Researchers at Tulane University have identified a potential new way to treat idiopathic pulmonary fibrosis (IPF), a deadly and currently incurable lung disease that affects more than 3 million people worldwide.
IPF is rapidly progressive and causes scarring in the lungs, making it difficult to breathe. Approximately 50% of patients die within three years of diagnosis, and current treatments can only slow the disease – not stop or reverse it.
In a study published in the Journal of Clinical Investigation, Tulane scientists found that an FDA-approved cancer drug may help the immune system clear out the damaged cells that cause the lung scarring, potentially restoring lung function in patients with the disease.
In healthy lungs, specialised cells called fibroblasts help repair lung tissue. But in people with IPF, some fibroblasts and nearby epithelial cells stop functioning properly. These so-called “senescent” cells no longer divide or die as they should. Instead, they build up and contribute to stiff, scarred lungs.
Tulane researchers discovered that these senescent cells appear to accumulate when the immune system’s natural ability to remove them is blocked. The culprit: a protein called CTLA4, which acts as an emergency brake on immune system activity.
By using ipilimumab — an immunotherapy drug currently used to treat various cancers — the researchers were able to block CTLA4 in mice. This released the “brakes” on certain immune cells called T cells, reactivating their ability to clear out the senescent fibroblasts. As a result, the mice showed significantly improved lung tissue regeneration and reduced scarring.
“The CTLA4 protein normally functions to prevent excessive inflammation by blocking overactive T cells,” said senior author Dr. Victor Thannickal, professor and Harry B. Greenberg Chair of Medicine at Tulane University’s John W. Deming Department of Medicine. “Too much of this ‘blocker protein’ may result in losing the ‘good’ inflammation that is needed to remove senescent cells. What we’re doing is blocking the blocker.”
The researchers zeroed in on CTLA4 as a potential therapeutic target when they analyzed both human and mouse IPF lung tissue and found unusually high levels of CTLA4 on the T cells in the areas where scarring was most prevalent.
Mice that received ipilimumab showed significantly improved lung repair ability and recovered faster than mice that did not receive the drug.
“This opens up an entirely new direction for potential treatment of IPF,” said lead author Santu Yadav, PhD, assistant professor of medicine at the Tulane University School of Medicine. “Instead of using drugs to kill senescent cells, we are re-activating our own immune system to clear them out.”
More research is needed to determine the efficacy of drugs that target CTLA4 or other so-called “checkpoint proteins” to rejuvenate the immune system. A primary concern is determining a safe dosing strategy that allows for the immune system to attack senescent cells without causing harmful levels of inflammation.
IPF is a disease of aging and is rarely seen before age 50. These findings also offer hope that this approach could work for other similar aging related diseases.
“If it works in IPF, this immune rejuvenating approach to treatment may be effective in other diseases such as Alzheimer’s or cardiovascular diseases in which senescent cells are known to accumulate,” Thannickal said. “Can the right drug activate T cells in a way that clears senescent cells without causing collateral damage? If so, we may be closer to combating many aging related diseases and perhaps even aging itself.”
A collection of immune cells known as a granuloma that results from chronic inflammation in the interstitial lung disease sarcoidosis. White dots indicate the receptor NRP2, which is overexpressed in response to inflammation. Credit: Scripps Research
Pulmonary sarcoidosis is a lung disease characterised by granulomas—tiny clumps of immune cells that form in response to inflammation. It’s the most inflammatory of the interstitial lung diseases (ILDs), a family of conditions that all involve some level of inflammation and fibrosis, or scarring, of the lungs. In the U.S., pulmonary sarcoidosis affects around 200 000 patients. The cause is unknown, and no new treatments have been introduced in the past 70 years.
In a paper published in Science Translational Medicine, scientists at Scripps Research and aTyr Pharma characterised a protein, HARSWHEP, that can soothe the inflammation associated with sarcoidosis by regulating white blood cells. Reducing inflammation slows the disease’s progression and results in less scarring. A phase 1b/2a clinical trial of efzofitimod, a therapeutic form of HARSWHEP, showed promising results.
“Taken together, these results validate a new way to approach immune regulation in chronic lung disease,” says Paul Schimmel, professor of molecular medicine and chemistry at Scripps Research and the study’s senior author.
The drug’s power lies in its gentle nature. “It’s not a hammer; it’s not overly suppressing the immune system. It’s just nudging the immune system in a certain way,” explains Leslie A. Nangle, Vice President of Research at aTyr Pharma and the paper’s first author. “And if you can quiet the inflammation, you can stop the cycle of ongoing fibrosis.”
HARSWHEP is part of an ancient class of proteins known as aminoacyl-tRNA synthetases (aaRSs). Typically, aaRSs play a key role in protein synthesis. “They’re in every cell in your body. They’re in every organism on the planet,” Nangle says. Over time, new versions known as splice variants have emerged that bind to receptors on the outsides of cells and initiate different events throughout the body.
One such variant, HARSWHEP, entered the picture about 525 million years ago. Nangle and Schimmel screened more than 4,500 receptors and were surprised to find that HARSWHEP will bind only to the receptor neuropilin-2 (NRP2). This receptor is known for its role in development of the lymphatic system—the circulatory system through which immune cells travel—not immune function. But the researchers found that when small, circulating white blood cells known as monocytes enter a tissue in response to inflammation and develop into larger, more specialized white blood cells known as macrophages, those cells start to express high levels of NRP2.
