Six years after the height of the COVID-19 pandemic, scientists are still uncovering surprising ways the virus can wreak havoc on the body. A new UCLA study published in Science Advances describes a previously unrecognized way the SARS-CoV-2 nucleocapsid protein—a structural protein less familiar than the spike protein that has dominated public attention and much vaccine research—can push the immune system into dangerous overdrive.

The nucleocapsid protein’s main job is to package and protect the virus’s genetic material. Like several other coronavirus proteins, it’s also known to suppress the body’s early antiviral defenses, helping the virus get a foothold.

Scientists led by virologist Melody Li set out to see whether SARS-CoV-2’s version of this immune-dampening protein worked the same way as those found in SARS and MERS, earlier coronaviruses known to cause severe disease.

“Coronaviruses are notorious for encoding proteins that antagonize the body’s natural antiviral defenses,” said Li, an associate professor of microbiology, immunology and molecular genetics and member of the UCLA Broad Stem Cell Research Center. “When SARS-CoV-2 first appeared, almost nothing was known about it, so we wanted to find out whether it was using the same playbook.”

A hidden protein with an outsized effect

The project led the researchers to a less-explored question: how the nucleocapsid protein behaves inside macrophages. These immune cells patrol tissues for signs of infection and release chemical signals called cytokines and chemokines to rally the body’s defenses.

What they found upended their original hypothesis. The nucleocapsid protein appeared to be a “double-edged sword,” Li said. While it still suppressed signals that trigger an early antiviral response, it also amplified inflammatory pathways in macrophages, which can fuel tissue-damaging immune responses.

“We set out looking for a protein that suppresses the immune response, and we found the opposite,” said Zhenlan Yao, co-first author of the study and a former postdoctoral researcher in Li’s lab, who will soon begin a research assistant professorship at Hong Kong University. “It was surprising, but it lines up with what we already know about COVID-19: The virus dampens the immune response early on, then overactivates it later—and that’s when a lot of the tissue damage happens.”

The researchers examined nucleocapsid proteins from several SARS-CoV-2 variants, as well as from SARS-CoV-1 and MERS-CoV, and found the pro-inflammatory effect was conserved across pathogenic coronaviruses—with the delta variant’s version proving by far the most inflammatory.

“It’s a bit like a thief trying to slip past a bank’s security system, but instead of staying quiet, it trips the alarm,” Li said. “We don’t think these viruses intend to do this—a virus’s whole goal is to spread, not to make its host severely sick. But this looks like an unintended side effect that, in the case of COVID, ends up fueling the disease.”

In the body, that immune “alarm” does not stay confined to macrophages. When these cells become overactivated, they release inflammatory signals that can affect nearby tissues, including the cells that line blood vessels.

Cracks in the body’s protective barriers

To investigate whether those effects could help explain COVID-19 complications involving the brain and heart, the team turned to two human cell-based models: a stem cell-derived model of the blood-brain barrier and a model of the coronary artery lining.

These barriers are made of endothelial cells, which line blood vessels and help control what passes from the bloodstream into surrounding tissues. In the brain, this barrier is especially tight, helping protect delicate neural tissue from pathogens, toxins and other harmful substances.

When the researchers exposed both models to fluid containing signals from macrophages producing the delta variant’s nucleocapsid protein, the heart barrier broke down significantly—a phenomenon known as vascular leakage.

Because the heart depends on tight, selective blood vessel linings to function normally, the finding points to a possible mechanism that could help explain the cardiac injury seen in severe cases of COVID-19.

Rethinking how severe COVID-19 is treated

The findings also suggest a path toward more targeted COVID-19 treatments.

Severe cases can be treated with broad anti-inflammatory drugs like corticosteroids, which dampen harmful inflammation but do not specifically target the viral mechanisms that may be driving it. A therapy or vaccine that targets the nucleocapsid protein, Li said, could potentially rein in hyperinflammation more precisely and, in doing so, help protect the blood vessel barriers that support brain and heart health.

And because macrophages play a similar double-edged role in many infections beyond COVID-19, she said, the same mechanism could turn out to matter well beyond this one virus.

