The complex shape of respiratory syncytial virus is one hurdle limiting the development of treatments for an infection that leads to hospitalisation or worse. New images of the virus published in Nature from researchers at the University of Wisconsin–Madison may hold the key to preventing or slowing RSV infections.
RSV is of greatest concern in young children, the elderly and adults at high risk for respiratory complications. Yet unlike the flu and other common, communicable respiratory illnesses that annually sweep through schools, there are few options for fighting RSV. In the US, prophylactic treatments are available for young children, and existing vaccines are approved only for pregnant women and the elderly.
The virus’s structure, which consists of tiny, bending filaments, have eluded researchers. This has made it difficult to identify key drug targets, including viral components that are conserved across related viruses.
RSV F proteins, shown in this image created by University of Wisconsin–Madison researchers using a technique called cryo-electron tomography, may make RSV more potent by keeping it from infecting cells prematurely. Image by Wright Lab, UW–Madison
“There are a number of viruses related to RSV that are also significant human pathogens, including measles,” says Elizabeth Wright, a UW–Madison biochemistry professor. “What we know about related viruses gives us clues about RSV protein structures, but to identify drug targets we need a closer look at RSV proteins that are intimately associated with the membranes of host cells.”
Using an imaging technique called cryo-electron tomography, Wright and her team have now revealed details of molecules and structures essential to RSV’s form and function. They published their findings recently in Nature.
Cryo-ET freezes viral particles or other molecules at ultracold temperatures, stopping biological processes in action. This allows researchers to examine the structures of organisms, cells and organelles, and viruses and capture small-scale images of structures frozen in time. Flash-freeze many RSV particles, and cryo-ET imaging will capture (nearly) all the virus’s possible configurations from many different angles. These 2D images are combined to produce a representation of the virus’s 3D structures at high resolutions – even at the level of individual atoms.
Wright’s recent study produced high-resolution images detailing the structure of two RSV proteins, RSV M protein and RSV F protein, that are crucial to the interaction between the virus and the host cell membrane. Both proteins are also present in related viruses.
RSV M protein interacts with host cell membranes, holding together the virus’s filamentous structure and coordinating viral components and other proteins – including RSV F proteins. RSV F proteins sit on the viral surface, ready to engage with host cell receptors and regulate the virus’s fusion and entry into the host cell. The scientists’ images reveal that in RSV, two F proteins come together to form a more stable unit. Wright says that this association may prevent the F proteins from prematurely infecting the host cell.
“Our primary findings reveal structural details that allow us to better understand not only how the protein regulates assembly of viral particles, but also the coordination of proteins that enable the virus to be infectious,” says Wright.
The scientists believe that F protein pairs may be a key to destabilising the virus before it is ready to infect its next host, making pairs of F proteins a possible target for future drug development. They will continue to explore how RSV proteins interact with each other to cause infection.
What factors lead to chronic respiratory disease? Researchers investigated this question using health data from about 780 infants. Their analysis, published in The Lancet Digital Health, shows that children’s risk of developing asthma later in life can be more reliably predicted by observing the dynamic development of symptoms during the first year of life.
Genetic predisposition, passive smoking, high levels of air pollution and infections are only a few of the risk factors for asthma. Each factor has only a small influence on its own. It is their interplay that makes asthma more likely, according to the hypothesis of an international research committee, of which Professor Urs Frey of the University of Basel and the University Children’s Hospital Basel is a member.
Together with Dr Uri Nahum from his team and international colleagues, Frey investigated how the interaction of these factors during the course of the first year of life affected children’s developing respiratory systems. The analysis was based on health data from two cohorts, amounting to around 780 healthy infants born in various European countries.
A new way of looking at chronic illness
For both cohorts the researchers calculated the network of interactions between a range of known risk factors for every week of each child’s life, and then compared these with the appearance of symptoms such as coughing or wheezing. “Observing this interaction of risk factors in the context of dynamic development over time is a new way of looking at chronic illnesses,” underlines Frey. It is a case of watching the developing lungs adapting to their environment.
And it was exactly this, the adaptation of the lungs, that differentiated the group of children who developed asthma at between two and six years of age from those who had not developed it by the time they started school (generally at six years old in Switzerland). “It’s a nice, practical example of the value of digital health data, which were first quantified mathematically using these kinds of dynamic network analyses,” says Frey.