“We had a protein with an unknown function. We had a receptor that was doing something on immune cells that had never been characterized. So we had a couple things we had to match up,” Nangle says.
The team found that HARSWHEP binding to NRP2 physically transforms the macrophage. “It’s creating a new type of macrophage that is less inflammatory and actually helps to resolve inflammation,” Nangle explains.
To characterise HARSWHEP’s mechanism of action, the team administered the protein in mice and rats and found that it reduced lung inflammation and the progression of fibrosis.
In separately published clinical trial data, the team saw a positive impact on patients who were treated with efzofitimod while tapering off of oral corticosteroids. Long-term steroid treatment, currently the first-line option, is associated with significant weight gain and organ damage, and the immunosuppressive effects leave patients vulnerable to infection.
The team also characterised patients’ circulating immune cells before and after efzofitimod treatment. They saw that it reduced key indicators of the inflammation that drives sarcoidosis, such as the concentration of macrophages and other inflammatory immune cells.
While they’re exploring sarcoidosis first, efzofitimod is a potential treatment for many interstitial lung diseases, Nangle explains. The aTyr team plans to explore treating other ILDs and is running a clinical trial now for scleroderma-related ILD.
The work highlights macrophages as a possible target for treating ILDs, and the promise of HARSWHEP could foretell other aaRSs’ therapeutic potential.
Nangle describes this work as moving “from concept to clinic.” Schimmel has worked on aaRSs throughout his tenure at Scripps Research. aTyr Pharma spun out of Schimmel’s lab; his former graduate student Nangle was the company’s first employee upon opening their labs in 2006.
“Original work that happened at Scripps gave rise to the idea that this could be a new class of therapeutic molecules, Nangle says. “We have now moved it all the way to clinical development. It’s a proof of concept for this whole class of molecules and the work Paul has done.”
Whooping cough, or pertussis, was once a leading cause of death for children worldwide before the introduction of vaccines in the 1940s. In the decades since, the bacterial disease was nearly eradicated in the U.S., with fatalities falling to double digits each year.
But the disease has made a troubling comeback in recent years as vaccine coverage declined after the COVID-19 pandemic. In 2024, several outbreaks left public health officials and hospitals scrambling to accommodate a sudden influx of patients, primarily infants, who are often too young to be vaccinated and suffer the most severe symptoms.
Now, new research from The University of Texas at Austin could aid in improving whooping cough vaccines to once again push this disease toward eradication by targeting two key weaknesses in the infection.
A New Target
Against this backdrop, a team of researchers, including members of UT’s McKetta Department of Chemical Engineering and Department of Molecular Biosciences, has made significant strides in understanding and enhancing pertussis immunity. One of the things that makes pertussis infections dangerous is pertussis toxin (PT), a chemical weapon produced by the bacteria that weakens a patient’s immune response and causes many of the severe symptoms associated with whooping cough.
The new research, described in a new study published in the Proceedings of the National Academy of Sciences, focuses on two powerful antibodies, hu11E6 and hu1B7, which neutralise the PT in different ways.
Using cutting-edge cryo-electron microscopy approaches, the researchers identified the specific epitopes on PT where these antibodies bind. Epitopes are chemical targets the immune system can zero in on to fight pathogens. Hu11E6 blocks the toxin from attaching to human cells by interfering with sugar-binding sites, while hu1B7 prevents the toxin from entering cells and causing harm. These findings are the first to precisely map these critical regions, providing a blueprint to improve vaccines.
“There are currently several promising new pertussis vaccines in the research and clinical trial phases,” said Jennifer Maynard, professor of chemical engineering at the Cockrell School of Engineering and corresponding author of the new study. “Our findings could be incorporated into future versions quite easily, improving overall effectiveness and longevity of protection.”
She pointed to innovations like mRNA technology used in the COVID-19 vaccine, as well as breakthroughs in using genetic engineering on pertussis toxin (PTgen) to generate safer and more potent new recombinant acellular pertussis vaccines as technologies preserving neutralizing epitopes that can combine with her team’s new findings.
“Training the immune system to target the most vulnerable sites on the toxin is expected to create more effective vaccines,” Maynard said. “And the more effective and longer-lasting a vaccine is, hopefully, the more people will take it.”
In addition to helping guide future vaccine designs, the hu1B7 and hu11E6 antibodies themselves hold promise as therapeutic medicines for infected and high-risk infants. Previous work by Maynard and colleagues show that they can prevent the lethal aspects of pertussis infection. UT researchers are actively seeking partnerships to develop ways to prevent lung damage and death in newborns exposed to the disease.
A Persistent Threat
Caused by the bacterium Bordetella pertussis, whooping cough is infamous for its violent coughing fits, which can lead to complications like pneumonia, seizures, and even death, particularly in infants. One nickname for the disease is the 100-days cough because the painful coughing fits can linger for months, even in mild or moderate cases. The disease kills an estimated 200 000 people each year worldwide, most of them infants and children, and survivors of severe illness can be left with brain damage and lung scarring.
