi-million dollar RO1 grants from the National Institutes of Health for this work, only granted for highly important and influential research.
“I am fascinated by Borrelia, and this discovery will open the door for much more work to treat and control important diseases like Lyme disease,” says Pal.
Dr. Pal’s paper, Plasticity in early immune evasion strategies of a bacterial pathogen, is published in the Proceedings of the National Academy of Sciences.
How can bacteria in your gut interact with your immune system?
We are still learning how gut bacteria and the immune system interact. Research suggests that the interaction evolved over time to manage the balance between reacting to harmful pathogens and tolerating non-harmful organisms. You want your immune system to react to the pathogens that can make you sick, while letting the beneficial bacteria living in your gut go about their business.
We are still learning what a healthy gut microbiome looks like. Evidence suggests that a balanced and diverse microbiome might contribute to better health overall, and a less diverse or less balanced microbiome can have a negative impact on health.
A review article from 2014 suggests that the overuse of antibiotics, changes in diets and the elimination of beneficial organisms that work with bacteria (like nematodes, a kind of worm) in high income countries may have resulted in gut microbiomes that lack the resilience and diversity of functions required to establish balanced immune responses. Why does that matter?
Having less diverse gut bacteria has been linked to inflammatory bowel diseases and the increase in autoimmune diseases in developed countries.
For instance, a 2013 study found that children living in Bangladesh have more diverse gut microbiomes than children from the United States. Researchers suggest that dietary differences – with children in the US eating more animal fats and protein – are a factor.
What do gut bacteria have to do with vaccines? Shutterstock
When your immune system becomes your worst enemy
The immune system, which is our best weapon against uninvited guests such as bacteria, is built like a defence against invasion.
Front-line soldiers continuously scout for enemies and sound the alarm when danger is detected. We call this the &lsquoinnate immune system.&rsquo
It does not matter if they haven&rsquot seen the enemy before as they simply regard all foreigners as hostiles. The foot soldiers consist of proteins and white blood cells, which react against the enemy&mdashand generally they do their job well.
But the innate immune system can also turn into our own worst enemy, when it becomes overactive or is tricked into attacking the body. This can lead to cardiovascular disease, exacerbate septicaemia (blood poisoning), or neurological diseases, and in the worst case scenario they can cost the patient their life.
Immune system can &lsquoexplode&rsquo
There are two problems in particular with the innate immune response.
First, the innate immune system is the first responder to the scene and can become overactive when it meets serious infection, major injuries, or burns.
The intention is to kill the bacteria or repair the damaged tissue, but the result can be an &lsquoexplosion&rsquo that not only fights the invasive microbes but also attacks the host (patient).
This causes an inflammation in the body, which can get out of control and end up doing more damage than the bacteria ever would. In the worst case scenario it can lead to organ failure and death.
All of us have an innate immunity that can &lsquoexplode.&rsquo Think of it as an undetonated bomb, which only causes harm when it actually explodes.
The immune system can react against the body&rsquos own tissue
Luckily, this rarely happens.
Normally, the immune system takes care of the bacteria, but if it spreads to the bloodstream, as is the case in septicaemia, it can sometimes initiate a type of &lsquoimmunological suicide&rsquo where our innate immune system harms us in an attempt to save us.
Second, the innate immune response can react against the body&rsquos own tissue in the event of an injury such as an acute heart attack, rejection of a transplant organ, or a chronic vascular disease that leads to atherosclerosis.
In cases such as these, the foot soldiers do not react against the enemy invaders, but against our own damaged tissue.
The immune system will help to repair the damage, but if it is too extensive the foot soldiers can misunderstand the situation and start a war in an attempt to fight the supposed outsiders.
Previous attempts to dampen the immune system failed
When the foot soldiers register a threat, they begin to inform others to react, and an entire battalion of biological actors set to work. These molecules&mdashcytokines&mdashcause inflammation.
Scientists have tried to study a number of them before without success. They tried to inhibit them while treating patients for blood poisoning and a range of other diseases, where the innate immune system can overreact and harm the patient.