The findings cannot yet be used for early diagnosis in individual children. However, according to Frey: “With greater amounts of data and machine learning, it would certainly be conceivable to calculate a risk profile for individual children in the future.” Nowadays, digital health data is relatively easy to collect with the help of smartphone apps.
Women who are being treated for asthma are more likely to miscarry and need fertility treatment to get pregnant, according to a large study presented at the European Respiratory Society (ERS) Congress in Vienna, Austria. The study also suggests that most women with asthma are able to have babies.
The study was presented by Dr Anne Vejen Hansen from the department of respiratory medicine at Copenhagen University Hospital, Denmark.
She said: “Asthma is common in women of reproductive age. Previous studies have shown that it takes women with asthma longer to get pregnant than those without asthma when undergoing fertility treatment, and that asthmatic women who succeed in getting pregnant have more often had fertility treatment than non-asthmatic women. But most existing studies are on women who have actually got pregnant, so we wanted to examine fertility outcomes on a national scale, to also include those that might not become pregnant at all.”
The team analysed reproductive outcomes for all Danish women born from 1976 to 1999, following them from 1994 to 2017. In total, 769,880 women were included and followed; anyone who took anti-asthma medication on a regular basis was classified as asthmatic.
They found that women with asthma experienced a higher degree of foetal loss compared to women without asthma (17.0% vs. 15.7%) and more use of fertility treatment (5.6% vs. 5.0%). However, the proportion who subsequently gave birth was 77% in women with and without asthma, suggesting that asthma does not seem to affect the number of live births.
Dr Vejen Hansen said: “We found that women fulfilling the definition of asthma had a higher rate of foetal loss and an increased use of fertility treatment. The more severe the asthma and the more flare ups the women experienced, the more likely they were to need fertility treatment. Why this is, is not clear. It might be related to systemic inflammation throughout the body, including women’s reproductive organs.
“But the numbers also show that these same women who redeem asthma medication still have as many live births in the end as women who don’t. This suggests that most women with asthma probably do manage to become pregnant and have babies in the end.
“We also plan to investigate the possible effect of male asthma on fertility, and, therefore, have another similar registry-based study in the pipeline.”
Professor Lena Uller is Chair of the ERS group on Airway Pharmacology and Treatment and Head of the Respiratory Immunopharmacology research group at Lund University, Sweden, and was not involved in the research. She said: “It’s reassuring that women seem to have the same live birth rate regardless of their asthma. However, the results also indicate that women with asthma should take into consideration potential reproductive challenges in their family planning. If women with asthma are worried about their fertility, they should speak to their doctor.
“The results of this study also underscore the importance of managing asthma in reproductive-aged women. The fact that the more severe the asthma, the more the problems with fertility, suggests that uncontrolled asthma is the problem and we should be helping women to get their asthma under control.”
There were no differences in quality of life, symptoms, hospital admissions or mortality between a group of patients with pulmonary disease and low oxygen levels in the blood that received oxygen therapy at home for 24 hours a day, and a group that received the same therapy for 15 hours a day, according to a study in the New England Journal of Medicine.
“This has considerable significance for patients with chronic obstructive pulmonary disease and other pulmonary diseases who are undergoing long-term oxygen therapy at home,” says study leader Magnus Ekström of Lund University.
Every year, there are about a million patients in the US alone with severe sub-optimal oxygen levels who begin oxygen therapy at home. The patient must wear a nasal oxygen mask 24 hours a day, which is often felt to be restrictive and burdensome. In addition, the gas is cold and dry, which may cause problems such as dryness, ulcers and inflammation of the airways. Using the equipment may also be perceived as stigmatising by patients.
The aim of the therapy is to prolong life, but its application differs and the scientific evidence for the therapy’s efficacy has been inadequate.
In a randomised, controlled large multicentre study, the researchers have now examined the effect of different durations of oxygen therapy on important health outcomes. A total of 241 patients with chronic and severely low oxygen levels in the blood from 20 different clinics in Sweden were randomised to receive oxygen therapy for either 24 hours a day or 15 hours a day. The patients were followed for one year, and all completed the study. There was a high level of compliance with the prescribed daily therapy duration.
“There were no differences between the groups regarding hospital admission or the risk of dying. And again, when we compare self-reported quality of life and physical activity, symptoms and fatigue between the groups, we see no differences or indication of advantages if oxygen is used for more than 15 hours a day,” says Magnus Ekström, researcher in respiratory andpalliative medicine at Lund University.
