In a new study, Yale researchers found that the immune cells within fat that are designed to burn calories to protect us from cold temperatures start to turn against us as we age, making the elderly more vulnerable to the cold.
The study, published in Cell Metabolism, found that the fat tissue of older mice loses the immune cell group 2 innate lymphoid cells(ILC2) which restore body heat in cold temperatures. However, trying to stimulate production of new ILC2 cells in aging mice actually makes them more prone to cold-induced death, showing how difficult it is to solve aging-related problems.
“What is good for you when you are young, can become detrimental to you as you age,” said Vishwa Deep Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology and co-corresponding author of the study.
Prof Dixit and former colleague Emily Goldberg, now an assistant professor at UCSF, were curious about why there are immune cells in fat tissue, as they are usually concentrated in pathogen-exposed areas like nasal passages, lungs, and skin. When they sequenced genes from cells of old and young mice they found that older animals lacked ILC2 cells, a deficit which limited their ability to burn fat in cold conditions.
When they introduced a molecule that boosts the production of ILC2 in aging mice, the immune system cells were restored but the mice were surprisingly even less tolerant of cold temperatures.
“The simple assumption is that if we restore something that is lost, then we are also going to restore life back to normal,” Dixit said. “But that is not what happened. Instead of expanding healthy cells of youth, the growth factor ended up multiplying the bad ILC2 cells that remained in fat of old mice.”
However, when ILC2 cells were taken from younger mice and transplanted into older mice, the older animals’ cold tolerance was restored.
“Immune cells play a role beyond just pathogen defense and help maintain normal metabolic functions of life,” Dixit said. “With age, the immune system has already changed and we need to be careful how we manipulate it to restore the health of the elderly.”
Researchers have described how tissue-resident memory T (TRM) cells behave in different tissues around the body, in a step towards novel, long-lasting vaccines.
Applications include second generation COVID vaccines, that would target lung tissue directly.
TRM cells are an immune cell that are exclusively found in tissues, not in circulation or the blood, and have been found to be critical for immune protection against viral infection and are also able to control melanoma growth in the skin.
In this study, led by University of Melbourne Professor Laura Mackay and published in Nature Immunology, examined the behaviour of TRM cells in a number of different body tissues.
By comparing barrier organs that are exposed to the environment, like the skin, to solid organs such as the liver, the team found that the location in which TRMs are raised significantly impacts the way they contribute to immunity, demonstrating that “one size does not fit all” when it comes to these cells.
Postdoctoral researcher Dr Susan Christo said that discovering the distinct molecular signatures and behaviours of TRM cells in specific tissues will help the development of effective T cell-based vaccines and immunotherapies.
“For example, if you want effective T-cell mediated immunity against a respiratory virus like SARS-CoV-2 or influenza, you want to induce TRM cells in the lung. That way, the memory of the infection exists at the site of potential pathogen encounter,” Dr Christo said.
“We found that TRM cells act like chameleons when they enter into a new tissue — they rapidly adapt to the molecules and proteins around them and can take on a new ‘image’ or phenotype.
“The tissue surroundings also control how these cells behave — TRM cells in the skin are suppressed by a particular protein called TGF-b which acts like a handbrake to stop these cells from unnecessary activation that may cause autoimmunity, such as psoriasis, but still allows them to fight against dangers like melanoma.
“One key advantage of skin TRM cells is that they can last a really long time and will be ready to attack when the body is in true danger.
The team found the TRMs inside the liver do not have this TGF-b brake, and so have a greater ability to form a bigger pool of cells.
“You could think of them as generating a large army of soldiers that fight the infection. However liver TRMs have a shorter half-life and might not be around to fight future battles,” Dr Christo explained.
“To give the example of malaria, if you want to target immune cells in the liver, you need to work out what needs to be done to make those cells live longer.
“This is also the case for short-lived TRM cells in the lung, which has significant implications on the durability of vaccines against the flu and COVID. Therefore, our study provided the first evidence of what our immune cells need to last the distance and protect us for a long time.”
Colourised scanning electron microscope image of a natural killer cell. Credit: National Institutes of Health
A newly discovered lipid ‘shield’ that prevents natural killer cells from being destroyed by their own deadly biological weapons also allows some cancer cells to evade an immune system attack, a study at Columbia University has found.