All previous clinical trials were halted before the remedy could be used. So what do you do?
Two central systems must be blocked
One of us, Tom Eirik Mollnes, suggested that the only way you can dampen the explosion of the innate immune system response is to block certain groups of foot soldiers before they can cause inflammation and damage organs.
This treatment targets two particular groups, which react as soon as danger approaches. They are two of the most important systems in the foot soldiers&rsquo war:
Mollnes and his team discovered that it is significantly more effective to inhibit these systems right from the start, before the explosion in inflammation can happen. We&rsquove now demonstrated this in samples of human blood in the laboratory.
We then showed that it also worked in both mice and pigs suffering from blood poisoning. They survived longer when the molecules in these two central systems (C5 in the complement system and CD14 in the TLR family) were simultaneously inhibited.
These results were completely at odds with previous studies, which blocked single molecules released after the complement system and TLR were activated.
So we suggest that blocking these two systems immediately when they discover danger is the most effective treatment in cases where a patient is at risk of death by the immune system&rsquos overly explosive counter attack.
Foot soldiers misinterpret their duties
There are also a number of cases, which are not nearly as dangerous as blood poisoning, where it may also be relevant to block our immune system response.
This applies when groups of foot soldiers (the complement system and the TLR) misinterpret their duties.
The think they should attack an enemy, but instead attack the patient&rsquos own damaged tissue, which they don&rsquot recognise as a part of the body due to the damage.
This is the case for a number of diseases, such as atherosclerosis, kidney disease (including rejected transplant organs), and autoimmune disease (such as arthritis), where the body produces antibodies against its own tissue and activates the complement system.
The same problem occurs in dangerous neurological diseases and any number of other diseases where it could help to inhibit the complement and/or TLR systems. We therefore need to test medicine that inhibits both systems simultaneously.
We hope that our strategy can form the basis of future treatments for a range of diseases caused by the innate immune system.
In order to ensure your immune system is top-top, make sure you have all the necessary immunizations. Adults often forget to refresh vaccinations they had when they were young. Check if you need booster shots for tetanus, diphtheria, whooping cough, polio, hepatitis, pneumococcus, meningitis, measles, mumps, rubella, the flu and others. Be sure to talk to your doctor!
Viruses and bacteria don't stand a chance with a strong immune system
In your class
This article highlights the role that chemists play in vaccine production and the importance of chemistry in biology. Vaccines help us fight off diseases caused by bacteria or viruses and chemists have discovered ways of keeping vaccines active even when they’re not refrigerated. Scientists also use chemistry to amplify vaccines’ immune response in more vulnerable people. Use this article to provide real-world contexts when teaching about salts and the particle model and to make cross-curricular links with biology.
All vaccines work against a specific germ. They do this by targeting chemical building blocks that both viruses and bacteria contain. In such germs, genes made of DNA or similar RNA molecules act similarly to how a computer program might control a robot. They encode instructions on how to assemble small amino acid molecules into larger proteins that make up germs’ bodies.
Bacteria, which are much larger than viruses, can travel through our blood and multiply on their own, copying themselves many times. Eventually our immune systems learn to make another type of protein, called an antibody, which can recognise bacterial protein shapes. Antibodies stick to bacteria using intermolecular forces like hydrogen bonding. The antibodies can then signal for white blood cells to come and kill the unwelcome invaders. Most vaccines train our immune systems to make antibodies needed for bad germs before they infect us, Katie explains.
During vaccine production, viruses are often grown in chicken eggs or cultured human cells
Vaccines are often made from germs that have already been killed or tamed. Exposing our immune system to such inactive germs lets antibodies learn to recognise them. For example most flu vaccines use weakened, but live, flu viruses. During the manufacturing process, the viruses are injected into chicken eggs, where they multiply. Companies can then take the virus back out through a needle for use in vaccines. In most cases the vaccine itself is combined with another component, called an adjuvant, just before it’s given to people. Aluminium phosphate and aluminium hydroxide are among the most common adjuvants used.