While modern vaccines have reduced the toll, their effectiveness wanes over time, with protection only lasting two to five years. Modern pertussis vaccines are acellular, which means they contain portions of the bacteria that train the immune system to recognize the pathogen, including PT.
Recent outbreaks of whooping cough around the world have stunned public health officials. This fall, New York City saw a 169% increase in whooping cough cases since 2023. Cases have increased 500% since 2019. Australia is currently suffering through the largest outbreak of whooping cough since the introduction of the vaccine in the 1940s, with an estimated 41,000 cases reported this year.
Health officials point to missed initial and booster vaccinations as major contributors to the outbreaks.
Overcoming Hesitancy
While advances in fighting pertussis are exciting, they face a dual challenge: overcoming the biological complexity of pertussis and the societal hurdles of vaccine hesitancy. The most effective way to prevent pertussis in vulnerable newborns is for mothers to be vaccinated during pregnancy, which confers protection to the newborn until it is old enough to be vaccinated. According to the CDC, the full vaccination rate against pertussis in kindergarteners is typically over 90% in the US, but under 60% of mothers receive the vaccine during pregnancy. Skepticism about vaccine safety and slow normalization of routine vaccination after the COVID-19 pandemic has led to pockets of under-vaccinated communities and overall low protection of newborns, providing fertile ground for deadly outbreaks. This environment, coupled with the limitations of current vaccines, makes innovation essential.
Co-author Annalee W. Nguyen, a research professor in chemical engineering, emphasized the importance of prevention over treatment. “It’s always easier to prevent disease in a high-risk person,” she said. “Once someone is extremely ill, their immune system isn’t functioning well, and it’s harder to help them recover. Mothers have an incredible opportunity to shield their babies after they are born by getting a pertussis booster vaccination during pregnancy, and parents can continue to protect their families by working with their pediatrician to ensure children and teens are up-to-date on vaccinations.”
By focusing on neutralizing epitopes—areas where antibodies can effectively block the toxin—new vaccines can potentially provide stronger, longer-lasting immunity. This could help bolster public confidence in pertussis vaccines and curb the disease’s resurgence.
For centuries, it was believed that tuberculosis spread primarily when a vulnerable person spends hours in a poorly ventilated space with someone infectious. But new findings suggest that much TB transmission also occurs through casual contact.
Conventional thinking held that enclosed spaces such as households, prisons, and shelters, where people spent long periods of time together, were where most TB transmission took place. But new data suggest that casual contact at social settings like shopping malls, restaurants, bars, and places of worship also account for much TB transmission.
A recent study found that close contact explained only 9% of TB transmission links, while casual contact accounted for 49%. The study, called CONTEXT (Casual Contact and Migration in XDR TB), was conducted in KwaZulu-Natal.
The study’s lead author, Professor Neel Gandhi of Emory University in Atlanta, recently presented the findings at the Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco. The work has not yet been published in a peer-reviewed medical journal.
The new findings come in the context of other research (much of which was conducted in Cape Town) that suggest TB could be transmitted through breathing, and growing evidence that people with asymptomatic TB can transmit the infection.
Where transmission occurs
Gandhi tells Spotlight that TB transmission has traditionally been linked to prolonged, close contact, with previous studies showing that 9 to 30% of cases could be attributed to this type of contact. A compelling alternative argument, he says, is that the remaining 70% of transmission occurs due to casual contact in community settings – which is what their research sought to explore.
He elaborates: “For much of history, we have thought that most TB transmission occurs through close and prolonged contact, meaning that a susceptible person is spending a lot of time in a poorly ventilated area with somebody who is infectious. And so most often we think of households as places where transmission occurs; or congregate settings, places like prisons or homeless shelters.”
On defining casual contact, he says: “In our research, we wanted to understand less intense forms of contact where transmission can occur. So, we understood where people lived, but we also asked them where they spent time in a typical week. The phrase we used was: ‘where do you spend two hours or more, most weeks?’ To try to identify the places people spend substantial amounts of time; and seeing whether they crossed paths with somebody else to whom their molecular fingerprints (of their TB bacteria infection) match.”
Genotyping, and geomapping
In their study, Gandhi and his colleagues made use of both genotyping and geospatial mapping to figure out where TB transmission likely occurred.
Genotyping, explains Gandhi, is a technology developed about 30 years ago that allows us to examine the genetic code of TB bacteria, and to compare similarity between patients’ bacteria.
“TB is a bacteria that keeps its genetic code similar across many generations of replication. In layman’s terms, we call this molecular fingerprinting. If I were to transmit TB to somebody else; my TB bacteria and that person’s TB bacteria’s genetic codes would look very similar – almost identical – so we could use this fingerprinting technique by sequencing the genomes of the two TB bacteria to try to fully get a sense of what the likelihood of transmission was.”
Commenting on their geospatial methodology, he says: “When our participants told us where they live or where they spend time in the community, or where they get outpatient healthcare; our team went to those sites and captured a GPS coordinates.
“Just like we use GPS for mapping when we’re trying to get around town, we would get specific coordinates… If two people went to the same shop, they might have used different names for that shop, or let’s say they went to a shopping mall, they may have used different names for those places; but we used GPS coordinates allowing us to determine whether they were at the same place or close to one another. And we used the concept of proximity to try to understand the likelihood that they may have crossed paths.”