“It’s critical to keep studying COVID-19 so that we can constantly improve patient care—not everyone responds well to vaccines, and people who are immunocompromised often have limited treatment options,” said Pablo Alvarez, co-first author of the study and a former graduate student in Li’s lab. “These studies can also help us prepare for future coronavirus outbreaks.”

Ears are built to listen to sounds from the world around us, but for some people, the sound comes from within. Tinnitus causes people to hear ringing or other noises in one or both ears or in their heads, even when there is no actual sound outside. While tinnitus is frequently associated with hearing loss, a substantial proportion of individuals with clinically normal hearing thresholds still experience it, and the underlying mechanism remains murky to scientists. A recent study investigated how brain network patterns change as tinnitus progresses from a new condition to a long-term chronic one in people with clinically normal hearing.

After recording the electrical activity in the brains of people with acute and chronic tinnitus, the researchers found that the two conditions have very different neurophysiological profiles. People with recent-onset tinnitus showed an imbalance between two important brain networks: the salience network, which detects salient or potentially threatening signals, and the executive control network, which supports attention and decision-making. The brain significantly increases its focus on the former while decreasing the latter’s activity. Those with chronic tinnitus showed much more balanced switching between these networks, meaning the brain began to adapt rather than worsen.

The findings are published in iScience.

Tracking shifts in neural networks

About 10% to 15% of adults worldwide live with the distressing neurological condition. Most studies looking into neurological changes associated with tinnitus focus on participants with hearing loss. This made it nearly impossible to tell whether the observed brain changes were caused by tinnitus itself or simply by the brain reacting to hearing loss.

In people with normal hearing test results, tinnitus often traces back to subtle inner-ear changes that standard tests can’t detect. It is driven by cochlear synaptopathy, in which connections between inner hair cells and auditory nerve fibers are lost. Along with phantom sounds, this can result in high-frequency hearing loss above 8 kHz, a range that regular tests don’t check. These small changes in the ear can lead to bigger changes in the brain, disrupting how key networks function when the condition is new and acute versus when it becomes chronic.

In this study, the researchers directly compared neurological changes at different stages of the condition in people with normal hearing. The team recruited 45 participants and divided them into three equal groups of 15: acute tinnitus, chronic tinnitus and healthy controls with no tinnitus. Brain activity was recorded using a 64-channel electroencephalography (EEG) cap, which captured rapid, millisecond-long snapshots of the brain’s electrical activity. The researchers focused on four EEG microstate maps—Classes A, B, C and D—which correspond to the auditory, visual, salience and executive networks, respectively.

The collected data were then analyzed using dynamic functional network (DFN) analysis, which examined how effectively different parts of the brain within the microstates communicated and at what speeds, or frequency bands, ranging from slow delta waves to fast gamma waves.

The team found that tinnitus is not a fixed condition but a dynamic process in which the brain reorganizes itself as the disorder progresses. During the early stage of tinnitus (less than 6 months), the brain is in a state of imbalance and hypervigilance. The salience network becomes more active, while the executive network becomes less active.

As tinnitus becomes chronic, the brain undergoes compensatory rebalancing to find a new normal. Its activity patterns become more stable over time, shifting from high-frequency activity to low-frequency waves (delta and beta bands) in the executive and auditory networks, thereby regaining control over the phantom sound experienced by those with the condition.

While standard static connectivity analysis found no differences between groups, the dynamic approach did, suggesting that tinnitus’s neural signatures are fleeting rather than constant. The study’s approach was able to glimpse how the brain reorganizes its networks in real time. The distinct signatures across tinnitus stages revealed in the findings not only offer new insights into the disorder’s underlying mechanisms but also could act as biomarkers to help clinicians distinguish recent-onset from chronic tinnitus and tailor care accordingly.

Researchers have developed an implant that could deliver next-generation therapies for ovarian cancer precisely where they are needed while simultaneously monitoring how the disease responds.

The project was carried out by a team at CÚRAM, the Research Ireland Centre for Medical Devices based at the University of Galway, along with collaborators from the University of Minnesota, Massachusetts Institute of Technology (MIT) and the Wyss Institute.

The research was published in the journal Device. It showed how the team developed a flexible, porous implant designed to sit inside the peritoneal cavity—the space surrounding the abdominal organs in a woman’s body where ovarian cancer predominantly occurs. The device is designed to connect to an external port through the skin so it can be replenished with therapeutic agents as often as needed without requiring further surgery.