Using adjuvants is a tricky process, because ‘we don’t know completely how they work’, Katie admits. ‘They amplify the immune response to whichever protein you’re trying to use in your vaccine,’ she says. ‘Adjuvants are really important for vaccinating young children and the elderly, where we know that responses to vaccines are not as good as in adults. But if you give too much of an adjuvant, you get a very sore arm, and so on. It’s usually the adjuvant that gives you any side effects.’
A boost for poor countries
Another problem is that vaccines can break down, explains Manjari Lal, who researches vaccine formulation at PATH, an international non-profit organisation focused on health innovation. ‘The most common degradation is protein denaturation, which involves unfolding of the three-dimensional structure,’ she says. This could be caused by heat, physical force, or chemical breakdown. Chemical breakdown can be especially important when vaccines are converted from liquid to powder through freeze-drying. In this approach, PATH’s workers freeze solutions containing sugar stabilisers and remove ice by putting the vessel they’re in under vacuum. The vaccine’s pH has to stay stable during this process to avoid chemical damage. Manjari and her colleagues have to add the right combination and type of salts to ensure this.
Similarly, heat breakdown is a problem when vaccines need to go to poor, hot countries where fridges are scarce. Katie’s Jenner Institute colleagues have found a way to make mixtures survive heat using common table sugar, sucrose and a different form of sugar, trehalose. The scientists leave a mixture of these sugars and the vaccine and adjuvant to dry slowly on a filter or membrane, where they solidify into a thin, sugary film. Alcohol functional groups on the sugars hold vaccine proteins’ shape steady using intermolecular interactions, again including hydrogen bonding.
Manjari and her PATH co-workers also use a similar approach, and she emphasises the importance of stopping proteins moving. Because there’s little water, it’s also hard for other substances to get into the film to break the protein down. Degradation reaction rates slow down enormously. In the Jenner Institute method, vaccine makers then put the membrane into a simple plastic cartridge that can sit on the end of a syringe. Then, when the vaccine is needed, medical staff can just flush it with water, releasing the vaccine and injecting it into a patient.
Explore cross-curricular links between chemistry and biology
Synoptic revision, age range 16–18
Make cross-curricular links with biology with these synoptic questions to get your students thinking about chemistry in unfamiliar contexts. There are two versions of the resource, one where the questions are grouped into topics and another where they are ungrouped. Questions could be selected and used to stimulate discussion in class. Alternatively they could be used in a worksheet for a revision or extension activity, either at the end of a topic (the grouped questions) or at the end of the course (synoptic questions).
Download the resource with grouped questions (as MS Word or pdf) or synoptic questions (as MS Word or pdf).
For many widely-used vaccines, researchers found the right trigger to form antibodies from because they ‘got lucky early in the process’, Katie says. With limited scientific knowledge, vaccines for other diseases have been out of reach. These diseases are often caused by viruses, which antibodies sometimes don’t work against. That’s because viruses can recognise and grab proteins on the surface of our cells. Viruses force their way inside these cells and hijack their protein machinery to churn out copies of themselves.
‘Then, the job is much more difficult because you’ve got to clear the virus from inside those infected cells, and antibodies can’t do that,’ Katie notes. One option, which Katie and her teammates have used to develop an Ebola vaccine, is to block viruses from getting into cells. This is possible because over the last decade it’s become much cheaper to read the genes encoding how germs are built. She can work out which genes relate to proteins that Ebola uses to grab onto our cells.
‘We can then generate a vaccine that produces antibodies against those proteins,’ Katie says. ‘That’s very straightforward, because there are only seven proteins encoded within the Ebola genome.’ Making an Ebola vaccine is surprisingly easy – none that have been tested in people have been unsuccessful, she notes. They mainly hadn’t existed because no one had prioritised developing them.