The findings, which may lead to new treatments for aggressive cancers, were published in the journal PLoS Biology.
Natural killer cells are efficient assassins that can eliminate up to six infected or cancer cells each day. The deadly immune cells grab onto their target and blast it with toxic proteins and enzymes that punch holes in the cell’s membrane. But these substances are also capable of destroying the natural killer cell’s membrane during the attack.
But how do natural killer cells survive releasing this blast of deadly substances? “I’ve been working on natural killer cells since the early 1990s, and every time I gave a talk about these cells, someone always asked that question,” said study leader and immunology expert Jordan Orange, MD, PhD, a professor at Columbia University Vagelos College of Physicians and Surgeons. “And nobody really knew until now.”
Avoiding self-destruction
Yu Li, a graduate student working with Prof Orange to understand how natural killer cells work and co-author of the study, thought the answer might lie in the double layer of lipids that makes up the outer membranes of all cells. Compared with other cells, Li noticed, the membranes of natural killer cells looked more orderly and more densely packed with lipids when viewed under a microscope.
“There were a lot of hypotheses about why natural killer cells don’t kill themselves during their attack on other cells, but they all proposed there might be a magic, unknown protein protecting these cells,” Li says. But Li had doubts. “Based on biophysical considerations, I didn’t think a protein would be strong enough to protect the cells. When I looked at the cells, I thought of lipids.”
To test out his idea, he exposed the membranes to a compound that weakens the structure of the lipid layer. With less dense and less orderly membranes, the natural killer cells were unprotected from their own toxic blast—and perished along with their targets.
Shields up
To survive their own toxic blast natural killer cells reinforce their membranes immediately beforehand, Li found. The small granules holding the deadly substances move to the outer edge of the natural killer cell. As the granule unleashes its cargo into the space between the killer and target cells, its own unusually dense lipid membrane merges with and reinforces the natural killer cell membrane.
“In essence, Li found that the membrane turns into a blast shield,” Prof Orange says. “And the protection comes from the way the membrane’s lipids are arranged. When the lipids are arranged in a more orderly fashion, more lipids can be packed into the membrane. The toxic substances simply can’t find a way into the membrane,” Orange says.
Cancer cells steal the idea
Besides natural killer cells, some cancer cells have adopted this defence against natural killer cells’ attacks, Li and Prof Orange found. They may also use this as a defence from cytotoxic T cells, another immune cell that uses lipids for self-protection.
Li found that cells from an aggressive breast cancer known to be impervious to natural killer cells fortify their membranes during the attack. The reinforcement was vital for the cancer cells, Li discovered, because when he added a membrane compound that disrupts lipid packing, the cancer cells were rendered vulnerable.
“We don’t know yet if this is a general mechanism by which cancer cells resist natural killer cells,” Li said. “If it is generalisable, we can start to think of therapies that disrupt the tumor cell membrane and make it more susceptible to attack by the immune system.”
Neutrophil interacting with two pink-colored, rod shaped, multidrug-resistant (MDR), Klebsiella pneumoniae. Photo by CDC on Unsplash
Scientists have found evidence suggesting that giving patients ACE inhibitors reduces the ability of their immune system to resist bacterial infections. the group describes testing of multiple ACE inhibitors in mice and human cells.
ACE inhibitors are typically given to patients with hypertension, and some instances to people with heart failure, kidney disease or diabetes. The drugs relaxes the walls of arteries, veins and capillaries, reducing blood pressure. Some prior studies had shown that the drugs also help the immune system by boosting neutrophils, which are produced to fight bacteria. In this new study, published in the journal Science Translational Medicine, the researchers have found the opposite to be true.
In order to see the effects of ACE inhibitors on the immune system, researchers at Cedars-Sinai Medical Center administered different brands of ACE inhibitor such as Zestril and Altace, to mice and then tested their ability to resist bacterial infections. Compared to untreated mice, those with the ACE inhibitors had greater difficulty in recovering from bacterial infections such as staph.