The results differ from previous studies conducted in the 1970s, which suggested that therapy for 24 hours a day could increase the survival rate.
“The older studies were small and only included patients with chronic obstructive pulmonary disease, not least because it is difficult to recruit such seriously ill individuals for a randomised study. Also, the patients included in the older studies differ from those who start oxygen therapy at home nowadays. The strength of this study is that we have been able to include twice as many patients, and that it represents the reality nowadays in which many of those receiving oxygen therapy at home are older, also have cardiovascular diseases and are women,” says Josefin Sundh, adjunct senior lecturer at Örebro University and pulmonologist at the University Hospital in Örebro, who was co-leader of the study.
“The group treated with oxygen 15 hours a day received this during the night when, in general, oxygenation is poorer. The results show that it seems to be safe for this type of patient to be without oxygen for quite a large part of the day. This is important as it may reduce the side effects of the therapy and mean that the patients can adapt it more to their everyday life,” says Magnus Ekström.
The researchers based the study on data from Swedevox, the Swedish National Registry for Respiratory Failure.
The researchers are now moving on to examine whether therapy using a high flow rate of warmed-up, more humidified oxygen at night can improve prognoses and patient well-being.
Using hypertonic saline nasal drops can reduce the length of the common cold in children by two days, according to a study presented at the European Respiratory Society (ERS) Congress in Vienna, Austria [1]. They can also reduce the onward transmission of colds to family members.
The results of the ELVIS-Kids randomised controlled trial were presented by Professor Steve Cunningham from Child Life and Health, University of Edinburgh, UK.
He said: “Children have up to 10 to 12 upper respiratory tract infections, what we refer to as colds, per year, which have a big impact on them and their families. There are medicines to improve symptoms, such as paracetamol and ibuprofen, but no treatments that can make a cold get better quicker.”
ELVIS-Kids Chief Investigator Dr Sandeep Ramalingam, consultant virologist, NHS Lothian, Edinburgh, UK, had noted that salt-water solutions are often used by people in South Asia, as nasal irrigation and gargling, to treat a cold and wanted to explore if this clinical benefit could be replicated in a large study.
The research team recruited 407 children aged up to six years to a study where they were given either hypertonic saline ~2.6% (salt-water) nasal drops or usual care when they developed a cold. Overall, 301 children developed a cold; for 150 of these, their parents were given sea salt and taught to make and apply salt-water nose drops to the children’s noses (three drops per nostril, a minimum of four times per day, until well) and 151 children had usual cold care.
Professor Cunningham explains: “We found that children using salt-water nose drops had cold symptoms for an average of six days where those with usual care had symptoms for eight days. The children receiving salt water nose drops also needed fewer medicines during their illness.
“Salt is made up of sodium and chloride. Chloride is used by the cells lining the nose and windpipes to produce hypochlorous acid within cells, which they use to defend against virus infection. By giving extra chloride to the lining cells this helps the cells produce more hypochlorous acid, which helps suppress viral replication, reducing the length of the virus infection, and therefore the duration of symptoms.”
When children got salt-water nose drops, fewer households reported family members catching a cold (46% vs 61% for usual care). Eighty-two per cent of parents said the nose drops helped the child get better quickly and 81% said they would use nose drops in the future.
Professor Cunningham added: “Reducing the duration of colds in children means that fewer people in their house also get a cold, with clear implications for how quickly a household feels better and can return to their usual activities like school and work etc.
“Our study also showed that parents can safely make and administer nose drops to their children and therefore have some control over the common cold affecting their children.”
Professor Alexander Möeller is Head of the ERS Paediatric Assembly and Head of the Department for Respiratory Medicine at the University Children’s Hospital Zurich, Switzerland, and was not involved in the research. He said: “This is an important study that is the first of its kind to investigate the impact of salty nose drops in children with colds. Although most colds usually don’t turn into anything serious, we all know how miserable they can be, especially for young children and their families.
“This extremely cheap and simple intervention has the potential to be applied globally; providing parents with a safe and effective way to limit the impact of colds in their children and family would represent a significant reduction in health and economic burden of this most common condition.”
The team hope to further investigate the effect of saltwater nose drops on wheeze during colds, after initial results from this study showed that children who received the drops had significantly fewer episodes of wheeze (5% vs 19%).
Reference
[1] Abstract no: OA1985 “A randomised controlled trial of hypertonic saline nose drops as a treatment in children with the common cold (ELVIS-Kids trial)”, by Dr Sandeep Ramalingam et al; Presented in session “Advancements in paediatric infectious respiratory health” at 15:45–17:00 CEST on Sunday 8 September 2024.
