Scientists predict that we are entering the era of pandemics.
A sustainable global commitment to pandemic preparedness is instrumental to maintaining the upper hand and winning the battle.
In collaboration with the Abbott Pandemic Defense Coalition, CERI unveiled a new genomics facility to help identify, analyse and test infectious diseases in Africa to enable early detection and rapid responses to potential viral threats.
With the increasing rates of urbanisation, global travel and climate change, infectious disease experts predict the world is entering a new era of pandemics. In response to this, Abbott founded the Abbott Pandemic Defense Coalition which comprises of 20 scientific and public health organisations from across the globe who are committed to detecting and responding to emerging viral threats.
Since its launch in 2021, the global Coalition has partnered with organisations in Africa to build up the network and capabilities in the region. The Centre for Epidemic Response and Innovation (CERI) at Stellenbosch University is one of the recent partners, who recently unveiled a new genomics facility that will enable early detection and the rapid response to emerging threats in Africa in collaboration with the Abbott Pandemic Defense Coalition.
“No one organisation, network or country is strong enough to effectively fight against viral pathogens,” says Mary Rodgers, principal scientist at Abbott’s diagnostics business. “We therefore must have an ongoing global commitment to pandemic preparedness – and key to that is collaboration across the private and public sectors to detect and have a rapid response to emerging threats. Our partnership with CERI will expand testing capacity to continue research in understanding how known viruses are spreading in order to identify new viral outbreaks, so that we can stop them from becoming the next pandemic.”
New Technology to Detect Viral Threats in Africa
The state-of-the-art genomics facility is equipped with new technology such as the Metagenomics Next Generation Sequencing which is revolutionising how viruses are discovered – creating a genome that once took years to complete can now be sequenced and analysed in a day or two. The genomics center will also have access to Abbott’s diagnostics molecular lab testing capabilities to provide fast and scalable molecular testing, as well as provide researchers the ability to create molecular tests for new and emerging viral threats.
Professor Tulio de Oliveira, director of CERI concludes, “The partnership with the Abbott Pandemic Defense Coalition will help train Africa’s next generation of virus hunters and public health experts in cutting-edge sequencing, bioinformatics, and other technologies so that they can track and identify viruses faster and smarter. The launch of this new genomics facility is a testament to our shared commitment to advancing scientific knowledge and protecting public health in Africa.”
Colourised transmission electron micrograph of hepatitis B virus particles (colourised red and yellow). Credit: NIAID and CDC (Transmission electron micrograph image courtesy of CDC; colourisation by NIAID).
In 2020, bulevirtide (BLV) was conditionally approved for treating chronic hepatitis delta (CHD), an inflammation of the liver caused by hepatitis D virus (HDV). Now, as reported in the Journal of Hepatology, real-world studies confirm that long-term suppressive therapy with BLV monotherapy reduces viral replication and improves liver tests of these difficult-to-treat patients.
Two of the studies, led by Pietro Lampertico, MD, PhD, were designed to assess the effectiveness and safety of patients with advanced HDV-related compensated cirrhosis being treated with BLV 2mg monotherapy and the consequences of discontinuing this treatment.
“HDV is the most severe form of chronic viral hepatitis,” explained Dr Lampertico. “For many years, the only therapeutic option was the off-label administration of pegylated-interferon-alpha (PegIFNa), an approach characterised by suboptimal efficacy, an unfavourable safety profile and several contraindications.”
In a study of 18 patients with HDV-related advanced cirrhosis treated with BLV 2mg/day for 48 weeks, Dr. Lampertico and colleagues demonstrated significant virological, biochemical and combined response rates associated with improvement of liver function.
“The efficacy and safety of BLV monotherapy in patients with advanced compensated cirrhosis were unknown before this study. Virological and biochemical responses to BLV monotherapy that we observed in our difficult-to-treat patients with HDV-related compensated cirrhosis were similar to those shown in the phase III registration study,” Dr Lampertico noted.
In a case report, Dr Lampertico and colleagues demonstrated that HDV could be successfully eradicated from both serum and liver following a three-year course of BLV monotherapy. This was despite the persistence of HBsAg, in a patient with HDV-related compensated cirrhosis and oesophageal varices. During the 72-week off-BLV follow-up, liver biopsy, intrahepatic HDV RNA and hepatitis D antigen were undetectable, less than 1% of hepatocytes were HBsAg positive and all were negative for hepatitis B core antigen.
