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Study Shows Interaction Between Nervous and Immune Systems Occurs In Fatal Lung Infections

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When the body is fighting infection, the immune system kicks into high gear. But emerging evidence hints at the involvement of another, a rather surprising player in this process: the nervous system.

New research from Harvard Medical School, conducted in mice, shows just how the interaction between the nervous and the immune systems occurs in deadly lung infections—a tantalizing clue into a complex interplay between two systems traditionally viewed as disconnected.

The findings, published March 5 in Nature Medicine, reveal that neurons carrying nerve signals to and from the lungs suppress immune response during infection with Staphylococcus aureus, a bacterium that is growing increasingly impervious to antibiotics and has emerged as a top killer of hospitalized patients, who are often immunocompromised and weakened overall.

The results, the researchers said, suggest that targeting the nervous system could be one way to boost immunity and can set the stage for the development of nonantibiotic approaches to treat recalcitrant bacterial infections.

“With the rapid emergence of drug-resistant organisms, such as methicillin-resistant Staph aureus, nonantibiotic approaches to treating bacterial infections are sorely needed,” said senior study investigator Isaac Chiu, assistant professor in the Department of Microbiology and Immunobiology at Harvard Medical School.

“Targeting the nervous system to modulate immunity and treat or prevent these infections could be one such strategy.”

Sensory neurons play a protective role by sensing adverse stimuli and alerting the body that something is awry. In the lungs, the neurons’ projections detect mechanical pressure, inflammation, temperature changes and the presence of chemical irritants, then send an alert to the brain—a notification that can come in the form of pain, airway constriction or a cough that expels harmful agents or particles from the airways.

But the new study reveals that when mouse lungs are invaded by staph bacteria, these guardian neurons interfere with the organ’s ability to cope with infection. Specifically, they reduce the lungs’ ability to summon several types of disease-fighting cells in response to infection. A series of experiments conducted in mice revealed that disabling these neurons promoted immune cell recruitment, increased the lungs’ ability to clear bacteria and boosted survival in staph-infected mice.

The results, the researchers said, suggest that different classes of sensory neurons may be involved in restraining or promoting immune response. Another possibility is that certain pathogens may have evolved to hijack and exploit an immunosuppressive pathway to their benefit—a survival mechanism for some classes of infectious bacteria, said study co-author Stephen Liberles, professor of cell biology at Harvard Medical School.

The team’s interest in the crosstalk between the immune and nervous systems stems from recent work conducted by Chiu and colleagues. Chiu’s earlier research showed that when nerve cells detect bacterial invaders, they produce pain during infection. Other research has revealed nervous system involvement in animal models of allergic asthma.

The team suspected that nerve cells would play a protective role in bacterial infections by boosting immune response to shield the lungs, but the experiments revealed the exact opposite. Much to their surprise, the scientists found that neurons dampened lung immunity and worsened outcomes in mice with bacterial pneumonia.

To determine how nerve cells affect immunity, the scientists genetically or chemically disabled lung neurons and then compared the activity of several types of immune cells involved in infection protection. They also monitored animal survival and took physiological measures such as body temperature and number of bacteria in the lungs.

In an initial set of experiments, researchers injected mice—half with intact neurons and half with chemically disabled neurons—with drug-resistant staph bacteria. Compared with mice with intact nerve receptors, mice with disabled neurons controlled their body temperatures better, harbored 10 times fewer bacteria in their lungs 12 hours after the infection and were markedly more capable of overcoming and surviving the infection. Sixteen of 20 mice with intact neurons succumbed to the infection. By contrast, 17 of 18 mice with disabled neurons survived.

The lungs of mice with genetically or chemically disabled neurons were also better at recruiting neutrophils—the body’s pathogen-fighting troops that provide first responses during infections by devouring disease-causing bacteria. These mice summoned nearly twice as many infection-curbing neutrophils as did mice with intact neurons. But neutrophils in these animals were not simply more numerous. They were also more agile and more efficient in their performance. As a measure of agility, researchers compared how well neutrophils in both groups managed to patrol lung blood capillaries—a key ability that allows these cells to scan for the presence of disease-causing pathogens. Neutrophils in animals with chemically disabled neurons crawled farther, covering greater distances. They were also stickier and thus more capable of adhering to the walls of blood vessels, the site of their pathogen-gobbling action.