Dr. Aoibhín Sheedy, a Ph.D. graduate with CÚRAM at the University of Galway and lead researcher on the project, said, “One of the most frustrating aspects of treating ovarian cancer is that we know localized delivery of therapy works better, but the tools we’ve had until now weren’t built for the job. We designed this implant with ovarian cancer patients in mind. We wanted an implant that can deliver living cell therapies repeatedly, reliably and with real precision to the tumor site.”

Built for repeated local treatment

Ovarian cancer is often diagnosed at late stages, as symptoms such as bloating, pain and pelvic pressure are nonspecific and can be overlooked. Treatment often involves surgery to remove as much of the tumor as possible, but targeted treatments and effective methods of detecting recurrence are currently unavailable. There is a critical need for new therapeutic approaches for ovarian cancer.

The implant is made from a flexible biomaterial that conforms naturally to the body’s internal contours. Its porous membrane allows therapeutic cargo to diffuse gently and evenly into the surrounding tissue, reducing the risk of mechanical complications.

In preclinical studies, the implant remained fully functional for up to 70 days with no implant-related complications and showed significantly better tumor control over time than conventional treatments. The team has designed this implant to deliver living cell therapies, the most challenging type of therapy to deliver, but it could be used to deliver a range of cell- or non-cell-based therapies.

Dr. Martin Felices, co-senior author and associate professor of medicine at the University of Minnesota, said, “The tricky part about working with novel therapies, such as immunotherapies, in the setting of ovarian cancer is that repeated delivery is done with outdated materials that are not designed for this setting. It is also very difficult to sample through these systems. The delivery system, created by Dr. Eimear Dolan’s laboratory, allows for safer repeated delivery of cellular and biologic therapies in the context of the peritoneal cavity. It also allows us to sample the effects of those therapies in the tumor microenvironment in real time, which is extremely exciting.”

Sampling the tumor environment

A key feature of the implant is its monitoring capability. By applying gentle suction through the same external port, a sample of fluid can be drawn from inside the peritoneal cavity during treatment without any additional procedure.

Associate Professor of Biomedical Engineering at the University of Galway Dolan, and co-lead on the research, said, “What excites us most is the two-way nature of this approach. It doesn’t just deliver living cell therapies, it lets us create a picture of what’s happening inside the peritoneal space. Clinicians could use this to track how the immune cells are performing, whether the tumor is responding, and then adapt treatment accordingly. That kind of real-time intelligence is something we’ve never had access to before in this setting.”

The researchers envision that the implant would be put in place during the initial surgery patients undergo to remove as much tumor tissue as possible, allowing it to then address any residual disease in the weeks and months that follow. The ultimate aim would be to leave the implant in long term to allow for local monitoring of disease recurrence and early retreatment if required.

Professor Melissa Gellar, professor of gynecologic oncology and associate director of clinical research at the Masonic Cancer Center at the University of Minnesota and co-lead on the research, said, “This work represents a shift in how we think about treating ovarian cancer, bringing therapy directly to the disease site while simultaneously learning from the tumor microenvironment in real time, which provides important insights to guide precision care.”

Potential beyond ovarian cancer

The research also highlights the possibilities of cross-disciplinary research. While further studies are needed before this approach reaches clinical trials, the team of engineers and clinicians believe its versatile design could ultimately benefit patients with other peritoneal cancers, including gastric, colorectal and pancreatic disease.

The definition of autism may have become so broad that it risks confusion and even misdiagnosis, according to a new editorial by UCL professor Dame Uta Frith, whose pioneering research in the 1960s and ’70s laid the foundations for how we understand autism.

Autism is currently diagnosed as autism spectrum disorder (ASD), a single condition that includes a huge range of people, from those needing round-the-clock care to those who live independently.

In Frith’s editorial, published in Psychological Medicine, she argues that this “spectrum” may now be too broad to be useful.

“Autism wasn’t always defined this way—a sort of catch-all diagnosis for a huge variety of conditions,” she said.

“When it was first identified in the 1940s, it referred to a small group of children with severe difficulties in social interaction, communication and behavior. Over time, the definition has widened to include people with milder traits and no language or learning problems.