“We were surprised to demonstrate that HDV can be eradicated following a finite course of an entry inhibitor administered as monotherapy such as BLV 2mg/day, despite the persistence of HBsAg positivity,” commented Dr Lampertico.
In a study in JHEP Reports led by Katja Deterding, MD, investigators report the first data from the largest multicentre cohort of patients to date who were treated with BLV under real-world conditions. This included 50 patients with signs of significant portal hypertension, elevated pressure in the major vein that leads to the liver.
The retrospective analysis of 114 cases covered 4289 patient weeks of BLV treatment. Viral response was observed in 87 cases while hepatic inflammation improved, and treatment was well tolerated. More than 50% of patients showed a virologic response with less than 10% of patients not achieving an HDV RNA drop of at least 90% after 24 weeks. An improvement of biochemical hepatitis activity as measured by the liver enzyme alanine transaminase (ALT) values was observed regardless of virologic response. Investigators concluded that treatment was safe and well tolerated and associated with improvements in liver cirrhosis and portal hypertension with prolonged treatment.
“In line with other real-world cohorts and clinical trials our real-world study confirms the antiviral activity of BLV,” noted Dr Deterding. “We were surprised to see an improvement in biochemical hepatitis activity even in cases without viral response. Potential explanations for this phenomenon include anti-inflammatory properties of BLV.”
“This is the first time that patients with HDV-related chronic advanced liver disease can be treated with an antiviral therapy since 1977 when HDV was discovered. Long-term suppressive therapy with BLV 2mg/day has the potential to improve survival, of these difficult-to-treat patients for the first time in 45 years,” concluded Dr Lampertico. “We also found that BLV treatment can be successfully discontinued in some HDV patients who achieved long-term viral suppression while on therapy.”
HDV infection occurs when people become infected with both hepatitis B and D virus either simultaneously (co-infection) or acquire the hepatitis D virus after first being infected with hepatitis B (super-infection). According to the World Health Organization, HDV affects nearly 5% of individuals with a chronic infection resulting from hepatitis B virus (HBV). Populations that are more likely to have HBV and HDV co-infection include indigenous populations, haemodialysis recipients and individuals who inject drugs.
Pompe disease (PD) is an autosomal-recessively inherited neuromuscular disease that can be fatal if it is not diagnosed and treated early.1 Due to lack of acid alpha-glucosidase (GAA), there is progressive intracellular accumulation of glycogen, which can severely damage the muscles and heart.1
PD can present from early infancy into adulthood, with variable rates of disease progression.1 Severity is determined by age of onset, organ involvement, including the degree of muscle involvement (skeletal, respiratory, and cardiac), and rate of progression.1
Classification1
PD is classified into two groups: infantile and late-onset.
Infantile form:
• Classic infantile PD is most severe and rapidly progressive, and is characterised by prominent cardiomegaly, hepatomegaly, muscular weakness and hypotonia. Death results from cardiorespiratory failure in <1 year, if not treated.
• Infantile variant form (non-classic, in the <1-year group that has slower progression and less severe or absent cardiomyopathy).
Late-onset form:
• Childhood/juvenile or muscular variant (heterogeneous group) presenting later than infancy and typically excluding cardiomyopathy.
• Adult-onset form characterised by slowly progressive myopathy predominantly involving skeletal muscle and presenting as late as the 2nd – 6th decade of life.
Signs and symptoms
In infants, symptoms begin in the first months of life, with feeding problems, poor weight gain, breathing difficulties, profound hypotonia, and cardiomegaly.2 Many infants with PD also present with macroglossia.2
Kelly du Plessis, CEO and Founder of non-profit organisation, Rare Diseases SA (RDSA), says that the difficulty for both parents and healthcare professionals is that PD shows itself in many ways. “There is not one specific thing that you can pinpoint. My child, who is a PD sufferer, took longer to reach his milestones, and got slower as time progressed. It is better to be overcautious than under-cautious because early identification is critical to a positive outcome, and the damage done up until diagnosis cannot be undone.”
Du Plessis says that RDSA is also seeing many more adults being diagnosed with PD lately, and describes a few of the signs and symptoms: “In adults these include difficulty walking, particularly up stairs or inclines, recurring chest infections, being very fatigued, finding that their arms are getting weaker when they try to reach something on a top shelf, and falling over quite often owing to lower muscle tone and foot drop. Healthcare professionals need to be aware of this link with PD – because early intervention is critical to outcomes.”