Chronic cough is among the most common reasons for seeking medical care, with middle-aged women the group most affected. A pair of new studies published in ERJ Open Research and PLOS ONE suggest that this may be a hereditary condition.
“More than 10% of the population has a chronic cough, which has been shown to entail several negative consequences: reduced quality of life, reduced ability to work and voice problems. At present, we have insufficient knowledge about what causes coughing and how best to treat it,” notes Össur Ingi Emilsson, Docent in Lung, Allergy and Sleep Research at the Department of Medical Sciences at Uppsala University.
The two studies from the department have investigated both how cough is currently managed in Swedish healthcare, and whether chronic cough can be hereditary.
The PLOS ONE study, based on data from the Swedish healthcare register, showed that 1–2% of the entire Swedish population sought care for chronic cough between 2016 and 2018, usually in primary care. Of those who sought care, the majority appear to have had a long-standing cough. The prevalence is highest among women between the ages of 40 and 60, with around 21 000 women seeking treatment for cough in these three years.
“Women generally seem to have a slightly more sensitive cough reflex, so the threshold for abnormal coughing is lower in women than in men. For me, it was unexpected that only one to two percent of patients seek help for a troublesome cough when over ten percent are affected. This can be partly explained by the lack of effective treatments. There also appeared to be some differences in care between different parts of the country, suggesting that better guidelines are needed for investigating and treating chronic cough,” continues Emilsson.
The other study, in ERJ Open Research, has provided a clue as to why some individuals develop chronic cough. Cough appears to be a hereditary phenomenon. In a large population study in northern Europe of 7155 parents and their 8176 adult children aged 20 years and over, it was found that if one parent has had chronic dry cough, their offspring were over 50% more likely to have chronic dry cough. This link was independent of confounding factors such as asthma, biological sex and smoking.
“A similar relationship was seen for productive cough, but in those cases smoking had a greater impact on prevalence. These results suggest that there is a genetic link to chronic cough,” adds Emilsson.
The research team has already begun a treatment study into chronic cough. Based on these new findings, the group is now moving forward with studies on genetic variants in collaboration with the Icelandic company deCODE genetics, which analyses the human genome. The aim is to identify which genetic variants are linked to chronic cough.
“This could provide a better understanding of the occurrence of chronic cough, which may ultimately result in better treatments for this difficult-to-treat condition,” explains Emilsson.
Scientists at The University of Warwick have made a breakthrough which could help find new ways to prevent ventilator-associated pneumonia, which can affect up to 40% of hospital patients on mechanical ventilators.
Ventilator-associated pneumonia (VAP) is a common infection in ventilated patients, particularly for those with existing respiratory conditions. VAP is transmitted by pathogens, often antibiotic resistant, that form stubborn biofilms on the inside of endotracheal tubes. Up to 40% of ventilated patients in intensive care wards will develop VAP, with 10% of those patients dying as a result.
In a study recently published in Microbiology, researchers recreated hospital conditions to improve understanding of the infection. They used the same type of endotracheal tubes and created a special mucus to simulate the conditions inside a human body. Bacteria and fungi formed a biofilm on these tubes.
Dr Dean Walsh, Research Fellow, University of Warwick, said: “Our study found that the biofilms in our model were different and more complex than those usually grown in standard lab conditions, making them more realistic.
“The biofilms formed in this new model were very tough to get rid of, even with strong antibiotics, much like what happens in real patients.
“Significantly, when we combined antibiotics with enzymes that break down the biofilm’s protective slime layer, the biofilms were more successfully removed than with antibiotics alone. With the enzymes, we could halve the concentration of antibiotics needed to kill the biofilms. So, that suggests we can use our model to identify new VAP treatments that attack the slime layer.”
Dr Freya Harrison, School of Life Sciences, University of Warwick, added: “VAP is a killer, and there are currently no cost-effective ways of making the tubes harder for microbes to colonise. Our new model can help scientists develop better therapies and design special tubes that prevent biofilms, which could improve the health of patients on ventilators.”
This project was part of an international research program in antimicrobial resistance that brings together colleagues at the University of Warwick with those at Monash University in Melbourne and is supported by the Monash-Warwick Alliance.