Hatching different ideas
Another problem arises during production, when companies cultivate viruses in eggs. At this point, the viruses can change slightly and become less effective in vaccines. Instead, Katie and her fellow Jenner Institute scientists produce proteins for use in vaccines by genetically modifying bacteria, yeast or insect cells to make them. They can then blast the cells open, and separate out the proteins they need using chemical purification techniques like chromatography.
Such advances are part of a general improvement in vaccine production that also opens opportunities to make them more powerful than ever before. Katie specialises in making ‘sub-unit’ vaccines that can train a type of white blood cell called a T-cell to kill off virus-infected cells. ‘You take a common cold virus and delete about half of its genome,’ she explains. ‘It can’t reproduce inside a human, but can express a gene and show a protein to the immune system.’ This ‘is much more difficult’ than making antibody-training vaccines, she says, but it could help deal with an important problem: flu vaccines sometimes don’t work.
Source: © Amos Gumulira/AFP/Getty Images
A nurse waits to administer treatment to sick children at the beginning of the Malaria vaccine implementation pilot programme at Mitundu Community hospital in Lilongwe, Malawi, on 23 April 2019
This problem occurs because there are many different strains of flu, which are given names like H1N1 or H5N1. The H refers to a protein called haemagglutinin, which is what antibodies arising from conventional vaccines target. Currently, if a vaccine doesn’t cover the strain that infects us, our immune systems aren’t trained to it fight off. Haemagglutinin has a head and a stem, with antibodies from vaccines normally targeting the head part. However, that part varies between different versions of haemagglutinin. The stem is more uniform and stable, but usually ignored by the immune system. Using the gene for this stem to make a sub-unit vaccine could protect against every form of flu.
The Jenner Institute is using this approach on other illnesses where vaccines are urgently needed, including HIV, tuberculosis and especially malaria. ‘The big Ebola outbreak in West Africa two years ago killed around 11,000 people,’ Katie observes. ‘Malaria kills that number every two weeks!’ Malaria is caused by parasites that are much larger and more genetically complex than bacteria or viruses. It is therefore hard to decide which protein a vaccine should target.
Katie highlights a vaccine for malaria that entered large-scale human trials in April 2019, having been in development for 30 years. Now we understand the science much better, malaria could be one of the first diseases to benefit from improved ways of delivering immune self-defence, she suggests. ‘We can make the vaccine cheaper and easier to manufacture, potentially safer, and maybe more cost-effective – making it into the 21st century version, hopefully.’
The amazing influence of gut microbes in our immune system
Could autoimmune and allergic conditions like Crohn's disease, multiple sclerosis or type 1 diabetes one day be treated with microbes in your gut?
Inside your gut is a collective of bacteria, fungi and viruses known as the gut microbiota.
Amazingly, they start to develop immediately after we're born. With our mother's bacteria quickly colonising our body and gut, within weeks, our gastrointestinal tract is loaded with microbes.
This vast community of microorganisms live in our body and are critical for how parts of our bodies operate. In fact, these microorganisms are so important they are as prominent in our body as our own cells.
When it comes to our gut, the microbiota is mostly made up of bacteria, although there are also fungi and viruses.
Our gut contains billions of these bacterial cells at any one time, and one of their jobs is to produce essential vitamins our body can't make, like B1 through to B12, folate, vitamin K and thiamine.
Another important function of these microbes is their influence on the immune system. This is the body's first line of defence against infections. The immune system also keeps us healthy by eliminating our own cells when they become diseased.
In recent years, the microbes in our gut have been the focus of intense research. What has emerged are strong connections between our health and the presence or absence of specific groups of gut microbes.
Gut microbes and the immune system
Sarkis Mazmanian is Professor of Microbiology at the California Institute of Technology. He's been studying how gut microbes affect our health for over 15 years.
"Gut microbiota in people varies between individuals," says Sarkis.
"A new concept has emerged in biomedicine that the balance of different bacterial species in the gut can influence whether the immune system becomes activated or not.
"This is important, because an overactivated immune system can result in tissue damage and symptoms over time," he adds.
"[It's] believed to underlie the cause of many autoimmune, inflammatory and allergic disorders in humans."