“Today, anyone of any age or intelligence level can be diagnosed with autism if they meet certain criteria.”

The number of people diagnosed with autism has increased dramatically. In the 1960s, in the UK, about 4 in 10,000 children were diagnosed. Today, it’s around 1 in 57 schoolchildren in the UK—a more than 40-fold increase.

In the paper, Frith, emeritus professor of cognitive development at the UCL Institute of Neurology, suggests several reasons for this rise:

• Greater awareness and less stigma
• Broader interpretation of diagnostic criteria
• More people identifying with autism online
• Self-diagnosis and social media influence
• A cultural shift toward explaining everyday life problems via medical labels

In a career spanning more than 50 years, Frith has researched the cognitive underpinnings of autism longer than nearly anyone else.

With colleagues, she developed two landmark theories about how autistic minds might develop differently from neurotypical minds.

• Theory of mind deficit (mentalizing problems): The idea that autistic people may find it harder to infer other people’s thoughts, beliefs and intentions.
• Weak central coherence: This theory proposed that autistic cognition tends to focus on details rather than the bigger picture. Autistic individuals may excel at noticing fine details but find it harder to integrate them into a broader, contextual understanding.

She, along with colleagues at UCL, was also among the first to explore the neural basis of these differences using newly available brain scanners in the 1990s.

Two very different groups?

In her new paper, Frith argues that not all autism diagnoses look the same. The latest research shows a big difference between people diagnosed in childhood and those diagnosed later, as teenagers or adults.

• Early-diagnosed individuals often show clear signs from a young age and may have language or learning difficulties.
• Late-diagnosed individuals are more likely to have average or high intelligence and may also have conditions like anxiety, depression or ADHD.

Some studies even suggest these groups may have different genetic patterns, raising the possibility that they are not the same condition at all.

Could this lead to misdiagnosis?

In the paper, Frith warns that expanding the definition of autism may lead to overdiagnosis, in which people are given an autism label even when another condition might explain their difficulties.

“This matters because diagnoses shape treatment, identity and support. A wrong diagnosis can lead to the wrong help—or no help at all,” she said.

Frith also points out that:

• There is no biological test for autism
• Diagnosis often depends on judgment and self-report
• Concepts like “masking” (hiding difficulties) can make the criteria even broader

The role of culture and identity

She said, “Autism is no longer just a medical term—it has become part of popular culture. Social media, films and online communities have helped people share experiences, but they have also spread simplified or misleading ideas.

“At the same time, the idea of ‘neurodiversity’ has encouraged people to see autism as a difference rather than a disorder. While this helps reduce stigma, it also creates tension: If autism is not a disorder, why use a medical diagnosis?”

What needs to change?

The paper calls for a rethink of how autism is defined and diagnosed. Instead of one broad “spectrum,” it suggests:

• Splitting autism into clearer subgroups
• Focusing on individuals’ specific needs
• Prioritizing support for those with the greatest difficulties
• Improving diagnostic precision to avoid confusion and misdiagnosis

Frith said, “The time has come to examine whether the autism spectrum has become too broad. Without greater precision, we risk misunderstanding people’s needs and misdirecting care.”

Teeth and bones are among the hardest structures in the human body, but certain inherited conditions can rob them of that strength. One of them is hypophosphatasia (HPP), a rare, lifelong genetic bone disorder that disrupts the development of bones and teeth, leaving them unusually soft and fragile. A recent study set out to determine how common HPP is across Central and Eastern Europe and how it presents in patients.

After reviewing the medical records of patients in five European countries with clinically and genetically confirmed HPP, researchers found that the disorder causes a high burden of symptoms affecting many aspects of life. More than 70% of patients experienced constant bone and muscle pain, and in most cases, the pain was so severe that patients had to take multiple types of pain medication to get through their daily lives.

One of the most concerning findings was that, despite living with a debilitating genetic disorder, only one of the 34 patients in the study was receiving asfotase alfa, an enzyme replacement therapy (ERT) that targets HPP and is currently the only approved treatment for the disease.

The findings are published in Frontiers in Endocrinology.