Diagnosis
While making an early diagnosis is imperative to optimise disease management and outcomes,1 many patients experience a diagnostic odyssey.3
Monique Nel, Medical Advisor – Rare Diseases at Sanofi, says: “The diagnostic odyssey for PD can be quite long and complicated, as the symptoms can be similar to those of other conditions, and the disease is quite rare. The journey to diagnosis can take years, and many patients go through a battery of tests and specialists before finally receiving a correct diagnosis.”
In the United States it was reported that before implementation of newborn screening, there was, on average, a 3-month delay in diagnosing infantile-onset PD after the onset of symptoms.3 In late-onset PD, symptoms may begin any time from infancy to adulthood.3 In paediatric onset cases, on average: symptom onset occurs at approximately 6 years of age, yet diagnosis is generally made around 18 years of age, with a potential 12-year delay in diagnosis.3 The average age of symptom onset in adult-onset PD is 35 years, with a 7-year delay in diagnosis after symptom onset.3
Adds Nel: “In South Africa, we do enzyme activity testing via a dried blood spot test to measure the activity of the alpha-glucosidase enzyme. If the enzyme activity is low, it suggests that the individual may have PD. Genetic testing is currently performed abroad. This involves analysing a person’s DNA to look for mutations in the GAA gene. If two mutated copies of the GAA gene are found, it confirms a diagnosis of PD.”
Treatment
Enzyme replacement therapy (ERT) is available for all forms of PD, and has dramatically changed patient outcomes.3 This life-changing therapy is more effective when started before the onset of symptoms.3
Since the end of 2012, ERT (as alglucosidase alfa) has been registered with the South African Health Products Regulatory Authority (SAHPRA) for use in PD patients.1 Patients with infantile-onset PD who receive ERT have significantly prolonged survival, decreased cardiomegaly, and improved cardiac and skeletal muscle function.1 Cardiac response appears to be good, irrespective of the stage of disease at initiation of ERT, while the skeletal muscle response appears more variable.1 The best skeletal muscle response occurs when ERT is administered prior to skeletal muscle damage.1
Says Nel: “Early screening for PD and prompt treatment is crucial to prevent or delay the onset of disease complications. Therefore, healthcare providers must consider PD as a potential differential diagnosis when evaluating patients with muscle weakness, respiratory difficulties, and other related symptoms.”
Says du Plessis: “With medication, you see a difference in the patients within weeks, and they have a lot more energy. RDSA advocates as much as is necessary to get patients approved for medication, since this treatment changes their lives and quality of life – and in fact saves their lives. We need to do everything we can now, with the treatments we have today, to keep these patients as healthy as possible, so that they can benefit from the treatments that come tomorrow.”
It may be better to let a mild fever run its course instead of automatically reaching for medication, new University of Alberta research suggests. Researchers found that, in fish models, untreated moderate fever helped them to quickly their infections, keep inflammation in check and repair damaged tissue. “We let nature do what nature does, and in this case it was very much a positive thing,” says ProfessorDaniel Barreda, immunologistand lead author on the study which is published in eLife.
Moderate fever is self-resolving, meaning that the body can both induce it and shut it down naturally without medication, Barreda explains. The health advantages of natural fever to humans still have to be confirmed through research, but the researchers say because the mechanisms driving and sustaining fever are shared among animals, it is reasonable to expect similar benefits are going to happen in humans.
That suggests the need to resist taking non-steroidal anti-inflammatory drugs at the first signs of a mild temperature, he says. “They take away the discomfort felt with fever, but you’re also likely giving away some of the benefits of this natural response.”
The study also sheds light on some benefits of moderate fever, which Barreda notes has been evolutionarily conserved across the animal kingdom for 550 million years. “Every animal examined has this biological response to infection.”
For the study, fish were given a bacterial infection and their behaviour was then tracked and evaluated using machine learning. Outward symptoms were similar to those seen in humans with fever, including immobility, fatigue and malaise. These were then matched to important immune mechanisms inside the animals.
The research showed that natural fever offers an integrative response that not only activates defences against infection, but also helps control it. The researchers found that fever helped to clear the fish of infection in about seven days – half the time it took for those animals not allowed to exert fever. Fever also helped to shut down inflammation and repair injured tissue.