Seven human patients who were taking an ACE inhibitor volunteered blood samples to measure their immune response. The researchers found that the neutrophils were unable to produce the molecules needed to fight off bacteria. They were also found to be in vitro ineffective against bacteria.
The researchers also tested another drug used to treat hypertension, an angiotensin II receptor drug, Cozaar. These drugs work by preventing arterial walls from constricting, which reduces blood pressure. They found no evidence of a negative impact on immunity. They did not test beta-blockers, which work by preventing adrenergic receptors from being stimulated, reducing cardiac action.
The researchers concluded that administering ACE inhibitors to patients puts them at an increased risk of bacterial infections, noting that doctors may want to try alternative drugs to treat their patients.
Journal information: Duo-Yao Cao et al, An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abj2138
Infected cell covered with SARS-CoV-2 viruses (yellow). Source: NIAID
New research with monkeys reveals that primates do not need T cells for the recovery of from acute COVID infections.
T cell depletion was also found not to induce severe disease, and T cells do not explain the natural resistance of rhesus macaques to severe COVID. Furthermore, it was found that strongly T cell-depleted macaques still develop potent memory responses to a second infection.
The findings, published in mBio, an open-access journal of the American Society for Microbiology, have implications for the development of second-generation vaccines and therapeutics.
Lead study author Kim Hasenkrug, PhD, senior investigator in the Laboratory of Persistent Viral Diseases, National Institutes of Health, explained: “We started this study early in the pandemic, trying to figure out how to make a good model to study the disease in humans using animals. The monkeys turned out to be more resistant to the disease than we expected, so we wanted to try to figure out why that was and try to gain some insights into the disease in humans as well. We now know that the antibody response is the most critical response for protection by vaccination, not the T cell response.”
In the new study, the researchers used classic reagents known to deplete CD4+ and CD8+ T cells in rhesus macaques. CD8+ T cells attack infected cells and kill them, and CD4+ T cells are helper T cells that set off the immune response by recognising pathogens and secreting cytokines, which signal other immune cells to act, including CD8+ T cells and antibody-producing B cells.
One week after depleting the macaques of CD4+ T cells, CD8+ T cells, or both at the same time, the researchers infected the animals with SARS-CoV-2. “We depleted, we infected them and then we continued the depletions during the first week of infection to make sure the animals were well depleted. Then we studied their blood to see how they were responding in terms of their T cells and B cells,” said Hasenkrug. Nasal swabs and bronchoalveolar lavages were performed over six weeks to measure virus in the nose, mouth and lungs, along with rectal swabs to check for virus shedding in the gut. After six weeks, the monkeys were re-challenged with SARS-CoV-2 and virus and blood samples collected, which let the researchers evaluate immune memory responses. “If there is a memory response, you get a much quicker immune response and control of the virus. That is how vaccinations work. Once your body has seen a viral pathogen, the next time it sees it, you can get a much faster and stronger immune response,” said Dr Hasenkrug.
Unexpected response
Even with T cell depletion, the monkeys were still able to mount a good memory response against the virus. “We found we got really good memory responses regardless of whether we depleted T cells or not. Basically, we found very strong virus neutralising antibodies, and they are the most important antibodies in controlling the infection. That was unexpected by most immunologists, virologists and vaccinologists,” said Dr Hasenkrug.
“The other thing that happens during a memory response is that antibodies mature, becoming stronger and more potent at binding the viral pathogen. We saw indications of this through what’s called ‘class switching’,” said Dr Hasenkrug.
‘Class switching’ was also not expected in these monkeys with depleted T cells. “We don’t have a firm explanation as to why that happened, but we think it involves some sort of compensatory response, which you can see in our study. For example, when we depleted CD8+ T cells, we saw stronger CD4+ T cell or B cells responses in some animals. When the animals are missing something, they will try to make up for it by making more of something else.”
Dr Hasenkrug doesn’t know why the T cells turned out to be not very important, but this may be a good thing, since people who fail to mount sufficient T cell responses still have opportunities to recover.
“This implies that the innate immune response is critical for initial control of the virus, rather than the adaptive immune responses we studied,” said Hasenkrug.
