Cells taken from the lungs of people with chronic obstructive pulmonary disease (COPD) have a larger accumulation of soot-like carbon deposits compared to cells taken from smokers without COPD, according to a study published in ERJ Open Research. Carbon can enter the lungs via cigarette smoke, diesel exhaust and polluted air.
The cells, called alveolar macrophages, normally protect the body by engulfing any particles or bacteria that reach the lungs. But, in their new study, researchers found that when these cells are exposed to carbon they grow larger and encourage inflammation.
The research was led by Dr James Baker and Dr Simon Lea from the University of Manchester, UK. Dr Baker said: “COPD is a complex disease that has a number of environmental and genetic risk factors. One factor is exposure to carbon from smoking or breathing polluted air.
“We wanted to study what happens in the lungs of COPD patients when this carbon builds up in alveolar macrophage cells, as this may influence the cells’ ability to protect the lungs.”
The researchers used samples of lung tissue from surgery for suspected lung cancer. They studied samples (that did not contain any cancer cells) from 28 people who had COPD and 15 people who were smokers but did not have COPD.
Looking specifically at alveolar macrophage cells under a microscope, the researchers measured the sizes of the cells and the amount of carbon accumulated in the cells.
They found that the average amount of carbon was more than three times greater in alveolar macrophage cells from COPD patients compared to smokers. Cells containing carbon were consistently larger than cells with no visible carbon.
Patients with larger deposits of carbon in their alveolar macrophages had worse lung function, according to a measure called FEV1%, which quantifies how much and how forcefully patients can breathe out.
When the researchers exposed macrophages to carbon particles in the lab, they saw the cells become much larger and found that they were producing higher levels of proteins that lead to inflammation.
Dr Lea said: “As we compared cells from COPD patients with cells from smokers, we can see that this build-up of carbon is not a direct result of cigarette smoking. Instead, we show alveolar macrophages in COPD patients contain more carbon and are inherently different in terms of their form and function compared to those in smokers.
“Our research raises an interesting question as to the cause of the increased levels of carbon in COPD patients’ macrophages. It could be that people with COPD are less able to clear the carbon they breathe in. It could also be that people exposed to more particulate matter are accumulating this carbon and developing COPD as a result.
“In future, it would be interesting to study how this carbon builds up and how lung cells respond over a longer period of time.”
A study in Nature Communications reveals, for the first time, how the transcriptomic profile of human tuberculosis lung lesions is correlated with clinical data from the same patients. The work could potentially lead to improved prognosis by using personalised strategies.
Dr Cristina Vilaplana led researchers from the Experimental Tuberculosis Unit (UTE) at the Germans Trias i Pujol Research Institute (IGTP) and the Germans Trias i Pujol University Hospital.
The study applied RNAseq techniques to 44 fresh tissue samples from lesional and adjacent lung areas of patients with drug-sensitive and multidrug-resistant tuberculosis who underwent therapeutic surgery. The results show a clear separation between lesional and non-lesional tissue, with high expression of pro-inflammatory genes in the lesions.
Weighted gene co-expression network analysis (WGCNA) identified 17 differential transcriptomic modules and revealed a gradient of immune response elements depending on their location within the lesion.
Although lesion transcriptomics has been studied previously, this is the first work to associate these molecular profiles with clinical indicators from the same patients.
“Individuals with more severe forms of the disease present more inflamed lesions, while patients with better clinical outcomes show profiles compatible with tissue repair phases,” explains Dr Vilaplana.
The researchers used two clinical surrogates: a validated respiratory quality of life questionnaire (SGRQ) and sputum culture conversion.
“We confirmed that when a patient says they feel unwell, it is also reflected at the molecular level: their lesions show a stronger inflammatory response,” adds Vilaplana.
Furthermore, patients who take longer to achieve sputum culture conversion, a factor previously linked to worse prognosis, also show higher immune activation at the lesion site.
“These data open the door to personalised strategies: If after two months the patient hasn’t cleared the bacillus, we may need to adapt the treatment to modulate the inflammatory response and avoid a worse clinical outcome,” she concludes.
Johannesburg, 26 May 2025: Despite national guidelines and access to essential medicines, severe asthma remains under-recognised and inconsistently managed within South Africa’s healthcare system. It is therefore critical to address ongoing patient challenges, particularly regarding access to diagnostic tools, limited use of phenotyping, and the imperative to align clinical practice with international best practice recommendations.