Professor Ana Traven, co-Director of the Monash-Warwick Alliance programme in emerging superbug threats, and co-author of the study, added: “It is exciting that we could join forces with our colleagues at Warwick for this important study. Many promising new anti-infectives fail because experiments done in the laboratory do not recapitulate very well the more complex infections that occur in patients. As such, the development of laboratory models that mimic disease, such as was done in this study, is important for accelerating the discovery of credible antimicrobial therapies that have a higher chance of clinical success.”
Taza Aya’s Worker Wearable Protection device keeps airborne virus particles from reaching a workers mouth and nose with an air curtain. That air is pre-treated to kill any viruses. Image credit: Jeremy Little, Michigan Engineering
An air curtain shooting down from the brim of a hard hat can prevent 99.8% of aerosols from reaching a worker’s face. The technology, created by University of Michigan startup Taza Aya, potentially offers a new protection option for workers in industries where respiratory disease transmission is a concern.
Independent, third-party testing of Taza Aya’s device showed the effectiveness of the air curtain, curved to encircle the face, coming from nozzles at the hat’s brim. But for the air curtain to effectively protect against pathogens in the room, it must first be cleansed of pathogens itself. Previous research by the group of Taza Aya co-founder Herek Clack, U-M associate professor of civil and environmental engineering, showed that their method can remove and kill 99% of airborne viruses in farm and laboratory settings.
“Our air curtain technology is precisely designed to protect wearers from airborne infectious pathogens, using treated air as a barrier in which any pathogens present have been inactivated so that they are no longer able to infect you if you breathe them in,” Clack said. “It’s virtually unheard of – our level of protection against airborne germs, especially when combined with the improved ergonomics it also provides.”
Fire has been used throughout history for sterilisation, and while we might not usually think of it this way, it’s what’s known as a thermal plasma. Nonthermal, or cold, plasmas are made of highly energetic, electrically charged molecules and molecular fragments that achieve a similar effect without the heat. Those ions and molecules stabilize quickly, becoming ordinary air before reaching the curtain nozzles.
Taza Aya’s prototype features a backpack, weighing roughly 10 pounds (4.5kg), that houses the nonthermal plasma module, air handler, electronics and the unit’s battery pack. The handler draws air into the module, where it’s treated before flowing to the air curtain’s nozzle array.
Taza Aya’s progress comes in the wake of the COVID pandemic and in the midst of a summer when the U.S. Centers for Disease Control and Prevention have reported four cases of humans testing positive for bird flu. During the pandemic, agriculture suffered disruptions in meat production due to shortages in labour, which had a direct impact on prices, the availability of some products and the extended supply chain.
In recent months, Taza Aya has conducted user experience testing with workers at Michigan Turkey Producers in Wyoming, Michigan, a processing plant that practices the humane handling of birds. The plant is home to hundreds of workers, many of them coming into direct contact with turkeys during their work day.
To date, paper masks have been the main strategy for protecting employees in such large-scale agriculture productions. But on a noisy production line, where many workers speak English as a second language, masks further reduce the ability of workers to communicate by muffling voices and hiding facial clues.
“During COVID, it was a problem for many plants – the masks were needed, but they prevented good communication with our associates,” said Tina Conklin, Michigan Turkey’s vice president of technical services.
In addition, the effectiveness of masks is reliant on a tight seal over the mouth and noise to ensure proper filtration, which can change minute to minute during a workday. Masks can also fog up safety goggles, and they have to be removed for workers to eat. Taza Aya’s technology avoids all of those problems.
As a researcher at U-M, Clack spent years exploring the use of nonthermal plasma to protect livestock. With the arrival of COVID in early 2020, he quickly pivoted to how the technology might be used for personal protection from airborne pathogens.
In October of that year, Taza Aya was named an awardee in the Invisible Shield QuickFire Challenge – a competition created by Johnson & Johnson Innovation in cooperation with the U.S. Department of Health and Human Services. The program sought to encourage the development of technologies that could protect people from airborne viruses while having a minimal impact on daily life.
“We are pleased with the study results as we embark on this journey,” said Alberto Elli, Taza Aya’s CEO. “This real-world product and user testing experience will help us successfully launch the Worker Wearable in 2025.”
Pneumonia diagnoses are marked by pronounced uncertainty, according to an AI-based analysis of over 2 million hospital visits. The study, published in Annals of Internal Medicine, found that more than half the time, a pneumonia diagnosis made in the hospital will change from a patient’s entrance to their discharge – either because someone who was initially diagnosed with pneumonia ended up with a different final diagnosis, or because a final diagnosis of pneumonia was missed when a patient entered the hospital (not including cases of hospital-acquired pneumonia).