Journal information: Hasenkrug, K.J., et al. (2021) Recovery from Acute SARS-CoV-2 Infection and Development of Anamnestic Immune Responses in T Cell-Depleted Rhesus Macaques. mBio. doi.org/10.1128/mBio.01503-21.
Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash
A potential treatment has been identified, that could boost the immune system’s ability to find and destroy cancer cells, by impeding certain cells which regulate the immune system, which in turn can unleash other immune cells to attack tumours in cancer patients.
“A patient’s immune system is more than able to detect and remove cancer cells and immunotherapy has recently emerged as a novel therapy for many different types of cancers,” explained study leader Nullin Divecha, Professor of Cell Signalling at the University of Southampton. “However, cancer cells can generate a microenvironment within the tumour that stops the immune system from working thereby limiting the general use and success of immunotherapy,” he continued.
One of a number of types of T cells, Teffector cells (Teffs) carry out the task of detection and removal of cancer cells . How well Teff cells work in detecting and removing cancer cells is partly governed by other T cells called T-regulatory cells, or Tregs for short. Tregs physically interact with the Teff cells, producing molecules which dampen the functioning of the Teff cells.
Prof Divecha added, “Tregs carry out an important function in the human body because without them, the immune system can run out of control and attack normal cells of the body. However, in cancer patients we need to give the Teff cells more freedom to carry out their job.”
Molecules released by tumour cells exacerbate the problem by attracting and gathering Tregs, reducing the activity and function of Teff cells even further. Though there are mechanisms to inhibit Treg cells, since Treg and Teff cells are very similar, Teff cells are also generally inhibited.
In this new study, published in PNAS, scientists from the University of Southampton and the National Institute of Molecular Genetics in Milan showed that inhibition of a family of enzymes in cells called PIP4K could be the answer to how to restrict Tregs without affecting Teffs.
The research team isolated Tregs from healthy donors and used genetic technology to suppress the production of the PIP4K proteins. They saw that loss of PIP4Ks from Treg cells stopped their growth and response to immune signals, in turn stopping them from impeding Teff cell growth and function.
Importantly, the loss of the same enzymes in Teff cells did not limit their activity.
“This was surprising because PIP4Ks are in both types of T cells in similar concentrations but our study shows that they seem to have a more important function for Tregs than Teffectors,” said Dr. Alessandro Poli who carried out the experimental research.
Scientists must next develop molecules in order to inhibition of PIP4K as a potential therapy for patients. “Towards this end we show that treatment with a drug like inhibitor of PIP4K could enable the immune system to function more strongly and be better equipped to destroy tumour cells.”
Researchers have found that the course of severe COVID could be determined very early on, depending on the body’s initial reaction to the disease in the upper airway as well as inflammatory reactions.
Scientists at the Ragon Institute of MGH, MIT, and Harvard; the Broad Institute of MIT and Harvard; Boston Children’s Hospital (BCH); MIT; and the University of Mississippi Medical Center (UMMC) wondered whether COVID’s path towards severe disease could start much earlier than expected — perhaps even within the initial response created when the virus enters the nose.
To test this, they studied cells taken from nasal swabs of patients at the time of their initial COVID diagnosis, comparing patients who went on to develop mild COVID to those who progressed into more severe disease and eventually required respiratory support. Their results showed that patients who went on to develop severe COVID exhibited a much more muted antiviral response in the cells collected from those early swabs, compared to patients who had a mild course of the disease. The paper appears in Cell.
“We wanted to understand if there were pronounced differences in samples taken early in the course of disease that were associated with different severities of COVID as the disease progressed,” said co-senior author José Ordovás-Montañés, an associate member in the Klarman Cell Observatory at Broad and assistant professor at BCH and Harvard Medical School. “Our findings suggest that the course of severe COVID may be determined by the body’s intrinsic antiviral response to initial infection, opening up new avenues for early interventions that could prevent severe disease.”
To understand the early response to infection, Sarah Glover of the Division of Digestive Diseases at UMMC and her laboratory collected nasal swabs from 58 people, 35 of whom were just recently diagnosed with COVID, representing a variety of disease states from mild to severe. Seventeen swabs came from healthy volunteers and six came from patients with other causes of respiratory failure. The team sequenced RNA from these samples to find out what kind of proteins the cells were making — a snapshot of the cell’s activity when collected.