“We observed a striking difference in neutrophil presence and behavior between the two groups,” said Pankaj Baral, a research fellow in microbiology and immunobiology at Harvard Medical School and first author on the study.

“Neutrophils in mice with disabled neurons were simply better at doing their job.”

Additionally, mice with disabled neurons marshaled more efficiently several types of cytokines, signaling proteins that regulate inflammation, infection and bacterial clearance. In animals with disabled neurons, the levels of these inflammatory cells ramped up and subsided much faster, indicating that these mice were capable of mounting a more rapid immune response in the early stages of infection.

Conversely, mice with intact neurons showed suppressed function in a class of protective immune cells known as gamma delta T cells, a type of protective white blood cell found mostly in barrier tissues that line a variety of organs, including the lungs.

A final set of experiments revealed just how neurons suppressed immunity. The researchers observed that an immune signaling molecule released locally by neurons—a neuropeptide known as CGRP—was markedly increased in mice with intact neuron receptors during infection but absent in mice with disabled neurons. Researchers observed that the release of this molecule interfered with the lungs’ ability to summon immunoprotective neutrophils, cytokines and gamma delta T cells. Experiments in lab dishes revealed that CGRP disrupted immune cells’ ability to kill bacteria. When researchers blocked the production of CGRP in live animals infected with staph, these mice showed an enhanced ability to fight infection.

Taken together, these findings show that lung neurons enable the release of CGRP during lung infections and that blocking the activity of CGRP improves survival in bacterial pneumonia.

“The traditional delineation between nervous and immune systems is getting blurry and our findings underscore the idea that these two systems cross-talk to regulate each other’s function,” Chiu said. “As we move forward, immunologists should think more about the role of the nervous system, and neuroscientists should think more about the immune system.”

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Children Carry Evidence Of Toxins From Home Flooring And Furniture

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Children living in homes with all vinyl flooring or flame-retardant chemicals in the sofa have significantly higher concentrations of potentially harmful semi-volatile organic compounds (SVOCs) in their blood or urine than children from homes where these materials are not present, according to a new Duke University-led study.

The researchers presented their findings Sunday, Feb. 17 at the annual meeting of the American Association for the Advancement of Science in Washington, D.C.

They found that children living in homes where the sofa in the main living area contained flame-retardant polybrominated diphenyl ethers (PBDEs) in its foam had a six-fold higher concentration of PBDEs in their blood serum.

Exposure to PBDEs has been linked in laboratory tests to neurodevelopmental delays, obesity, endocrine and thyroid disruption, cancer and other diseases.

Children from homes that had vinyl flooring in all areas were found to have concentrations of benzyl butyl phthalate metabolite in their urine that were 15 times higher than those in children living with no vinyl flooring.

Benzyl butyl phthalate has been linked to respiratory disorders, skin irritations, multiple myeolma and reproductive disorders.

“SVOCs are widely used in electronics, furniture and building materials and can be detected in nearly all indoor environments,” said Heather Stapleton, an environmental chemist at Duke’s Nicholas School of the Environment, who led the research.

“Human exposure to them is widespread, particularly for young children who spend most of their time indoors and have greater exposure to chemicals found in household dust.”

“Nonetheless, there has been little research on the relative contribution of specific products and materials to children’s overall exposure to SVOCs,” she noted.

To address that gap, in 2014 Stapleton and colleagues from Duke, the Centers for Disease Control & Prevention, and Boston University began a three-year study of in-home exposures to SVOCs among 203 children from 190 families.

“Our primary goal was to investigate links between specific products and children’s exposures, and to determine how the exposure happened — was it through breathing, skin contact or inadvertent dust inhalation,” Stapleton said.

To that end, the team analyzed samples of indoor air, indoor dust and foam collected from furniture in each of the children’s homes, along with a handwipe sample, urine and blood from each child.