Mapping HPP across Europe

HPP is a potentially fatal inherited disorder caused by mutations in the ALPL gene, which produces an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme is essential for the mineralization of bones and teeth—the process that hardens them by depositing minerals into their structure. More than 450 disease-causing variants of the ALPL gene have been identified so far.

As a result, HPP can range from mild to life-threatening, affecting both children and adults. It can cause weak bones, growth and mobility problems, premature loss of baby teeth and, in severe cases, breathing difficulties and seizures in infants.

Where diagnosis often breaks down

Because of the rarity of the disorder, it often goes undetected or is misdiagnosed, putting patients at risk without the care they need. Regional data can shed light on where patients fall through the cracks—because of missed diagnoses, limited access to treatment or too few specialists to turn to. To fill these gaps, researchers in this study focused on Central and Eastern Europe.

The team conducted a retrospective, multicenter study, reviewing existing medical records from five countries: Slovakia, Austria, Slovenia, Latvia and Hungary.

They began with 49 people suspected of having HPP, all of whom had a confirmed mutation in the ALPL gene and sufficient information for the researchers to study them properly. After excluding anyone with missing data or other diagnoses, the final group comprised 34 patients: 14 male and 20 female.

From the medical records, the researchers extracted demographic details and tracked chronic pain, fractures, bone deformities and dental problems such as early tooth loss. They also looked for laboratory tests showing low ALP levels, the hallmark sign of HPP, along with X-rays and bone density scans to assess how strong or fragile the patients’ bones were.

Symptoms shift with age

The study found that HPP presents very differently depending on when symptoms first appear. Although chronic musculoskeletal pain was the most common symptom overall, patients whose disease began in childhood were more likely to develop bone deformities, experience frequent fractures and lose their teeth early.

In contrast, those whose symptoms appeared in adulthood were more likely to experience persistent pain and joint problems. Overall, 44% of patients had fractures, 26% experienced premature tooth loss and 18% developed bone deformities.

The disease’s impact was not limited to the skeleton. Nearly 30% of patients experienced respiratory complications, including recurrent pneumonia, while more than 10% developed kidney stones or calcium deposits in the kidneys.

Nearly every patient, 97%, had low blood levels of the alkaline phosphatase (ALP) enzyme, the telltale sign of HPP. The researchers noted that this red flag is often missed in everyday clinical practice, as shown by the underuse of targeted treatment among participants.

The findings highlight a stark gap in awareness of and access to rare-disease therapies that needs to be closed urgently to ensure patients receive accurate diagnoses and timely treatment.

Major depressive disorder, commonly referred to as depression, is a debilitating psychiatric disorder estimated to affect roughly 5% of the global population. Depression is characterized by persistent sadness and hopelessness, difficulty concentrating on tasks, a lack of interest in everyday activities and changes in sleep and/or appetite.

While past studies have shed light on some of the factors that can contribute to the emergence of depression, the neural processes and brain changes associated with this disorder have not yet been fully elucidated. Better understanding how depression affects the brain could potentially guide the development of new tools and strategies for diagnosing or treating it.

Past research has linked depression with changes in various brain regions, including a reduction in the volume of gray matter in the hippocampus and frontal cortex. While earlier studies have provided some interesting insights, their findings were often inconsistent or inconclusive.

Researchers at Washington University School of Medicine analyzed thousands of brain scans collected from a population sample, including people with subclinical symptoms. The results of their analyses, published in Nature Mental Health, identified various changes in the brain that appear to be associated with depression, some of which are inconsistent with earlier observations.

“Determining how the brain changes in people with depression has been a longstanding scientific goal that many papers have tried to answer,” Janine D. Bijsterbosch, the paper’s senior author, told Medical Xpress.

“Despite substantial existing work, studies designed to identify agreement between previous studies (so-called ‘meta-analyses’) sometimes struggle to find consistent evidence for depression-related brain changes. Furthermore, prior studies often focus on target brain systems likely to be involved in depression and may therefore overlook findings in other parts of the brain (e.g., as suggested in our prior work).”

The analysis of over 23,000 brain scans

The main goal of the study by Bijsterbosch and her collaborators was to improve the current understanding of depression and how it is reflected in the brain. To do this, the researchers analyzed six available datasets individually and then compared the results they attained.