Understanding that uncertainty could help improve care by prompting doctors to continue to monitor symptoms and adapt treatment accordingly, even after an initial diagnosis.
Barbara Jones, MD, pulmonary and critical care physician at University of Utah Health and the first author on the study, found the results by searching medical records from more than 100 VA medical centres across the country, using AI-based tools to identify mismatches between initial diagnoses and diagnoses upon discharge from the hospital. More than 10% of all such visits involved a pneumonia diagnosis, either when a patient entered the hospital, when they left, or both.
“Pneumonia can seem like a clear-cut diagnosis,” Jones says, “but there is actually quite a bit of overlap with other diagnoses that can mimic pneumonia.” A third of patients who were ultimately diagnosed with pneumonia did not receive a pneumonia diagnosis when they entered the hospital. And almost 40% of initial pneumonia diagnoses were later revised.
The study also found that this uncertainty was often evident in doctors’ notes on patient visits; clinical notes on pneumonia diagnoses in the emergency department expressed uncertainty more than half the time (58%), and notes on diagnosis at discharge expressed uncertainty almost half the time (48%). Simultaneous treatments for multiple potential diagnoses were also common.
When the initial diagnosis was pneumonia, but the discharge diagnosis was different, patients tended to receive a greater number of treatments in the hospital, but didn’t do worse than other patients as a general rule. However, patients who initially lacked a pneumonia diagnosis, but ultimately ended up diagnosed with pneumonia, had worse health outcomes than other patients.
A path forward
The new results call into question much of the existing research on pneumonia treatment, which tends to assume that initial and discharge diagnoses will be the same. Jones adds that doctors and patients should keep this high level of uncertainty in mind after an initial pneumonia diagnosis and be willing to adapt to new information throughout the treatment process. “Both patients and clinicians need to pay attention to their recovery and question the diagnosis if they don’t get better with treatment,” she says.
Shared geographic origin between TB strain and human host could amplify risk for infection
Tuberculosis bacteria. Credit: CDC
For some forms of tuberculosis, the chances that an exposed person will get infected depend on whether the individual and the bacteria share a hometown, according to a new study comparing how different strains move through mixed populations in cosmopolitan cities.
Results of the research, led by Harvard Medical School scientists and published in Nature Microbiology, provide the first hard evidence of long-standing observations that have led scientists to suspect that pathogen, place, and human host collide in a distinctive interplay that influences infection risk and fuels differences in susceptibility to infection.
The study strengthens the case for a long-standing hypothesis in the field that specific bacteria and their human hosts likely coevolved over hundreds or thousands of years, the researchers said.
The findings may also help inform new prevention and treatment approaches for tuberculosis.
In the current analysis, believed to be the first controlled comparison of TB strains’ infectivity in populations of mixed geographic origins, the researchers custom built a study cohort by combining case files from patients with TB in New York City, Amsterdam, and Hamburg. Doing so gave them enough data to power their models.
The analysis showed that close household contacts of people diagnosed with a strain of TB from a geographically restricted lineage had a 14 percent lower rate of infection and a 45 percent lower rate of developing active TB disease compared with those exposed to a strain belonging to a widespread lineage.
The study also showed that strains with narrow geographic ranges are much more likely to infect people with roots in the bacteria’s native geographic region than people from outside the region.
The researchers found that the odds of infection dropped by 38 percent when a contact is exposed to a restricted pathogen from a geographic region that doesn’t match the person’s background, compared with when a person is exposed to a geographically restricted microbe from a region that does match their home country. This was true for people who had lived in the region themselves and for people whose two parents could each trace their heritage to the region.
This pathogen-host affinity points to a shared evolution between humans and microbes with certain biological features rendering both more compatible and fueling the risk for infection, the researchers said.
“The size of the effect is surprisingly large,” said Maha Farhat, the Gilbert S. Omenn, MD ’65, PhD Associate Professor of Biomedical Informatics in the Blavatnik Institute at HMS. “That’s a good indicator that the impact on public health is substantial.”
Why differences matter
Thanks to the growing use of genetic sequencing, researchers have observed not all circulating strains are created equal. Some lineages are widespread and responsible for much of the TB around the world, while others are prevalent only in a few restricted areas. Given that the complex nature of TB transmission in high-incidence settings where people often have multiple exposures to different lineages, researchers have not been able to compare strains under similar conditions and have been left to speculate about possible explanations for the differences between strains.