By studying a cell’s transcriptome, which is its collection of RNA, can researchers understand how a cell is responding to environmental changes such as a viral infection. It can even be used to see if individual cells are infected by an RNA virus-like SARS-CoV-2.
“Our single-cell sequencing approaches allow us to comprehensively study the body’s response to disease at a specific moment in time,” said co-senior author Alex Shalek, who is also an associate professor at MIT in the Institute for Medical Engineering & Science, the Department of Chemistry, and the Koch Institute for Integrative Cancer Research. “This gives us the ability to systematically explore features that differentiate one course of disease from another as well as cells that are infected from those that are not. We can then leverage this information to guide the development of more effective preventions and cures for COVID and other viral infections.”
Analysing the transcriptome, the team investigated how epithelial and immune cells were responding to early COVID infection from the single-cell transcriptome data. Firstly, in patients who progressed to severe COVID, the initial interferon-driven antiviral response was muted. Second, patients with severe COVID had higher amounts of highly inflammatory macrophages, and high inflammation levels are often seen in severe or fatal COVID.
Since these samples were taken well before COVID had peaked in the patients, both these findings indicate that COVID’s course may be determined by the initial response of the nasal epithelial and immune cells to the virus. The weak initial antiviral response may allow a rapid spread of the virus, making it more likely to move from upper to lower airways, while the recruitment of inflammatory immune cells could help drive the dangerous inflammation in severe disease.
Finally, the team also identified infected host cells and pathways associated with protection against infection — cells and responses unique to patients that went on to develop mild disease. These findings may allow researchers to discover new therapeutic strategies for COVID and other respiratory viral infections.
If the early stages of infection can determine disease, it could enable the development of early interventions that can help prevent the development of severe COVID. Potential markers of severe disease were also identified, genes that were expressed in mild, but not severe COVID.
“Nearly all our severe COVID samples lacked expression of several genes we would typically expect to see in an antiviral response,” said co-first author Carly Ziegler, a graduate student in the Health Science and Technology Program, MIT and Harvard.
“If further studies support our findings, we could use the same nasal swabs we use to diagnose COVID-19 to identity potentially severe cases before severe disease develops, creating an opportunity for effective early intervention,” said Ziegler.
Journal information: Ziegler, C G K., et al (2021) Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. Cell. doi.org/10.1016/j.cell.2021.07.023.
New research has shown that many fibromyalgia syndrome (FMS) symptoms are caused by antibodies that increase the activity of pain-sensing nerves throughout the body.
The results show that fibromyalgia is a disease of the immune system, rather than the currently held view that it originates in the brain.
Characterised by widespread muskoleskeletal pain, as well as fatigue and emotional distress, fibromyalgia is estimated to affect1 in 40 people (80% of which are women). It most commonly develops between the ages of 25 and 55, although children can also get it.
The study by Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, in collaboration with the University of Liverpool and the Karolinska Institute,, demonstrates that the increased pain sensitivity, muscle weakness, reduced movement, and reduced number of small nerve-fibres in the skin that are typical of FMS are all a consequence of patient antibodies.
The researchers injected mice with antibodies from people living with FMS and saw that the mice became more sensitive to pressure and cold, as well as displaying reduced movement grip strength. In contrast, those injected with antibodies from healthy people were unaffected, showing that patient antibodies cause at least part of the disease.
Furthermore, the mice injected with fibromyalgia antibodies recovered after a few weeks, when antibodies had been cleared from their system. This finding strongly suggests that therapies which reduce antibody levels in patients are likely to be effective treatments. Such therapies are already available and are used to treat other disorders that are caused by autoantibodies.
Primary investigator Dr David Andersson, from King’s IoPPN said: “The implications of this study are profound. Establishing that fibromyalgia is an autoimmune disorder will transform how we view the condition and should pave the way for more effective treatments for the millions of people affected. Our work has uncovered a whole new area of therapeutic options and should give real hope to fibromyalgia patients.