In the study they used the metric of “community proximity” defined as a radius of 500 metres, or less.
Gandhi illustrates the nuance of geomapping, using his university campus: “So the example I like to give is; I work in a building called the School of Public Health. Across the courtyard is the School of Nursing. If you just asked me, where do you work? I would tell you, I work in this building. If you ask the next person where they work, they may say, I work in the School of Nursing. That wouldn’t match up in terms of place name. But if we used a radius of 100 metres or 500 metres, we can determine that we work very close to one another. And there’s a cafe in yet another building that we may have eaten lunch in at the same time. TB being an airborne disease, I don’t have to sit next to that person or even to know that person; if I’m infectious, I could have transmitted to them if they were sitting and eating in the same room.”
Essentially, the researchers used genotyping, particularly molecular fingerprinting to help understand the likelihood of transmission between people who have drug resistant TB. And once individuals with similar molecular fingerprints were found, they used geomapping to see whether these patients could be connected through close contact – and if not close contact, then through casual contact.
He adds: “The most common place people told us were friends and family members’ homes. Then the next most common was places of shopping so shopping malls.”
At CROI, Gandhi responded to a question from a conference delegate around risk, saying that there appears to be a greater risk of TB transmission in social settings than previously understood.
Symptoms and disease
To Spotlight, he says more work is needed to understand why casual contact transmission is happening. “And it connects to another topic in the TB community that is gaining a lot of attention currently, which is trying to understand what the association is between symptoms and having TB disease,” says Gandhi.
He notes that the challenge for researchers moving forward is understanding the link between infectiousness and symptoms – specifically, understanding when a person becomes infectious, even if they show no symptoms.
Most TB public health interventions are still based on the assumption that people with TB will present at health facilities with classic TB symptoms such as persistent cough, night sweats, fever, weight loss, and chest pain. South Africa has however in recent years been offering TB tests to asymptomatic people thought to be at high risk of TB, as part of its targeted universal testing strategy.
“So you may have heard of this concept of what some people have called subclinical TB or asymptomatic TB. And that is to say, if you were to test a group of people who didn’t come to a health clinic, but let’s say you were on a street corner and you tested everybody who went by for TB, we’re coming to appreciate that as many as 50% of people may not either have any symptoms or may not have symptoms that are worrisome enough for them to seek healthcare, but are actually testing positive for TB disease,” Gandhi adds.
Gandhi says this reminds him of the early days of COVID-19, when scientists weren’t sure if people only became infectious after showing symptoms.
“Eventually we learned that people were infectious probably for a few days before they developed symptoms. And in the TB world, this may be an area we need to investigate. If there’s the possibility that somebody is infectious when they have absolutely no symptoms, they would go about their regular activities; going to work, going to school, going shopping, going to religious ceremonies, going to restaurants, and they may unknowingly be infectious with TB. So this is the challenge.”
The bigger picture
Commenting on the findings, Robert Wilkinson, Honorary Professor in the Department of Medicine at the University of Cape Town and director of the Centre for Infectious Diseases Research in Africa, says: “It is interesting, and the proportion of transmission estimated to occur outside the household is a low estimate, but not incompatible with other estimates.”
He notes that the phenomenon of transmission occurring after brief casual contact is not novel though, and has been investigated in previous studies.
Asked how the findings presented by Gandhi might affect the outlook on TB interventions, Wilkinson says: “Whilst close household exposure to infectious tuberculosis should prompt clinical evaluation especially if there are symptoms, finding a close contact by conventional contact tracing approaches is far from invariable. Therefore, in high incidence environments like South Africa more attention needs to be placed on mass radiographic (X-ray) and, or microbiological screening of asymptomatic persons.”
In a recent public lecture called ‘Hunting Bosons, Finding the Bummock’, Emeritus Professor in Medicine at the University of Cape Town, Robin Wood, former CEO of the Desmond Tutu Health Foundation, states: “I think we are changing the paradigm of tuberculosis.” He notes that research now targets “hidden reservoirs of TB transmission beyond visible, symptomatic cases… [as] TB silently spreads within communities through carriers who exhibit no symptoms yet contribute to transmission.” Asked about Gandhi’s findings, Wood told Spotlight he would reserve comment until the data is submitted for further peer review and publication.
Study details
The 305 respondents in the CONTEXT study were patients with extensively drug-resistant TB or pre-extensively drug-resistant TB. They were diagnosed between 2019 and 2022 in the eThekwini, Ilembe, Umgungundlovu, and Ugu regions. The average age was 36 years, with 137 (45%) women and 216 (73%) people living with HIV.
The study was conducted in collaboration with the Durban-based Centre for the AIDS Programme of Research in South Africa (CAPRISA).
“CAPRISA played a leadership role in conceptualising the science, development of the protocol and data collection instruments, oversight of all aspects of field work, including screening and enrolling patients, obtaining informed consent from patients or their proxy’s, field and laboratory data collection, data verification and data clean-up activities for all data used in this study,” says CAPRISA’s deputy director, Professor Kogieleum Naidoo.
CONTEXT was funded through the United States National Institutes of Health (NIH), the world’s largest health research funder which has in recent weeks terminated several grants in South Africa and elsewhere. “The funding period has ended,” says Gandhi. “Now we’re analysing all of the data, so it won’t be impacted by any changes happening at NIH.”