Many factors increase the risk of contracting tuberculosis from a close contact. One of the best predictors of whether a person will infect their close contacts is bacterial load, measured by a test called sputum smear microscopy, which shows how many bacteria a person carries in their respiratory system.
But the new study showed that for geographically restricted strains, whether a person has ancestors who lived where the strain is common was an even bigger predictor of infection risk than bacterial load in the sputum. In the cases analyzed in the study, this risk of common ancestry even outweighed the risk stemming from having diabetes and other chronic diseases previously shown to render people more susceptible to infection.
The findings add to a growing body of evidence of the importance of paying attention to the wide variation between different lineages of tuberculosis and to the details of how different lineages of tuberculosis interact with different host populations.
Previous studies have shown that some genetic groups of TB are more prone to developing drug resistance and that TB vaccines appear to work better in some places than others. There is also evidence that some treatment regimens might be better suited to some strains of TB than others.
“These findings emphasize how important it is to understand what makes different strains of TB behave so differently from one another, and why some strains have such a close affinity for specific, related groups of people,” said Matthias Groeschel, research fellow in biomedical informatics in Farhat’s lab at HMS; resident physician at Charité, a university hospital in Berlin; and the study’s first author.
In addition to the analysis of clinical, genomic, and public health data, the researchers also tested the ability of different strains of TB to infect human macrophages, a type of immune cell that TB hijacks to cause infection and disease. The researchers grew cells from donors from different regions. Once again, cell lines from people with ancestry that matched the native habitat of a restricted strain of tuberculosis bacteria were more susceptible to the germs than cells from people from outside the area, mirroring the results of their epidemiologic study.
Until now, most experiments of the interaction between human immune cells and TB have not compared how TB interacts with cells of hosts from different populations or places, the researchers said.
While this experiment was not designed to capture insights about the mechanism underlying the affinity between human and TB populations sharing geographic backgrounds, it highlights the importance of using multiple strains of TB and cells from diverse populations to inform treatment and prevention. It also points to the need for more basic research to understand the genomic and structural differences in how bacterial and host cells interface, the researchers said.
“It’s so important to appreciate that the great diversity of human and tuberculosis genetics can significantly impact how people and microbes respond to one another and to things like drugs and vaccines,” Farhat said. “We have to incorporate that into the way we think about the disease.”
“We’re at the very beginning of appreciating the importance of that diversity,” Groeschel said. “There’s so much more to learn about how it might impact the efficacy of drugs, vaccines, and the course that disease takes in different strains.”
Advances in gene sequencing create a new puzzle
While the closely related but distinct genetic groups of tuberculosis were discovered with more traditional methods of genotyping, the widespread use of whole genome sequencing by public health departments around the world allowed doctors and researchers to better profile TB germs and track outbreaks and drug resistance genetically.
The realization that highly localised stains didn’t spread well to other regions led researchers to speculate that regionally constrained strains were less infectious than widespread strains. Since the constrained strains persisted within their limited ranges, some researchers speculated that localised populations of the bacteria may have coevolved with their human hosts, making different human populations more susceptible to different types of TB. This could also mean, researchers hypothesised, that different strains of TB would have different susceptibility to different treatments and vaccines. For example, structural differences in the shape of the bacteria might prevent some drugs from binding effectively with bacteria from different strains.
Until recently, these hypotheses were nearly impossible to test, given the differences between cultural and environmental conditions that might affect infection rates in different communities and other parts of the world. Furthermore, the fact that the constrained stains strayed from home so rarely made it challenging to gather enough data to measure differences across strains.
Multidisciplinary science cracks the case
To overcome these obstacles, the research team collaborated with public health departments and research teams from the U.S., the Netherlands, and Germany to assemble a massive database integrating tuberculosis case reports, pathogen genetic profiles, and public health records of infection rates among close contacts. The analysis also incorporated demographic details about the social networks of infected people to assess how the different genetic lineages of tuberculosis spread in other populations. In total, the study included 5256 TB cases and 28 889 close contacts.
“This study is a great example of why it’s so important for researchers to collaborate with many different kinds of partners,” said Groeschel. “We were able to merge public health data from three big cities and use the powerful computational biology tools that we have access to in academic medicine to answer a complicated question that has important implications for public health and evolutionary biology, vaccine development, and drug research.”