“Previous exploration of therapies has been hampered by our limited understanding of the illness. This should now change. Treatment for FMS is focussed on gentle aerobic exercises, as well as drug and psychological therapies designed to manage pain, although these have proven ineffective in most patients and have left behind an enormous unmet clinical need.”
Dr. Andreas Goebel, the study’s principle clinical investigator from the University of Liverpool said, “When I initiated this study in the UK, I expected that some fibromyalgia cases may be autoimmune. But David’s team have discovered pain-causing antibodies in each recruited patient. The results offer amazing hope that the invisible, devastating symptoms of fibromyalgia will become treatable.”
Professor Camilla Svensson, the study’s primary investigator from Karolinska Institute said, “Antibodies from people with FMS living in two different countries, the UK and Sweden, gave similar results, which adds enormous strength to our findings. The next step will be to identify what factors the symptom-inducing antibodies bind to. This will help us not only in terms of developing novel treatment strategies for FMS, but also of blood-based tests for diagnosis, which are missing today.
Dr Craig Bullock, Research Discovery and Innovations Lead at Versus Arthritis said: “This research shows that antibodies found in human blood can cause fibromyalgia-like symptoms in mice, suggesting that these antibodies play a crucial role in the condition. Further research is needed but this offers hope to the millions of people with fibromyalgia that an effective treatment could be found in the relatively near future.”
Journal information: More information: Andreas Goebel et al, Passive transfer of fibromyalgia symptoms from patients to mice, Journal of Clinical Investigation (2021). DOI: 10.1172/JCI144201
A new study finds that a connective tissue protein also encourages immune responses that fight bacterial infections, while restraining responses that can be deadly in sepsis.
The study focuses on the extracellular matrix (ECM) of connective tissues, once viewed merely as structural material. It is now increasingly recognised as a signaling partner with nearby cells in normal function, as well as being involved in disease. Fibroblasts are important players in the ECM; these cells make tough structural matrix proteins like collagen. The study was published online June 28 in the Proceedings of the National Academy of Sciences.
The new analysis found that lumican, a protein-sugar combination (proteoglycan) secreted by fibroblasts, and known to partner with collagen in connective tissues, also promotes immune system responses in immune cells called macrophages that fight bacterial infections. The study also found that lumican protects tissues by holding back a different type of immune response that reacts to DNA, whether from an invading virus, or released from cell death.
Such inflammatory responses are a transition into healing, but in sepsis they grow out of control, causing damage to the body’s own tissues. Sepsis affects 48.9 million people worldwide, the authors said, but the ECM’s role the condition is largely unknown.
“Lumican may have a dual protective role in ECM tissues, promoting defense against bacteria on the one hand, and on the other, limiting immune overreactions to DNA that cause self-attack, or autoimmunity,” said corresponding study author Shukti Chakravarti, PhD, professor in the Department of Ophthalmology and the Department of Pathology at NYU Langone Health.
The findings suggest that connective tissue, and extracellular matrix proteins like lumican, usually operate outside of cells, but as disease or damage break down ECM, get sucked into and regulate immune cells homing in on the damage.
Lumican interacts with two proteins on surfaces of immune cells that control the activity of toll-like receptors, which recognise structural patterns common to molecules made by invading microbes, said the researchers. As they are less specific than other parts of the immune system, toll-like receptors can also cause attacks by immune cells on the body’s own tissues if over-activated.
In this study, the researchers found that lumican promotes the ability of toll-like receptor (TLR)-4 on the surfaces of immune cells to recognise bacterial cell-wall toxins called lipopolysaccharides (LPS). Lumican, by attaching to two proteins, CD14 and Caveolin1, probably using collagen-covered regions, stabilises their interactions with TLR4 to increase its ability to react to LPS. This results in production of the signalling protein TNF alpha, which amplifies immune responses.
Along with describing the effect of lumican on the surfaces of immune cells, the new study finds that lumican is taken up from outside cells into membrane-bound pouches, called endosomes, and pulled into cells. Such compartments deliver ingested bacteria to other endosomes that destroy them, heighten inflammation, or produce protective interferon responses. Once pulled inside, the researchers found, lumican bolstered TLR4 activity by slowing down its passage into lysosomes, pockets where such proteins are broken down and recycled.