Rutgers Health researchers have discovered that networks of misplaced immune cells drive an aggressive lung disease, potentially opening a path to new treatments for a condition that kills 80% of patients within a decade.
Idiopathic pulmonary fibrosis (IPF) scars lung tissue and makes breathing increasingly difficult until patients can’t get enough oxygen. Available drugs provide minimal benefit. Lung transplantation works for some patients, but transplants have a 50% five-year mortality rate.
This study in the European Respiratory Journal used advanced spatial mapping techniques to compare healthy lung tissues and tissues from patients with fatal IPF. The researchers discovered that disease-scarred lung tissue abounds in plasma cells – specialised immune cells that typically reside in bone marrow and produce antibodies.
“What we found most striking in this study is that all the fibrotic regions of IPF patients’ lungs are covered by antibody-producing plasma cells,” Qi Yang, an associate paediatrics professor at Rutgers and a senior author of the study. “In normal lungs, there are almost no plasma cells. But in IPF patients, the lungs are full of them.”
The researchers identified previously unknown cellular networks orchestrating this abnormal immune response. They discovered novel mural cells wrapping around blood vessels and producing signal proteins that organize immune responses. They also found unique fibroblasts secreting a protein that attracts plasma cells to damaged areas.
“This particular type of fibroblast has never been described before,” said Reynold Panettieri, director of the Rutgers Institute for Translational Medicine and Science and a senior author of the study. “People have shown that fibroblasts are the cell types responsible for scarring – in the skin, the lungs and the brain – but this particular type of fibroblast seems unique to the lung.”
Having found the plasma cells in lung tissue taken from people who died of IPF, the team began using live mice to see if reducing plasma in the lungs slowed disease formation. This work demonstrated that blocking signaling pathways reduced plasma cell accumulation and alleviated lung scarring. Targeting these same signaling pathways may thus prove an effective disease treatment in humans, the researchers said.
The research is particularly promising because drugs targeting plasma cells already exist. Medications used to treat multiple myeloma, a plasma cell cancer, could potentially be repurposed to treat IPF.
“If the plasma cells are really making the bad antibodies, I assume we may have to get rid of them,” said Yang, a member of the Institute for Translational Medicine and Science. “Otherwise, patients will keep making these antibodies that drive the disease.”
Previous studies have shown that IPF patients have heightened antibody responses and elevated lung antibody levels. The new research explains the origin of these antibodies and reveals how abnormal antibody-producing cells accumulate in the lungs.
The researchers said the antibodies may drive tissue damage through several mechanisms. Their data suggest that antibody-antigen complexes stimulate the production of transforming growth factor-beta from pulmonary macrophages, thus promoting fibrosis.
“Now that we have a target, a cell, a unique cell that Dr Yang has identified and phenotyped, we’re optimistic that we could affect that cell and not other fibroblasts that are important in normal injury repair response,” Panettieri said.
For patients with IPF, the findings offer hope of new treatments for a debilitating condition with limited therapeutic options. The disease typically affects men over 60 years of age, with most patients dying within five years of diagnosis.
The next steps for the research team include determining whether the plasma cells are producing autoantibodies against healthy tissues and further investigating how fibroblasts and mural cells develop their abnormal properties in IPF.
“Our research suggests that IPF might have a strong autoimmune link,” Yang said.
Researchers have found a potential new way to slow the progression of lung fibrosis and other fibrotic diseases by inhibiting the expression or function of Piezo2, a receptor that senses mechanical forces in tissues including stress, strain, and stiffness. The new study in The American Journal of Pathology, published by Elsevier, sheds light on the underlying mechanisms of pulmonary fibrotic diseases and identifies potential new targets and options for therapy to improve patients’ outcomes.
Pulmonary fibrotic diseases are a group of conditions that cause significant morbidity and sometimes mortality. Idiopathic pulmonary fibrosis (IPF) is a devastating progressive fibrotic lung disease with a median survival of 2.9 years from diagnosis. Lung fibrosis results in dramatic mechanical changes including increased stiffness in the tissue that cells can sense and respond to, making it difficult for the lungs to expand and contract properly during breathing.
Piezo channels are a newly discovered receptor that are sensitive to mechanical signals. Since the 2021 Nobel Prize in Medicine was awarded to Dr Ardem Patapoutian for the discovery of Piezo channels in 2010, interest has increased in their role in tissue homeostasis and disease outside of neuronal signalling, however, little has been published on their possible role in fibrotic lung diseases. A group of researchers driven to understand how mechanical forces in lung tissue contribute to and drive pulmonary fibrosis investigated the role of Piezo2 in pulmonary fibrosis using donor tissue from patients with IPF, mouse models of lung fibrosis, cell culture investigation of lung cells (fibroblasts) that create the fibrosis lesions, and by examining publicly available RNAseq datasets from other research groups.
Investigators found that:
Piezo2 is highly expressed in human lung tissue from patients with IPF and in multiple (different) mouse models of lung fibrosis.
Piezo2 is highly expressed in primary human lung fibroblasts in culture, the cells that are believed to play key roles in producing fibrosis in tissues (by proliferating and laying down matrix proteins, creating scar-like features).