The Severe Asthma Index 2025 found that South Africa scored below the global average in four out of five domains, revealing persistent gaps in policy coordination, equitable access, diagnostic capacity, and environmental health.¹ᵃ Of concern is the continued reliance on oral corticosteroids (OCS) without proper assessment or referral, especially where evidence-based, targeted biologics remain inaccessible or unfunded.1b+2a
Understanding asthma in South Africa
South Africa has robust asthma guidelines, but the absence of a national asthma strategy and lack of participation in global severe asthma registries limit insight into outcomes and weaken care coordination. Specialist care and phenotyping are largely confined to urban centres, and national data on hospitalisations and treatment outcomes is scarce. Although reported asthma-related societal costs and disability adjusted life years (DALYs) are relatively low, this likely masks the true burden among patients with severe, underdiagnosed, or poorly controlled disease.¹ᵇ Traditionally, asthma mortality in Southern Africa has been considered as relatively high due in large part to short-acting beta-agonists (SABAs) overuse.3
Environmental factors compound these challenges. High levels of particulate matter (PM2.5) and poor indoor air quality contribute significantly to disease severity, particularly in low-income areas. Meanwhile, access to advanced diagnostics and therapies remains limited. Biologic add-on therapies and fractional exhaled nitric oxide (FeNO) testing are not routinely available in the public sector, leaving most patients dependent on standard treatments with few options for escalation if the disease remains uncontrolled.¹ᵇ
Rethinking corticosteroid use
The Severe Asthma Index 2025 highlights the widespread use of oral corticosteroids (OCS) in South Africa as a persistent pattern that may pose long-term health risks if not carefully managed or replaced by more targeted therapies. While OCS play a critical role in treating acute exacerbations, frequent or prolonged use is linked to serious side effects, including osteoporosis, adrenal suppression, diabetes, and infections.²ᶜ
“There’s growing awareness that long-term OCS use can lead to significant health risks,” says Dwayne Koot, Medical Manager at Sanofi South Africa. “For severe asthma, the shift is towards biologic therapies that specifically target the underlying inflammation, not just the symptoms.1c As a simple regimen (where available), inhaled corticosteroid–formoterol combinations are now recommended as the preferred reliever across all severity levels.3 If high-dose ICS-LABA is needed, its use should be limited to 3 – 6 months, prompting phenotyping and biologic therapy add-on if asthma is not controlled. Low-dose maintenance OCS should only be considered as a last resort if no other options are available.”
Improving diagnosis and referral
Access to diagnostic tools remains uneven across South Africa, particularly in the public sector. Spirometry is not routinely available at primary care level, while FeNO testing, oscillometry, and biomarker analysis are largely limited to research centres or private practices.¹ᵇ
“This makes it difficult to accurately diagnose, phenotype, and manage asthma, potentially leading to suboptimal treatment decisions and poorer patient outcomes,” says Koot.
“There’s an opportunity to enhance the referral pathway to specialists and expand access to advanced diagnostic tools by defining referral criteria and partnering with specialised centres,” Koot says. “Routine phenotyping at GINA step 5, crucial for tailoring treatment plans and identifying suitable candidates for biologic therapies, is currently limited in many healthcare settings. Expanding these capabilities would enable a more personalised approach to asthma management.”3
To help close these gaps, the Severe Asthma Index 2025 recommends piloting basic phenotyping tools such as eosinophil counts at regional hospitals, establishing asthma registries to monitor outcomes and access, and expanding clinician training in severe asthma diagnosis and escalation pathways.¹ᵇ “Better data and better training could transform how we identify and treat severe asthma,” says Koot.
Next steps for clinical practice
Healthcare professionals have a pivotal role to play in strengthening asthma care — from recognising poor control early to ensuring patients access the most appropriate treatment in a timely manner. This includes reassessing those with persistent symptoms, reinforcing correct inhaler technique, referring for further investigation when needed, and considering alternative therapies when conventional options are no longer sufficient.3
South Africa already has many of the essential components in place: national treatment guidelines, access to key medicines, and clinical expertise. The next step is to ensure that patients with severe asthma are consistently identified, supported, and offered the full range of available interventions.
“As the World Asthma Day 2025 theme reminds us, the goal is to ‘Make Inhaled Treatments Accessible for ALL’, because inhaled medications are vital not just for preventing attacks, but for controlling chronic inflammation,” says Koot. “We encourage healthcare practitioners and policy makers to help make appropriate, evidence-based asthma care a reality for every South African asthmatic .”
For more information about asthma management and Sanofi’s commitment to respiratory health, please visit www.sanofi.co.za
A study led by the Barcelona Institute for Global Health (ISGlobal), a centre supported by ”la Caixa” Foundation, in collaboration with the Clínic-IDIBAPS, has shown for the first time, how lung capacity evolves from childhood to old age. The findings, published in The Lancet Respiratory Medicine, provide a new basic framework for assessing lung health.
Until now, it was thought that lung function increased until it peaked at around 20–25 years of age, after which it stabilised. It was also thought that in later adulthood, lung function begins to decline as the lungs age. However, this model was based on studies that did not cover the whole life course.
In contrast, the current study used an “accelerated cohort design”, meaning data from several cohort studies were combined to cover the desired age range. “We included more than 30 000 individuals aged 4 to 82 years from eight population-based cohort studies in Europe and Australia,” explains Judith Garcia-Aymerich, first author of the study and co-director of the ISGlobal programme on Environment and Health over the Life Course. Lung function and lung capacity parameters were assessed using forced spirometry, a test in which the patient exhales all the air as quickly as possible after taking a deep breath. Data on active smoking and asthma diagnosis were also collected.
Two growth phases and an early decline
The study showed that lung function develops in two distinct phases: a first phase of rapid growth during childhood and a second phase of slower growth until peak lung function is reached. Lung function was assessed using two parameters: forced expiratory volume in one second (FEV1), which measures the amount of air expelled in the first second of a forced breath after a deep inhalation; and forced vital capacity (FVC), which is the maximum amount of air a person can breathe out without a time limit after a deep inhalation.
In women, FEV1 peaks around the age of 20, while in men it peaks around the age of 23. Surprisingly, the study found no evidence of a stable phase following this peak. “Previous models suggested a plateau phase until the age of 40, but our data show that lung function starts to decline much earlier than previously thought, immediately after the peak,” explains Garcia-Aymerich.
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.”