“Our goal is to determine how to best take advantage of our medical advances while continuing to harness the benefits from natural mechanisms of immunity,” says Barreda.
The gingiva, the tissue area surrounding teeth, lets healthy teeth nestle firmly into the gums thanks to the many gingival fibres that connect the tooth to the gingiva. The gingiva is home to fibroblasts, cells that contribute to the formation of connective tissue. Scientists report in the journal Scientific Reportsthat they have discovered that gingival stiffness influences the properties of gingival fibroblasts, which in turn affects whether inflammation is likely to occur and make gingival fibres difficult to form.
“We discovered that soft gingiva results in inflammation and hinders the development of gingival fibres,” says Associate Professor Masahiro Yamada from Tohoku University’s Graduate School of Dentistry.
It has long been known that individuals with thick or stiff gingiva are less susceptible to gingival recessions. This is where the gingiva begins to recede and expose a tooth’s root. Many factors can lead to gingival recession, such as gum disease, over-brushing, and chewing tobacco. But this is the first time that gingival stiffness has been attributed to biological reactions.
Although fibroblasts play an important role in the maintenance, repair and healing of the gingiva, they also produce various inflammatory and tissue-degrading biomolecules which degrade the gingival fibers. In addition, fibroblasts are associated with immune responses to pathogens.
Yamada, along with his colleague Professor Hiroshi Egusa, also from the Tohoku University’s Graduate School of Dentistry, created an artificial culture environment that simulated soft or hard gingiva and cultured human gingival fibroblasts on them. They discovered that hard gingiva-simulated stiffness activated an intracellular anti-inflammatory system in the gingival fibroblasts that prevented inflammation. Yet, soft gingiva-simulated stiffness suppressed the fibroblastic anti-inflammatory system. This increased the likelihood of inflammation and resulted in less collagen synthesis.
“Our research is the first to demonstrate the biological mechanisms at play in regard to a patient’s gingival properties,” adds Yamada. “The results are expected to accelerate the development of advanced biomaterials to control local inflammation or microdevices that simulate the microenvironment of inflammatory conditions.”
A team of investigators has identified metabolic strategies used by Clostridioides difficile to rapidly colonise the gut, which involve a metabolic ‘jump start’. In addition, the findings identify methods to better prevent and treat the most common cause of antibiotic-associated diarrhoea and healthcare-acquired infections (HAIs). The team’s results are published in Nature Chemical Biology and have important implications for antibiotics and the study of metabolites.
“Investigating real-time metabolism in microorganisms that only grow in environments lacking oxygen had been considered impossible,” said co-corresponding author Lynn Bry, MD, PhD, director of the Massachusetts Host-Microbiome Center. “Here, we’ve shown it can be done to combat C. difficile infections – and with findings applicable to clinical medicine.”
“C. difficile is the leading cause of hospital-acquired infections and a leading cause of antibiotic-associated diarrhoea. Understanding its metabolic mechanisms at a cellular level may be useful for preventing and treating infections,” said co-senior author Leo L. Cheng, PhD, an associate biophysicist in Pathology and Radiology at MGH and an associate professor of Radiology at Harvard Medical School.
The anaerobic C. difficile causes infections by releasing toxins that allow the pathogen to obtain nutrients from damaged gut tissues. Understanding how C. difficile metabolises nutrients while colonising the gut could inform new approaches to prevent and treat infections.
To complete their study, Bry and Cheng used a technology called high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HRMAS NMR) to study real-time metabolism in living cells under anaerobic conditions. The team incorporated computational predictions to detect metabolic shifts in C. difficile as nutrient availability decreased, and then developed an approach to simultaneously track carbon and nitrogen flow through anaerobe metabolism. The researchers identified how C. difficile jump-starts its metabolism by fermenting amino acids before engaging pathways to ferment simple sugars such as glucose. They found that critical pathways converged on a metabolic integration point to produce the amino acid alanine to efficiently drive bacterial growth.
The study’s findings identified new targets for small molecule drugs to counter C. difficile colonisation and infection in the gut and provide a new approach to rapidly define microbial metabolism for other applications, including antibiotic development and the production of economically and therapeutically important metabolites.