Sarkis believes colonisation with bacteria with anti-inflammatory properties may prevent or even treat many diseases in the future.
At the core of an effective immune system is a delicate chemical balance that helps immune cells identify friends from foes. Gut bacteria are important players in this balance. They take the fibre you eat and digest it, turning it into smaller molecules.
One group of these molecules are short-chain fatty acids (SCFAs), a crucial part of our gastrointestinal health. SCFAs can influence a range of cells and functions within the body, leading to changes in the immune function of the gut.
These SCFAs also influence another important immune cell—regulatory T cells.
T cells are the immune system's informants, telling your body how to respond to invading pathogens or germs.
SCFAs produced by gut bacteria interact with T cells and can influence their behaviour, directing them to attack or spare cells.
Immune system overdrive in type 1 diabetes
Gut microbiota has also been linked to type I diabetes, an autoimmune disease affecting more than 150,000 Australians.
This condition stops the body from producing enough insulin because its own immune system is attacking the pancreatic cells in charge of this task.
In one study, researchers fed mice a number of special diets that were fermented by gut microbes. Dependent on the diet, this led to the production of large amounts of either acetate or butyrate, two common SCFAs produced by gut bacteria. These SCFAs appeared to protect the mice from diabetes.
"What was remarkable about this study was [these] SCFAs protected from diabetes at so many levels," says Charles Mackay, Professor of Immunology at Monash University.
SCFAs also influence another complex aspect of our biology—our epigenome.
Silently working alongside our genome, the epigenome is a vast repertoire of chemical tags placed on DNA molecules that regulate the function of many genes.
Called epigenetic modifications, these chemicals function almost like a coat. When they're placed on parts of the DNA or associated proteins, they influence their function.
A direct consequence of epigenetic modifications is that genes can be turned on or off, and studies have shown that SCFAs can influence these modifications.
In a 2016 study, researchers found that feeding mice with a Western diet—rich in fat and sugar but poor in fibre—had epigenetic consequences. These mice showed significantly lower levels of Bacteroidetes and a greater amount of Firmicutes (two common type of gut bacteria) compared to mice fed a fibre-rich diet.
"SCFAs, particularly butyrate, can influence the expression of certain genes that have a big impact on biology," explains Charles.
Other studies have established a link between the gut microbiota, epigenetics and the occurrence of conditions like inflammatory bowel diseases, immune problems and even cancer.
Our unique microbiome
We know it's important to keep our gut healthy, but one of the biggest challenges is yet to be solved—how do we do it?
"The current state of the art in microbiome research does not provide widely validated ways to improve your microbiome," says Charles.
"This is largely because more work needs to be done, but also there is likely not going to be a one-size-fits-all intervention."
Nevertheless, some sure ways to improve the health of your gut and the rest of your body is to eat a healthy diet, rich in fibre and low in fat, sugar and processed foods, as explained by the CSIRO. Also, exercising and sleeping well are a sure way to improve your gut and overall health.
This article first appeared on Particle, a science news website based at Scitech, Perth, Australia. Read the original article.
Resistance to antibiotics and to immune system are interconnected in bacteria
E. coli bacterium visualized by electron microscopy. Credit: Electron Microscopy Unit, IGC.
Antibiotics and the immune system are the two forces that cope with bacterial infections. Now, two studies from Isabel Gordo's laboratory, at Instituto Gulbenkian de Ciência (IGC, Portugal), show for the first time that resistance to antibiotics and to the immune system is interconnected in bacteria. The researchers further discovered that bacteria adaptation to the immune system influences the spectrum of antibiotic resistance and, as a side effect, bacteria become more resistant to some antibiotics, but also more sensitive to other classes of antibiotics. These results were now published in the scientific journals Antimicrobial Agents and Chemotherapy and Evolutionary Applications.