However, while it encouraged TLR4 activity on cell surfaces, lumican, once inside immune cells, had the opposite effect on toll-like receptor 9 (TLR9), which reacts to DNA instead of bacterial LPS.
Mice with the lumican gene deleted had trouble both fighting off bacterial infections (less cytokine response, slower clearance, greater weight loss), and trouble restraining the immune overreaction to bacteria (sepsis). Elevated lumican levels were also found in human sepsis patients’ blood plasma, and that human immune cells (blood monocytes) treated with lumican had elevated TLR4 activity but suppressed TLR9 responses.
“As an influencer of both processes, lumican-based peptides could be used as a lever, to tweak inflammation related to TNF-alpha, or endosomal interferon responses, to better resolve inflammation and infections,” suggested George Maiti, PhD, a postdoctoral fellow in Dr Chakravarti’s lab.
“Our results argue for a new role for ECM proteins at sites of injury. Taken up by incoming immune cells it shapes immune responses beyond the cell surface by regulating the movement and interaction of endosomal receptors and signaling partners,” said Dr Chakravarti.
Journal information: George Maiti et al., “Matrix lumican endocytosed by immune cells controls receptor ligand trafficking to promote TLR4 and restrict TLR9 in sepsis,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2100999118
Scanning electron micrograph of methicillin-resistant Staphylococcus aureus and a dead human neutrophil. Credit: NIAID
Researchers have uncovered a novel trick employed by the bacterium Staphylococcus aureus — MRSA uses toxins to ‘fight dirty’ and stifle the immune response. This finding is a step towards one day producing a vaccine against MRSA.
Every year, there are some 700 000 deaths due to the emerging global threat of antimicrobial resistance (AMR). Turning the tables against AMR requires immediate action, and the development of novel vaccines to prevent such infections in the first place, are an attractive and potentially very effective option.
Staphylococcus aureus is the causative agent of the infamous MRSA ‘superbug’, one of the chief concerns of AMR. Immunologists from Trinity College Dublin, working with scientists at GSK, discovered the deadly bacteria’s new trick to foil the immune system. They found that the bacterium interferes with the host immune response by causing toxic effects on white blood cells, preventing them from carrying out their infection-fighting jobs.
The study also showed that the toxicity could be lessened following vaccination with a mutated version of a protein specifically engineered to throw a spanner in the MRSA works. This could one day lead to a vaccine for humans.
Rachel McLoughlin, Professor in Immunology in Trinity’s School of Biochemistry and Immunology and the Trinity Biomedical Sciences Institute (TBSI), said: “As a society we are witnessing first-hand the powerful impact that vaccination can have on curbing the spread of infection. However, in the backdrop of the COVID epidemic we must not lose sight of the fact that we are also waging war on a more subtle epidemic of antimicrobial resistant infection, which is potentially equally deadly.
“In this study we have identified a mechanism by which a protein made by the bacterium – known as Staphylococcal Protein A (SpA) – attacks and rapidly kills white blood cells. This protein has been widely studied for its immune evasion capacity and has a well-documented role in rendering antibodies raised against the bacterium non-functional.
“Here we uncover a previously undocumented strategy by which SpA forms immune complexes through its interaction with host antibodies, that in turn exert toxic effects on multiple white blood cell types. This discovery highlights how important it will be for effective vaccines to be capable of disarming the effects of protein A.”
Dr Fabio Bagnoli, Director, Research & Development Project Leader, GSK, said: “Our collaboration with Trinity College Dublin and in particular with Professor Rachel McLoughlin, a worldwide recognised expert on staphylococcal immunology, is critical for increasing our knowledge on protective mechanisms against S. aureus.”
The study documents the latest discovery made by this group at Trinity under an ongoing research agreement with GSK Vaccines (Siena, Italy). Overall, this collaboration aims to increase understanding of the immunology of Staphylococcus aureus infection to advance development of next-generation vaccines to prevent MRSA infections.
Journal information: Fox, P. G., et al. (2021) Staphylococcal Protein A Induces Leukocyte Necrosis by Complexing with Human Immunoglobulins. Scientific Reports. doi.org/10.1128/mBio.00899-21.