Researchers at Massachusetts General Hospital have discovered a novel molecular mechanism behind the most common forms of acquired hydrocephalus – which could lead to the first non-surgical treatments for the life-threatening disease. Research in animal models uncovered a pathway through which infection or bleeding in the brain triggers inflammation, causing increased production of cerebrospinal fluid (CSF) by the choroid plexus and lead to swelling of the brain ventricles.
“Finding a nonsurgical treatment for hydrocephalus, given the fact neurosurgery is fraught with tremendous morbidity and complications, has been the holy grail for our field,” says Kristopher Kahle, MD, PhD, a paediatric neurosurgeon at MGH and senior author of the study in the journal Cell. “We’ve identified through a genome-wide analytical approach the mechanism that underlies the swelling of the ventricles which occurs after a brain bleed or brain infection in acquired hydrocephalus. We’re hopeful these findings will pave the way for approval of an anti-inflammatory drug to treat hydrocephalus, which could be a game-changer for populations in the US and around the world that don’t have access to surgery.”
Occurring in about 0.2% of births, acquired hydrocephalus is the most common cause of brain surgery in children, though it can affect people at any age. In underdeveloped regions where bacterial infection is the most prevalent form, hydrocephalus is often deadly for children due to the lack of surgical intervention. Brain surgery, where a shunt is implanted to drain fluid from the brain, is the only known treatment. But about half of all shunts in paediatric patients fail within two years of placement, according to the Hydrocephalus Association, requiring repeat neurosurgical operations and a lifetime of brain surgeries.
Pivotal to the process is the choroid plexus, the brain structure that routinely pumps cerebrospinal fluid into the four ventricles of the brain to keep the organ buoyant and injury-free within the skull. An infection or brain bleed, however, can create a dangerous neuroinflammatory response where the choroid plexus floods the ventricles with cerebral spinal fluid and immune cells from the periphery of the brain in a cytokine storm, swelling the brain ventricles.
“Scientists in the past thought that entirely different mechanisms were involved in hydrocephalus from infection and from haemorrhage in the brain,” explains co-author Bob Carter, MD, PhD, chair of the Department of Neurosurgery at MGH. “Dr Kahle’s lab found that the same pathway was involved in both types and that it can be targeted with immunomodulators like rapamycin, a drug that’s been approved by the US Food and Drug Administration for transplant patients who need to suppress their immune system to prevent organ rejection.”
MGH researchers are continuing to explore how rapamycin and other drugs which quell the inflammation seen in acquired hydrocephalus could be repurposed. “What has me most excited is that this noninvasive therapy could provide a way to help young patients who don’t have access to neurosurgeons or shunts,” says Kahle. “No longer would a diagnosis of hydrocephalus be fatal for these children.”
Scientistshave made an important breakthrough in understanding failures during the progression of inflammatory diseases and in doing so unearthed a potential new therapeutic target. The scientists report in Nature that an enzyme called Fumarate Hydratase is repressed in macrophages. These immune cells are already implicated in a range of diseases including Lupus, arthritis, sepsis and COVID.
Lead author Luke O’Neill, Professor of Biochemistry at Trinity said: “No-one has made a link from Fumarate Hydratase to inflammatory macrophages before and we feel that this process might be targetable to treat debilitating diseases like Lupus, which is a nasty autoimmune disease that damages several parts of the body including the skin, kidneys and joints.”
Joint first-author Christian Peace added: “We have made an important link between Fumarate Hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when Fumarate Hydratase is repressed, RNA is released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, thereby worsening inflammation. This process could potentially be targeted therapeutically.”
Fumarate Hydratase was shown to be repressed in a model of sepsis, an often-fatal systemic inflammatory condition that can happen during bacterial and viral infections. Similarly, in blood samples from patients with Lupus, Fumarate Hydratase was dramatically decreased.
“Restoring Fumarate Hydratase in these diseases or targeting MDA5 or TLR7 therefore presents an exciting prospect for badly needed new anti-inflammatory therapies,” said Prof O’Neill.
Excitingly, this newly published work is accompanied by another publication by a group led by Professor Christian Frezza, now at the University of Cologne, and Dr Julien Prudent at the MRC Mitochondrial Biology Unit (MBU), who have made similar findings in the context of kidney cancer.
“Because the system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” added Prof O’Neill.