Lung fibroblasts grown on stiffer substrates are reprogrammed to be more profibrotic, by proliferating, producing extra matrix proteins, and differentiating to scar-forming myofibroblasts.
Inhibition of Piezo2 with either RNA silencing or a peptide inhibitor, to prevent them from sensing the stiffness of their environment, reduces profibrotic programming.
Lead investigator Patricia J. Sime, MD, Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University, says, “We are excited to report that this research that suggests inhibiting expression or function of Piezo2 could be a potential new therapeutic route to treating lung fibrosis and other fibrotic diseases. This is especially important as there is an unmet need for additional therapies for fibrotic diseases.”
Despite the introduction of nintedanib and pirfenidone for therapy of some fibrotic lung diseases, pulmonary fibrosis can remain challenging to effectively treat. This is in part because lung cells can be driven to a profibrotic phenotype by multiple pathways that reinforce each other, so that targeting one pathway alone may not be effective to slow or stop disease progression.
First author Margaret A.T. Freeberg, PhD, Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University, continues, “Some types of lung fibrosis have been very difficult to treat. For example, IPF is a form of pulmonary fibrosis that often progresses. While there have been advances in therapy, the approved medications for IPF can slow, but do not always halt progression. One of the reasons that fibrosis can be difficult to effectively treat may be explained by the multiple profibrotic disease pathways that reinforce each other. Blocking Piezo2 signaling to prevent fibroblast reprogramming represents a new pathway we can target in our fight against fibrosis.”
Dr. Sime concludes, “This research identifies mechanical forces and a new specific target (Piezo2) that we can block to prevent fibrotic reprogramming of some lung cells. We believe this points to Piezo2 as an important new therapeutic target that might (by itself or in combination with other therapies) slow the progression of pulmonary fibrosis in our patients. Many new investigational drugs that target pulmonary fibrosis receive orphan drug designation from the FDA, and this may accelerate development and increase interest from pharmaceutical partners.”
Mycobacterium tuberculosis drug susceptibility test. Photo by CDC on Unsplash
By Catherine Tomlinson
Both TB treatment and TB preventive therapy involve taking lots of pills, usually for several months. Researchers are working on new long-acting formulations that might, for example, reduce an entire course of TB preventive therapy to a single injection.
The biggest HIV news of last year was that an injection containing an antiretroviral called lenacapavir provides six months of protection against HIV infection per shot. While it will be several years before the jabs become widely available, experts nevertheless hailed the development as a potential game-changer. In some countries, HIV treatment is already available as injections – containing the antiretrovirals cabotegravir and rilpivirine – administered every two months.
Scientists working on tuberculosis (TB) are trying to replicate the successes of the HIV field and develop similarly long-acting formulations of TB medicines. The good news is that they have several exciting products under development – the bad news is that the research is still at a very early stage and the pivotal studies that will tell us if these products work are likely still years away.
But if they work, they could make a big difference to patients. That is because TB treatment and TB preventive therapy mostly still requires swallowing lots of pills over a long period of time. There is some good evidence that many people would prefer long-acting injections.
The case for long-acting TB medicines
TB preventive therapy is used to stop someone suspected of having latent TB infection from falling ill with TB. In South Africa, such preventive therapy is recommended for all close contacts of someone sick with TB. Typically, it involves taking tablets for three or six months (a one-month course has been shown to work, but is not widely available). There is research that shows that the shorter the regimen the more likely it is to be completed.
The hope is that a long-acting product might do away with swallowing tablets altogether and reduce an entire course of preventive therapy to a single injection. This is likely to be more convenient for patients as well as come with the benefit of perfect treatment completion rates.
TB preventive therapy is a simpler target for long-acting formulations than TB treatment since it typically involves only one or two drugs and treatment durations are shorter. TB treatment typically takes six or more months to complete and usually involves taking four different drugs – often four for two months and then only two for the remaining four months in what is called the continuation phase. Some of the current thinking is that the continuation phase could potentially be replaced by long-acting formulations of TB medicines. This could shorten the duration of TB treatment to just two months of taking tablets.
Not an easy nut to crack
As explained by Dr Eric Nuermberger of Johns Hopkins University, not all TB medicines available as tablets make good candidates for translation to long-acting injectable formulations. He was presenting on long-acting TB drugs at the Conference for Retroviruses and Opportunistic Infections (CROI), recently held in San Francisco.
Nuermberger outlined three key characteristics that are needed for long-acting formulations. These are low water solubility (so the drug doesn’t dissolve to quickly), low clearance in plasma (so that the body doesn’t clear the drug too quickly), and high drug potency (so that a small volume of drug can be effective for a long period of time).
One key challenge, according to Nuermberger, is that scientists do not yet have reliable biomarkers to measure the effectiveness of long-acting TB preventive therapy in phase II trials. Biomarkers, such as blood levels of certain proteins, could in theory offer scientists a faster way to assess if TB preventative therapy is working, without having to monitor clinical trial participants for long periods of time to determine treatment outcomes.
Writing in the journal Clinical Infectious Diseases, scientists working to develop long-acting TB products explained: “The inability to culture or otherwise quantify viable bacteria during latent TB infection and the lack of validated surrogate biomarkers mean that there is no opportunity to obtain initial proof of efficacy… which is usually the domain of phase 2 trials. Instead, the development of new TPT regimens requires bridging directly from preclinical studies and phase 1 trials to phase 3 trials, which are themselves long and require large numbers of participants.”