“We wanted to see if a whole-brain approach using big datasets would help to find more consistent evidence of brain changes linked to depression,” explained Bijsterbosch.

“We used six big datasets covering the full lifespan that ranged from 185 to 11,000 participants per dataset. Each dataset was analyzed separately to relate summary indices of brain structure and function to depression measures (of severity and personality-based risk). The results were then combined across the six datasets.”

Consistent with earlier research, the researchers found that depression was linked to a reduction in gray matter in three brain regions: the frontal cortex, anterior cingulate cortex and insula. These areas of the brain are known to play a role in the regulation of emotions, decision-making, motivation and the internal processing of bodily sensations.

“A key surprising finding was that smaller brain regions in motor and visual regions were linked to higher levels of depression,” said Bijsterbosch. “It has been known that reduced brain size in other (e.g., frontal) parts of the brain is linked to depression, but the location of these new results was surprising because we don’t usually link symptoms of depression to sensory processing or motor action.”

Earlier research had also linked depression to changes in regions in the basal brain, such as the amygdala and hippocampus. Bijsterbosch and her colleagues, however, observed little evidence of this. It is possible that this discrepancy is linked to the population datasets that were used, which do not tend to include patients with high levels of depression severity.

Toward a better understanding of depression

This study was one of the most detailed and comprehensive explorations of brain changes associated with depression to date. Overall, its findings suggest that depression affects a broad network of brain regions that have been implicated in important mental functions.

The team’s efforts could soon inform further studies exploring how the uncovered brain changes could relate to specific symptoms of depression. Eventually, they could help paint a clearer picture of this common mental health disorder, potentially also informing the development of promising new diagnostic tools or treatments.

“One of the first authors of our paper, Kassandra Hamilton, is currently planning a follow-up study to test whether visual and motor regions encode specific symptoms of depression,” added Bijsterbosch.

Researchers at Tel Aviv University have presented new findings indicating that the experimental drug Davunetide may significantly slow the progression of progressive supranuclear palsy (PSP) in women, who exhibited a markedly different response to treatment than men. These results reinforce the need for sex-specific medicine in neurodegenerative diseases.

The new publication, led by Prof. Illana Gozes of the Sagol School of Neuroscience and the Gray Faculty of Medical and Health Sciences at Tel Aviv University, used updated FDA-recommended outcome measures to reanalyze data from a 52-week international clinical trial involving more than 300 patients with PSP, a rare and fatal neurodegenerative disease caused by the abnormal accumulation of tau protein in the brain. There is currently no effective drug treatment for the disease.

The research team included current and former students Dr. Guy Shapira, Jason Blatt and Liri Guz, together with Prof. Noam Shomron. The study was published in the journal Molecular Psychiatry.

A different picture for women

In contrast to the original conclusions of the clinical trial, which found that the drug was safe but ineffective, the researchers conducted an advanced analysis that separated male and female participants and reexamined the data using updated assessment measures now recommended by the FDA. The results revealed a completely different picture: Women treated with Davunetide experienced a significant slowing of disease progression, while no similar effect was observed in men.

The researchers found that the treatment helped preserve essential motor and functional abilities, including balance, fine motor skills and everyday activities such as using cutlery, buttoning clothes and washing the face and hands. In addition, the treated women showed significant improvements in cognitive measures, including language abilities, working memory and overall cognitive function.

Tau patterns diverged by sex

Another key finding of the study was the discovery of profound molecular differences between women and men. The researchers found that the relationship between the quantities of pathological tau in cerebrospinal fluid (a biomarker of the disease) and clinical symptoms was completely reversed between the two sexes. For example, language abilities significantly decreased with increased tau pathology in women, but not in men. This finding suggests that the disease mechanisms themselves may operate differently in women and men, potentially explaining their different responses to treatment.

According to Gozes, the study’s findings highlight that overlooking biological differences between the sexes may obscure genuine therapeutic efficacy. “Our data show that analyzing women and men separately is not merely a statistical exercise, but an essential tool for developing more effective treatments for neurodegenerative brain diseases,” she says.