A new study details the step-by-step cascade that allows bacteria to break through the brain’s protective layers, the meninges, and cause meningitis, a highly fatal disease. Published inNature, the mouse-based research shows that bacteria exploit nerve cells in the meninges to suppress the immune response and allow the infection to spread into the brain.
“We’ve identified a neuroimmune axis at the protective borders of the brain that is hijacked by bacteria to cause infection – a clever manoeuvre that ensures bacterial survival and leads to widespread disease,” said study senior author Isaac Chiu, associate professor of immunology in the Blavatnik Institute at Harvard Medical School.
The study identifies two central players in this molecular chain of events that leads to infection – a chemical released by nerve cells and an immune cell receptor blocked by the chemical. The study experiments show that blocking either one can interrupt the cascade and thwart the bacterial invasion.
If replicated through further research, the new findings could lead to much-needed therapies for this hard-to-treat condition that often leaves those who survive with serious neurologic damage.
Such treatments would target the critical early steps of infection before bacteria can spread deep into the brain.
“The meninges are the final tissue barrier before pathogens enter the brain, so we have to focus our treatment efforts on what happens at this border tissue,” said study first author Felipe Pinho-Ribeiro, a former post-doctoral researcher in the Chiu lab, now an assistant professor at Washington University in St. Louis.
A recalcitrant disease in need of new treatments
More than 1.2 million cases of bacterial meningitis occur globally each year, according to the US Centers for Disease Control and Prevention. Untreated, it kills seven out of 10 people who contract it. Treatment can reduce mortality to three in 10. However, among those who survive, one in five experience serious consequences, including hearing or vision loss, seizures, chronic headache, and other neurological problems.
The meninges are three membranes that lie atop one another, wrapping the brain and spinal cord to shield the central nervous system from injury, damage, and infection. The dura mater, outermost of the three layers, contains pain neurons that detect signals. Such signals could come in the form of mechanical pressure: blunt force from impact or toxins that make their way into the central nervous system through the bloodstream. The researchers focused on the dura mater as the site of initial interaction between bacteria and protective border tissue.
Recent research has revealed that the dura mater also harbours a wealth of immune cells, and that immune cells and nerve cells reside right next to each other – a clue that captured Chiu’s and Pinho-Ribeiro’s attention.
“When it comes to meningitis, most of the research so far has focused on analysing brain responses, but responses in the meninges – the barrier tissue where infection begins – have remained understudied,” Ribeiro said.
What exactly happens in the meninges when bacteria invade? How do they interact with the immune cells residing there? These questions remain poorly understood, the researchers said.
How bacteria break through the brain’s protective layers
In this particular study, the researchers focused on two pathogens – Streptococcus pneumoniae and Streptococcus agalactiae, leading causes of bacterial meningitis in humans. In a series of experiments, the team found that when bacteria reach the meninges, the pathogens trigger a chain of events that culminates in disseminated infection.
First, researchers found that bacteria release a toxin that activates pain neurons in the meninges. The activation of pain neurons by bacterial toxins, the researchers noted, could explain the severe, intense headache that is a hallmark of meningitis. Next, the activated neurons release a signalling chemical called CGRP. CGRP attaches to an immune-cell receptor called RAMP1. RAMP1 is particularly abundant on the surface of immune cells called macrophages.
Once the chemical engages the receptor, the immune cell is effectively disabled. Under normal conditions, as soon as macrophages detect the presence of bacteria, they spring into action to attack, destroy, and engulf them. Macrophages also send distress signals to other immune cells to provide a second line of defence. The team’s experiments showed that when CGRP gets released and attaches to the RAMP1 receptor on macrophages, it prevented these immune cells from recruiting help from fellow immune cells. As a result, the bacteria proliferated and caused widespread infection.
To confirm that the bacterially induced activation of pain neurons was the critical first step in disabling the brain’s defences, the researchers checked what would happen to infected mice lacking pain neurons.
Mice without pain neurons developed less severe brain infections when infected with two types of bacteria known to cause meningitis. The meninges of these mice, the experiments showed, had high levels of immune cells to combat the bacteria. By contrast, the meninges of mice with intact pain neurons showed meagre immune responses and far fewer activated immune cells, demonstrating that neurons get hijacked by bacteria to subvert immune protection.