However, they added that “[t]he search for biomarkers that act as prospective signatures of risk for developing TB disease is a very active research area and an important scientific priority for the field”.
Back at CROI, Nuermberger also told participants that most products in the pipeline remain at pre-clinical stages and are still being tested in mice. He explained that differences in how depot drugs — drugs released slowly over time — work in mice and humans make it hard to apply findings from mice to humans. But modeling is being done to help bridge this gap.
‘Expanded remarkably’
Despite these challenges, Nuermberger said “the number of long-acting drug formulations in development [for TB] has really expanded remarkably in the last few years, which is a very promising development”.
The product that is furthest along in the development pipeline, but still at a very early stage of research, is a long-acting form of bedaquiline. This drug is currently used for the treatment of drug-resistant forms of TB and falls in a class of antibiotics known as diarylquinolines.
The Belgian pharmaceutical company Janssen is currently running a phase I trial of long-acting injectable bedaquiline in Austria. Phase I trials are conducted in a small group of healthy individuals to assess the safety and tolerability of an experimental medicine. In the phase 1 bedaquiline trial, researchers are investigating the safety and tolerability of different doses of long-acting injectable bedaquiline.
Several other long-acting TB medicines are being investigated in preclinical research, including long-acting versions of the TB medicines rifabutin and rifapentine, as well as the second generation diarylquinolines, TBJ-876 and TBA-587, which are under development by the TB Alliance. The second generation diarylquinolines are being tested on their own and in combination with pretomanid and telacebec.
In addition, the University of Liverpool, Johns Hopkins University, University of Southern Denmark, University of North Carolina and the US pharmaceutical company Inflamamasome Therapeutics, are all involved in pre-clinical research on long-acting formulations. These efforts are supported financially by Unitaid, the US National Institutes of Health, and the Gates Foundation.
The treatments being developed include aqueous nanoparticle suspensions, in-situ forming implants, and rod implants. Aqueous nanoparticle suspensions are drugs turned into tiny particles and delivered in a water-based solution via injection. In-situ forming implants are injected as a liquid that then solidifies into an implant under the skin. Rod implants are small, rod-shaped devices inserted under the skin with a needle-like tool after numbing the area with a local anaesthetic.
What users prefer
At CROI, delegates also learned about patient and provider preferences for long-acting TB treatment.
Dr Marcia Vermeulen from the University of Cape Town presented the results of a survey involving over 400 patients in South Africa and India, as well as 94 healthcare providers.
Seventy-five percent of healthcare workers said they would prescribe a long-acting injectable product rather than pills for tuberculosis preventative therapy if it was priced the same or lower. Similarly, 75% of patients said they would try an injectable product for TB prevention if it became available.
“As a TB survivor, I am excited about long-acting TB treatment as it doesn’t require frequent facility visits, saving a person’s time and money, and can thereby increase adherence and improve treatment outcomes,” TB Proof’s Phumeza Tisile told Spotlight.
She added that communities should be at the heart of rollout plans because they understand the needs of people affected by TB and know how to communicate effectively to encourage involvement and adoption.
Disclosure: The Gates Foundation is mentioned in this article. Spotlight receives funding from the Gates Foundation but is editorially independent – an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.
Targets for universal access, national roadmaps and more affordable and accessible care are vital to help fill the medical oxygen gap affecting more than half of the world’s population, according to a new global report.
The Lancet Global Health Commission report details for the first time how future investment in strengthening medical oxygen systems could have a huge impact by saving millions of lives and improving pandemic preparedness.
Almost 400 million children and adults require medical oxygen every year. More than five billion people, 60 per cent of the world’s population, don’t have access to safe and affordable medical oxygen services.
MCRI Dr Hamish Graham said the COVID-19 pandemic had put a spotlight on the longstanding global inequities in accessing medical oxygen.
“Oxygen is required at every level of the healthcare system for children and adults with a wide range of acute and chronic conditions,” he said. Previous efforts, including the major investments in response to the COVID-19 pandemic, largely focused on the delivery of equipment to produce more oxygen, neglecting the supporting systems and people required to ensure it was distributed, maintained, and used safely and effectively.”
Dr Graham said channelling investments into national oxygen plans and bolstering health systems, including wider use of pulse oximeters (a small device that measures how much oxygen is in the blood), would help solve the medical oxygen crisis.
“We urgently need to make high-quality, pulse oximeters more affordable and widely accessible,” he said. Pulse oximeters are available in 54 per cent of general and 83 per cent of tertiary hospitals in low- and middle-income countries, with frequent shortages and equipment breakdowns.
“Concerningly, in these countries the devices are performed for only 20 per cent of patients presenting to general hospitals and almost never for those at primary healthcare facilities. We see the greatest inequities in small and rural government health facilities and across Sub-Saharan Africa.”
Dr Graham said the importance of medical oxygen must also be recognised and integrated into broader national strategies and pandemic preparedness and response planning.