A case for tailored trials

The researchers believe their findings provide a strong scientific basis for future clinical trials and for treatment protocols designed from the outset to account for patients’ sex, evaluating Davunetide as a targeted treatment for women with PSP. They say this new approach may pave the way for the development of more precise medicine for patients with tau-related diseases, including the much more common Alzheimer’s disease and other neurodegenerative disorders of the brain.

The study was supported by ExoNavis Therapeutics, which is developing Davunetide for brain diseases under a license from Ramot, Tel Aviv University’s technology transfer company. Prof. Gozes serves as the company’s Vice President for Drug Development, and Dr. Guy Shapira serves as a consulting statistician. The results were independently validated by several additional statisticians.

Beyond the nucleus, no other organelle in eukaryotic cells captures the public’s imagination quite like mitochondria: They are the engines of cellular energy production; they possess their own DNA, and they are passed from generation to generation from mothers to offspring.

Now scientists have revealed that these bean-shaped energy factories, known for the production of ATP, the key fuel of life, also play an extraordinary role in harnessing the immune response during infection—these organelles are critical in mediating a powerful antibacterial defense.

The discovery by investigators at Australia’s University of Queensland, who worked with collaborators in Switzerland and Spain, demonstrates an unexpected role for these crucial constituents of cells. The team showed that mitochondrial fission underlies an immune response, producing antibacterial capability in a host of organisms from the lowly worm to complex mammals. Results of the research are published in Science Immunology.

Fission is key to fighting invaders

“Our findings suggest that mitochondrial fission is an evolutionarily conserved pathway that provides cell-autonomous control of infection and can be targeted to combat antibiotic-resistant bacterial pathogens,” Ronan Kapetanovic and colleagues write in the journal.

Mitochondrial division—or fission—can promote antibacterial defense pathways in mammalian macrophages and worms, according to the study, which identified the regulatory mechanisms that control these defense pathways. Findings from the research could inform future therapeutic targets while highlighting unique mitochondrial functions in the fight against infection.

Going into their study, the University of Queensland team knew that earlier research had shown that microbial signals and stress can induce mitochondrial changes, but it had remained unclear whether mitochondrial fission can enhance host immune defenses.

Kapetanovic and colleagues showed that E. coli infections triggered mitochondrial fission in cultured mouse and human macrophages as well as in the worm, Caenorhabditis elegans, which then boosted bacterial clearance.

Additional experiments by the team of investigators revealed that mitochondrial fission triggered the formation of antimicrobial lipid droplets and activated a stress pathway called the mitochondrial unfolded protein response, UPR^mt.

The UPR^mt prompted the nuclear translocation of transcription factor ATF5, driving the expression of antimicrobial effector genes. However, the researchers also determined that ATF5 inhibited the production of fission-mediated lipid droplets, curtailing excessive defense responses. The UPR^mt, the team found, aids restoration of cellular homeostasis.

Fission creates more mitochondria

As a first step in their experiments, scientists infected mouse macrophages with E. coli and found that the number of mitochondria increased, a direct result of fission. The fission, in this instance, was induced in response to E. coli infection.

Then, with the help of a cocktail of compounds and the silencing of a gene involved in fission, scientists wanted to see what would happen if the organelles were directed toward mitochondrial fusion—the opposite pathway of fission. The result was increased intracellular E. coli in the macrophages.

Still, the lesson learned from E. coli was not universal, and there apparently are significant differences in mitochondrial immune reactions from one pathogen to another. With Salmonella typhimurium, for example, researchers found that the pathogen survives inside macrophages and orchestrates mitochondrial behavior to the benefit of the bacteria, preventing mitochondrial fission and the substantial increase in additional mitochondria.

But Kapetanovic and colleagues had an answer to the craftiness of Salmonella typhimurium: Inhibiting the enzyme HDAC6 promoted mitochondrial fission and lipid droplet formation, enhancing bacterial clearance—and suggesting that HDAC6 could be a therapeutic target to control otherwise recalcitrant infections.

In an editorial commentary, Claire Olingy, a senior editor at Science Immunology, writes that mitochondria are central signaling and metabolic hubs “whose function is dynamically regulated by the processes of fusion and fission.”

“Kapetanovic and colleagues found that mitochondrial fission enhances bacterial clearance in macrophages and Caenorhabditis elegans,” Olingy continued, noting that “bacterial infection triggered mitochondrial fission, activating the mitochondrial unfolded protein response and production of antimicrobial lipid droplets.”