To confirm that CGRP was, indeed, the activating signal, researchers compared the levels of CGRP in meningeal tissue from infected mice with intact pain neurons and meningeal tissue from mice lacking pain neurons. The brain cells of mice lacking pain neurons had barely detectable levels of CGRP and few signs of bacterial presence. By contrast, meningeal cells of infected mice with intact pain neurons showed markedly elevated levels of both CGRP and more bacteria.
In another experiment, the researchers used a chemical to block the RAMP1 receptor, preventing it from communicating with CGRP, the chemical released by activated pain neurons. The RAMP1 blocker worked both as preventive treatment before infection and as a treatment once infection had occurred.
Mice pretreated with RAMP1 blockers showed reduced bacterial presence in the meninges. Likewise, mice that received RAMP1 blockers several hours after infection and regularly thereafter had milder symptoms and were more capable of clearing bacteria, compared with untreated animals.
A path to new treatments
The experiments suggest drugs that block either CGRP or RAMP1 could allow immune cells to do their job properly and increase the brain’s border defenses.
Compounds that block CGRP and RAMP1 are found in widely used drugs to treat migraine, a condition believed to originate in the top meningeal layer, the dura mater. Could these compounds become the basis for new medicines to treat meningitis? It’s a question the researchers say merits further investigation.
One line of future research could examine whether CGRP and RAMP1 blockers could be used in conjunction with antibiotics to treat meningitis and augment protection.
“Anything we find that could impact treatment of meningitis during the earliest stages of infection before the disease escalates and spreads could be helpful either to decrease mortality or minimize the subsequent damage,” Pinho-Ribeiro said.
More broadly, the direct physical contact between immune cells and nerve cells in the meninges offers tantalizing new avenues for research.
“There has to be an evolutionary reason why macrophages and pain neurons reside so closely together,” Chiu said. “With our study, we’ve gleaned what happens in the setting of bacterial infection, but beyond that, how do they interact during viral infection, in the presence of tumour cells, or the setting of brain injury? These are all important and fascinating future questions.”
Scanning Electron Micrograph of Pseudomonas aeruginosa. Credit: CDC/Janice Carr
Pseudomonas aeruginosa bacteria are a common menace in hospital wards, causing life-threatening infections, and are often resistant to antibiotics. Researchers have discovered a mechanism that likely contributes to the severity of P. aeruginosa infections, which could also be a target for future treatments. The results were recently appeared in the journal EMBO Reports.
Many bacterial species use sugar-binding molecules called lectins to attach to and invade host cells. Lectins can also influence the immune response to bacterial infections. However, these functions have hardly been researched so far. A research consortium led by Prof Dr Winfried Römer at the University of Freiburg and Prof Dr Christopher G. Mueller at the CNRS/University of Strasbourg has investigated the effect of the lectin LecB from P. aeruginosa on the immune system. It found that isolated LecB can render immune cells ineffective: The cells are then no longer able to migrate through the body and trigger an immune response. The administration of a substance directed against LecB prevented this effect and led to the immune cells being able to move unhindered again.
LecB blockades immune cells
As soon as they perceive an infection, cells of the innate immune system migrate to a nearby lymph node, where they activate T and B cells, triggering a targeted immune response. LecB, according to the current study, prevents this migration. “We assume that LecB not only acts on the immune cells themselves in this process, but also has an unexpected effect on the cells lining the inside of the blood and lymph vessels,” Römer explains. “When LecB binds to these cells, it triggers extensive changes in them.” Indeed, the researchers observed that important structural molecules were relocated to the interior of the cells and degraded. At the same time, the cell skeleton became more rigid. “The cell layer thus becomes an impenetrable barrier for the immune cells,” Römer said.
An effective agent against LecB
Can this effect be prevented? To find out, the researchers tested a specific LecB inhibitor that resembles the sugar building blocks to which LecB otherwise binds. “The inhibitor prevented the changes in the cells, and T-cell activation was possible again,” Mueller said. The inhibitor was developed by Prof Dr Alexander Titz, who conducts research at the Helmholtz Institute for Pharmaceutical Research Saarland and Saarland University.
Further studies are needed to determine how clinically relevant the inhibition of the immune system by LecB is to the spread of P. aeruginosa infection and whether the LecB inhibitor has potential for therapeutic application. “The current results provide further evidence that lectins are a useful target for the development of new therapies, especially for antibiotic-resistant pathogens such as P. aeruginosa,” the authors conclude.