Bacterial infection requires an effective answer from the immune system. Macrophages are the immune cells that first respond to bacterial infection, by recognizing, engulfing and killing microorganisms. Paulo Durão and colleagues, at Isabel Gordo's laboratory, investigated the ability of bacteria that are resistant to several antibiotics to survive in the presence of macrophages. For this study, they used Escherichia coli bacteria with mutations that confer resistance to two antibiotics, rifampin and streptomycin, which are common in pathogenic bacteria. The researchers observed that these bacteria could survive better inside macrophages than non-resistant bacteria. Paulo Durão: "In our experiments there are no antibiotics present and still, in the harsh environment found inside macrophages, the E. coli strains which have antibiotic resistance seem to be fitter than the susceptible strain. This means that antibiotic treatment selects for antibiotic resistance and simultaneously selects for a higher resistance to the innate immune system."
At the same time, other team members of Gordo's Laboratory investigated the other side of the question: what happens when bacteria become resistant to the immune system? Ricardo Ramiro, first author of this study, conducted a series of experiments, forcing bacteria to evolve in the presence of macrophages. This resulted in bacteria capable of surviving better inside macrophages. Ramiro and colleagues discovered that these bacteria, initially without any resistance to antibiotics, became more resistant to a specific class of antibiotics, the aminoglycosides, and more sensitive to other classes of antibiotics.
"This side effect of bacterial adaptation to the immune system could be used in our favor to better select antibiotics for treatment of infections", says Ricardo Ramiro. "While adapting to the immune system, bacteria become more sensitive to some antibiotic classes. Thus, using those antibiotic classes for treatment of infections, should allow for a faster cure of the infection while minimizing the emergence of antibiotic resistant bacteria."
Isabel Gordo adds: "Our results with E. coli set the ground for future experiments in other important bacterial species, such as M. tuberculosis and Salmonella."
Bacterial resistance to antibiotics has been increasing, posing a serious threat to human health. Understanding the relation between bacteria, immune system and antibiotics can open new avenues to cope with such public health problem.
Paulo Durão et al. Enhanced Survival of Rifampin- and Streptomycin-Resistant Escherichia coli Inside Macrophages, Antimicrobial Agents and Chemotherapy (2016). DOI: 10.1128/AAC.00624-16
Antibiotics can have adverse effects on your immune system
The immune system is your body's defense against invasive bacteria, viruses, and other harmful pathogens. This infection-fighting work happens on a cellular level: White blood cells (leukocytes) fight infections, B cells make antibodies to fight bacteria, and T cells destroy infected cells.
"Sometimes, the body's immune system cannot fight the bacterial infection off alone, which is when antibiotics enter the picture," says Kathleen Dass, MD, a Michigan-based immunologist and allergist. Antibiotics work to either kill off bacteria, or prevent them from reproducing, she explains.
And, in most cases, these drugs are incredibly effective. "In 1900, the top three causes of death were all due to infectious disease. That's no longer the case today, and that's because of… better hygiene, sanitation, vaccines, and antibiotics." says Alex Berezow, PhD, a microbiologist at the American Council on Science and Health.
However, these powerful drugs are not without a downside. For instance, taking antibiotics can destroy the normal, healthy bacteria in your gut. "This can affect the functioning of your digestive system, metabolism, and parts of the immune system that are in the digestive tract," Berezow says.
As Case Western Reserve University researchers found in one lab-based study on mice, antibiotics can destroy the good bacteria that work on behalf of the immune system to fight off fungal infections. Another mice study found that antibiotics made immune cells less effective at destroying bacteria, as well as changing their cells in ways that caused them to protect (instead of kill) the pathogen.
In humans, Berezow notes that changes to gut flora, or the bacteria living within your digestive tract, can also make you more susceptible to infection. And, the changes to the important microorganisms in your gut due to antibiotics can be permanent. "Your normal flora may never actually return completely to normal," Berezow says.
What a glowing green worm can teach us about our immune systems
Dennis Kim , associate professor of biology at MIT, spends his days carefully raising worms that are no bigger than a comma. The students in his lab feed them, watching them grow and multiply on petri dishes that sit in a plastic tub.
Then they infect the worms with deadly bacteria and watch them fight for their lives.