“These findings,” Olingy added, “identify a conserved, targetable axis linking mitochondrial dynamics to innate immune defense.”

Approximately 850 million people globally (9.1% of the world’s population) have chronic kidney disease (CKD). The number of affected individuals has grown steadily during the past 20 years and is on track to continue rising. Existing drugs, such as RAAS inhibitors and angiotensin receptor blockers, are commonly prescribed, but their effectiveness varies from patient to patient. Moreover, these drugs can slow disease progression but cannot stop it.

Now, a research team from the Autonomous University of Aguascalientes in Aguascalientes, Mexico, argues that cannabinoid pathways may serve as a novel therapeutic target. Their discussion of this possibility appears in Frontiers in Pharmacology.

CKD mortality and financial burden

The need for new therapies is urgent. Many people with CKD also live with diabetes, high blood pressure and obesity, which collectively account for more than two-thirds of disability-adjusted life years among this population. Overall population aging also plays a part in increasing diagnoses of the disease.

In its later stages, CKD can lead to heart disease and end-stage renal disease (ESRD). The review authors note, “… patients with ESRD can only be treated by dialysis and/or kidney transplant. However, these therapies are insufficient and often hamper the quality of life of patients. For example, patients on dialysis have a higher risk of infection and premature death.”

Indeed, a report published in 2019 shows that dialysis can substantially reduce life expectancy. For dialysis patients ages 20–44, life expectancy is approximately 33 years shorter than for age-matched individuals in the general population. For patients ages 45–64, life expectancy is about 21 years shorter.

The 2019 report also shows that transplant patients ages 20–44 have a life expectancy approximately 15 years shorter than that of age-matched individuals in the general population. While the U.S. national transplant list records about 90,000 new patients annually, only 30% (about 27,000) receive a transplant.

The financial impact of these ESRD treatments is also sobering.

“For example, 2–4% of the world’s health care budget is allocated to dialysis and kidney transplants even though they represent 0.15% of the total patient population,” state the authors of the Frontiers in Pharmacology review.

How CKD progresses at the cellular level

The glomerulus, the kidney’s filtration barrier, includes a glomerular basement membrane; fenestrated endothelial cells, which feature tiny pores; and podocytes, specialized epithelial cells whose foot-like extensions help filter blood as they wrap around blood vessels. The glomerulus and renal tubules comprise a nephron, the kidney’s basic filtering unit.

As CKD progresses, it diminishes the podocyte basement membrane, decreases the proteins nephrin and podocin, interferes with crucial podocyte foot processes, promotes cell death, and causes tubular fibrosis and collapse.

Interestingly, both glomeruli and renal tubules have been identified as sites of cannabinoid receptors.

“The specific localization of cannabinoid receptors within renal structures, such as glomeruli and tubules, and their physiological actions may reveal their pharmacological utility,” the review authors note. “There is evidence in animal models that targeting the cannabinoid receptors could modulate the progression of CKD and AKI [acute kidney injury].”

However, while the human endocannabinoid system (ECS) could represent a new CKD treatment target, reaching this target may not be straightforward.

ECS function within CKD risk factors

The ECS plays a complex role in glucose control, inflammation, obesity and cardiovascular regulation. Mixed results from existing studies point to the need for deeper investigation of how cannabinoids might work in CKD caused by specific conditions.

For example, nearly a third of CKD cases result from diabetes, while high blood pressure causes almost another third. In a 2011 study, blocking CB1 receptors modulated glucose uptake and lipid metabolism but exhibited considerable potential for causing severe mood disorders.

Regarding high blood pressure, the current review cites recent studies showing drops in blood pressure after acute THC administration but noting an association between prolonged THC use and a greater presence of hypertension.

“Therefore, cannabinoids could impact the cardiovascular and metabolic system in opposite directions when targeting kidney disease, for example, decreasing adiposity and insulin resistance on one hand, but inducing hypertension on the other, highlighting the complex role of ECS,” the authors write.

Despite such contraindications, the researchers contend that cannabinoids hold promise in kidney disease research. Future work should include in vitro and animal studies as well as multi-organ analysis, they recommend.