“Governments should bring together public and private sector partners with a stake in medical oxygen delivery, including health, education, industry, energy and transport to design a system and set up a governance structure that supports the new Global Oxygen Alliance (GO₂AL) and replenishing The Global Fund with a strong oxygen access mandate,” he said.
Despite new medication, cystic fibrosis often leads to permanent lung damage. Working with an international team, researchers from the Technical University of Munich (TUM) have discovered that the disease causes changes in the immune system early in life, presumably even in newborns. These changes lead to frequent inflammation and are not affected by drugs targeting the altered mucus production.
Cystic fibrosis is caused by hereditary genetic mutations that impair or halt the production of the CFTR protein. The respiratory tract is most severely affected. There, the mucus becomes so viscous that pathogens like bacteria cannot be removed by coughing. The result is often a deadly cycle of infection and inflammation.
In recent years, doctors have started using so-called CFTR modulator therapies to enhance the protein’s function. This reduces mucus formation and significantly improves the quality of life for those affected. However, clinical studies show that airway inflammation continues to occur frequently. In older patients, the decline in lung function seems unstoppable.
Current research aims to uncover additional processes in cystic fibrosis. “We specifically looked at how the immune system behaves in cystic fibrosis before the cycle of infection and inflammation begins,” said Prof. Nikolai Klymiuk from TUM. He is part of the international team that recently published a study on cystic fibrosis in Science Translational Medicine.
Immature immune cells in blood samples from children
The researchers found that in blood samples from children with cystic fibrosis and biological material from pigs with the same genetic defect, certain cells of the innate immune system are immature. This makes them less effective at fighting bacteria. Pigs with cystic fibrosis also showed an increased number and significantly altered composition of immune cells in the lungs at birth. The strong resemblance between the immune systems of pigs and humans suggests that this finding likely applies to human patients as well.
‘Emergency program’ responsible?
According to the authors, one possible explanation for the changes in the immune system could be a kind of “emergency program”. The program stimulates the body to produce a large number of immune cells particularly quickly or over a longer period of time. One consequence is the formation of immature immune cells, which could contribute to the fatal cycle of infections and inflammation in cystic fibrosis: Although immune cells are present in the lungs, they are ineffective and cause damage to the lung tissue without preventing infections in the long term.
Since immune cells generally produce only very small amounts of CFTR, the research team believes that the influence of cystic fibrosis on the immune system is indirect. This could explain why defective immune reactions cannot be treated well with novel CFTR modulator therapies.
Changes not a result of frequent infections
“We don’t yet know exactly why the immune cells in cystic fibrosis show such changes,” says Nikolai Klymiuk, Professor of Cardiovascular Translation in Large Animal Models. “However, we can show that these occur early in life. They then persist in the further course of life.” According to Klymiuk, although altered immune cells were known from blood samples of adults with cystic fibrosis, they were seen as a consequence of the numerous infections.
“To enable people with cystic fibrosis to live without symptoms, we probably need to tackle the disease on several levels,” said Klymiuk. “We hope our work will help us better understand the causes of the defective immune system and correct them in the future”
Air pollution is a well-known risk factor for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) – but its contribution to lower respiratory infections is less well known, especially in adults. To address this, a team from the Barcelona Institute for Global Health (ISGlobal), a centre supported by the ”la Caixa” Foundation, assessed the effect of air pollution on hospital admissions for lower respiratory infections in adults, and which subgroups that could be particularly vulnerable to these infections. The results have been published in the journalEnvironment International.
The research shows that long-term exposure to particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2) and ozone (O3) air pollution is associated with more hospital admissions for lower respiratory tract infections in adults. The associations were stronger in men, people over 65 years of age and those diagnosed with hypertension.
The study involved 3 800 000 adults from the COVAIR-CAT cohort, a large cohort of 7.7 million people based on the health system of Catalonia. The research team used exposure models to estimate annual average concentrations of PM2.5, PM10, NO2 and ozone during the warm season (May-September) between 2018 and 2020 at the participants’ residences. Information on hospital admissions, mortality and comorbidities was obtained from various administrative databases. The study included hospital admissions for all lower respiratory infections and, separately, the subgroup of hospital admissions for influenza and pneumonia. A statistical model was then used to assess the association between air pollution and hospital admissions.
“The association between air pollution and hospital admissions for lower respiratory tract infections was observed even at pollution levels below current EU air quality standards,” says Anna Alari, ISGlobal researcher and first author of the study. “It is crucial to adopt stricter air quality standards, as more ambitious measures to reduce air pollution would decrease hospital admissions and protect vulnerable populations,” she adds.
Stronger association in men and people over 65
The association between air pollution and hospitalisations for lower respiratory tract infections was more pronounced in people over 65 years of age or with comorbidities, compared with younger people or those without comorbidities. Specifically, elevated levels of air pollution were associated with approximately three times higher rates of hospital admissions for lower respiratory infections among people aged 65 years and older compared with younger people.
In addition, exposure to elevated levels of NO2, PM2.5 or PM10 (but not O3) was associated with about a 50% increase in hospital admissions in men, while the association was about 3% higher in women.
The team observed the same pattern for hospital admissions for influenza or pneumonia, but with smaller associations compared to lower respiratory infections. “This may be due to the influence of available vaccines against the pathogens responsible for influenza and most cases of pneumonia,” says Cathryn Tonne, senior author of the study.