But as the worms die, humans learn how the simplest immune system can stave off a deadly infection while swimming in a world of bacteria.
“We’re interested in how (the worm) defends itself against bacteria,” Kim said. “They have an immune response that has a lot in common with a very ancient and kind of basic sort of branch of the human immune system, called the innate immune system.”
Kim’s lab is studying the innate immune system, which is a first line of defense against infections. It’s a more primitive defense system, where physical barriers keep out bacteria and immune cells swarm to infection sites to fight off pathogens. All multicellular organisms — humans, worms, plants — have this general protection, Kim said.
Humans also have what is known as an adaptive immune system. When our body is attacked by a virus or bacteria, our white blood cells develop highly specialized antibodies to attack the disease.
That response can take days to kick in, and it’s up to the innate immune system to trigger it, said Stephen Calderwood , chief of infectious disease at Massachusetts General Hospital. If the immune system is weakened, either by medications, severe injury or genetic disorders like cystic fibrosis, infections can run rampant.
“Some of the mortality that occurs from bacterial infections occurs very early, in the first 24 hours, and that’s a time when the innate immune system is most relevant. Antibiotics are very effective of course, but often don’t have an opportunity to interact with the bacterium that quickly,” Calderwood said.
The worms, seen through a microscope, swim in a “lawn” of E. coli bacteria.
Why a Tiny Worm May Have the Answers
That innate immune response is the first line of defense in humans, Kim said. But even without highly specialized antibodies, microscopic organisms can fend off infections.
“Worms and flies don’t have that adaptive immune response, so it’s that first branch where they recognize that there’s a problem, and do what they can to either neutralize or kill the microbe with making proteins that can, for example, kill bacteria,” he said.
To understand how they do it, Kim’s lab has been studying Caenorhabditis elegans , usually just called C. elegans or “the worm.” It’s a tiny worm that lives in places teeming with bacteria, like soil, compost and rotting fruit. They eat bacteria E. coli is the regular worm chow in the lab.
At first glance, worms don’t have anything in common with humans. Each adult has about 1,000 cells, 302 of which are neurons or brain cells. They are transparent. They’re hermaphrodites, meaning each worm can create both sperm and eggs. That means each of its babies is a clone of its parent.
Despite those differences, a third of the worm’s genes have human counterparts, said Joshua Meisel, one of the graduate students in Kim’s lab. To understand which genes affect its simple immune system, Meisel creates random mutations in the worm, then looks for the mutant worms that have an impaired immune response.
“So you ask in this mutant, what is the gene I mutated that is producing this defect?”, Meisel said. “So you’re understanding the function of an unknown gene that has a human counterpart that no one has ever known before. And you would not have been able to get there if you had to guess at what the gene was that was controlling the immune response.”
And its a lot simpler to do this with worms rather than mice, he said.
“To do a genetic screen in mice like that you would need many, many years and a building the size of the MIT campus to hold all the mice. But in worms we can do a forward genetic screen where we mutate all the genes in the worm genome in a shoebox like this in 10 days.”
Associate professor Dennis Kim says that studying these worms may be able to teach us how to better coexist with bacteria.
Pseudomonas aeruginosa: The ‘Scourge of the Burn Unit’
About 30 feet down the hallway from the lab is a room the size of a coat closet, where beakers full of greenish fluid are kept at 98.6 degrees Fahrenheit. Machines whir to keep the beakers spinning, circulating air inside the beakers to allow the bacteria Pseudomonas aeruginosa to thrive.
Pseudomonas is unusual because it can infect just about any organism, Kim said. If this strain was injected into a plant, it would kill the plant. Put it in a mouse, and the mouse would develop sepsis and die, he said.
The strain of Pseudomonas in his lab was cultured from a patient across the river at Massachusetts General Hospital in the 1990s, and it remains the “scourge of the burn unit,” Kim said.
Pseudomonas is one of the top five nastiest hospital-acquired infections, Calderwood said. The bacteria is in the environment all around us, and for those of us with healthy immune systems, it rarely becomes a problem, he said.
But the bacteria is notoriously antibiotic resistant, making infections tough to treat, he said. In a hospital, Pseudomonas can be carried into a patient’s lungs or blood through medical equipment — breathing tubes, IVs, needles — and it’s a common cause of hospital-acquired pneumonia.
It’s a nasty infection to look at in some patients, Calderwood said. For one thing, it has a cloyingly sweet smell to it. Kim describes it as being grape-like. Zoe Hilbert, a graduate student in Kim’s lab, says it smells like a dirty gym locker room. The bacteria can also create inflammation and cause infected wounds to ooze green pus.
And for burn patients, Pseudomonas can be fatal. Pseudomonas kills the patient’s skin tissue, and patients wait in agonizing pain for a skin graft.
“Burn wound infections with Pseudomonas can be quite difficult to look at, and obviously if you’re the patient, quite difficult to tolerate. They’re usually heavily sedated with pain medicine, obviously to keep them out of pain while the treatment takes hold,” Calderwood explained.
View through a microscope of C. elegans worms that have been tagged with a green protein.
Seeing Green and Watching the Immune System at Work
One of the advantages of using C. elegans is biologists can watch how the entire organism reacts to an infection, Kim said. But the worms are see-through, and the bacteria are even smaller that the millimeter-long C. elegans.
So the researchers make the worms and bacteria light up with a green fluorescent protein that is found in jellyfish. Scientists take the jellyfish gene for fluorescence and splice it into the DNA of a protein they want to study and watch it glow in the dark. They can tag specific tissues or individual cells, said Doug Cattie, a graduate student in Kim’s lab.
For one experiment, researchers engineered the bacteria with the glowing green protein so they could watch how the microbes made the worms ill.
“Normally when C. elegans eat bacteria, the bacteria die and burst open,” Cattie said. “When the worms get sick and the bacteria start growing inside of their intestine, then you’ll actually have division of the bacteria inside the intestine of the worm and you can see this green fluorescence glow as the bacteria become pathogenic to the worm.”
How the Worm — and Humans — Can Win
The Pseudomonas can kill the worm in just a couple of days, Kim said. But the worm can win. Its innate immune response uses a protein as warning flag, signaling to the worm’s cells to mount an attack against the Pseudomonas.
Studying those proteins can help us understand how humans’ immune systems deal with bacteria too.
“It turns out that if you look at the proteins that are involved (in) signaling the worm, many of those proteins actually have a function in mice or human cells, in defending mammalian hosts against pathogenic infection,” he said.
But what has been more surprising is that the worms learn to avoid the bad bacteria in the first place, Kim said. Not only do their bodies adapt to fight the Pseudomonas, they learn behaviors to avoid the bad bacteria. And it turns out that worms help other worms stay alive.
“They’re social organisms. They make small molecules that allow them to sense crowdedness … we think, actually, some of these sort of cues are also involved in their responses to pathogenic bacteria. So in some ways, it’s a group effort,” Kim said.
This is how worms survive in a world full of bacteria, Kim said. And by continuing to study how they survive and avoid the bad bacteria, we may understand how our own cells cope with a world of microscopic invaders, which, he said, outnumber our cells 10-1.
But we’re really not battling these bacteria all the time. “In fact, we’re just coexisting with them,” said Kim. “Yet there’s emerging evidence that there’s some communication going on.” In other words, if a worm can avoid the bad bacteria, maybe our cells can do it too, he explained.
And for those who work in infectious disease, understanding how the body’s first line of defense works could mean better survival for their high-risk patients.
“If you could figure out better how the innate immune system works, then you could probably stimulate it in a non-specific way, non-specific in relation to what kind of infection is going on,” Calderwood said. “Even if you didn’t know the infection yet for another day or two, while you’re still getting tests, the innate immune system could respond … That’s what happens in most normal people, so the question is: could we reproduce that in people who aren’t responding in a normal way, to influence the mortality in that first 24 hour window?”