“We quantified 44 biomarkers of exposure to phthalates, organophosphate esters, brominated flame retardants, parabens, phenols, antibacterial agents and perfluoroalkyl and polyfluoroalkyl substances (PFAS),” Stapleton said.

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Your Home Is A Hidden Source Of Air Pollution

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Cooking, cleaning and other routine household activities generate significant levels of volatile and particulate chemicals inside the average home, leading to indoor air quality levels on par with a polluted major city, University of Colorado Boulder researchers have found.

What’s more, airborne chemicals that originate inside a house don’t stay there: Volatile organic compounds (VOCs) from products such as shampoo, perfume and cleaning solutions eventually escape outside and contribute to ozone and fine particle formation, making up an even greater source of global atmospheric air pollution than cars and trucks do.

The previously underexplored relationship between households and air quality drew focus today at the 2019 AAAS Annual Meeting in Washington, D.C., where researchers from CU Boulder’s Cooperative Institute for Research in Environmental Sciences (CIRES) and the university’s Department of Mechanical Engineering presented their recent findings during a panel discussion.

“Homes have never been considered an important source of outdoor air pollution and the moment is right to start exploring that,” said Marina Vance, an assistant professor of mechanical engineering at CU Boulder.

“We wanted to know: How do basic activities like cooking and cleaning change the chemistry of a house?”

In 2018, Vance co-led the collaborative HOMEChem field campaign, which used advanced sensors and cameras to monitor the indoor air quality of a 1,200-square-foot manufactured home on the University of Texas Austin campus. Over the course of a month, Vance and her colleagues conducted a variety of daily household activities, including cooking a full Thanksgiving dinner in the middle of the Texas summer.

While the HOMEChem experiment’s results are still pending, Vance said that it’s apparent that homes need to be well ventilated while cooking and cleaning, because even basic tasks like boiling water over a stovetop flame can contribute to high levels of gaseous air pollutants and suspended particulates, with negative health impacts.

To her team’s surprise, the measured indoor concentrations were high enough that that their sensitive instruments needed to be recalibrated almost immediately.

“Even the simple act of making toast raised particle levels far higher than expected,” Vance said.

“We had to go adjust many of the instruments.”

Indoor and outdoor experts are collaborating to paint a more complete picture of air quality, said Joost de Gouw, a CIRES Visiting Professor. Last year, de Gouw and his colleagues published results in the journal Science showing that regulations on automobiles had pushed transportation-derived emissions down in recent decades while the relative importance of household chemical pollutants had only gone up.

“Many traditional sources like fossil fuel-burning vehicles have become much cleaner than they used to be,” said de Gouw.

“Ozone and fine particulates are monitored by the EPA, but data for airborne toxins like formaldehyde and benzene and compounds like alcohols and ketones that originate from the home are very sparse.”

While de Gouw says that it is too early on in the research to make recommendations on policy or consumer behavior, he said that it’s encouraging that the scientific community is now thinking about the “esosphere,” derived from the Greek word ‘eso,’ which translates to ‘inner.’

“There was originally skepticism about whether or not these products actually contributed to air pollution in a meaningful way, but no longer,” de Gouw said.

“Moving forward, we need to re-focus research efforts on these sources and give them the same attention we have given to fossil fuels. The picture that we have in our heads about the atmosphere should now include a house.”

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Diet Drinks May Be Associated With Strokes Among Post-Menopausal Women

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Among post-menopausal women, drinking multiple diet drinks daily was associated with an increase in the risk of having a stroke caused by a blocked artery, especially small arteries, according to research published in Stroke, a journal of the American Heart Association.

This is one of the first studies to look at the association between drinking artificially sweetened beverages and the risk of specific types of stroke in a large, racially diverse group of post-menopausal women. While this study identifies an association between diet drinks and stroke, it does not prove cause and effect because it was an observational study based on self-reported information about diet drink consumption.

Compared with women who consumed diet drinks less than once a week or not at all, women who consumed two or more artificially sweetened beverages per day were:

  • 23 percent more likely to have a stroke;
  • 31 percent more likely to have a clot-caused (ischemic) stroke;
  • 29 percent more likely to develop heart disease (fatal or non-fatal heart attack); and
  • 16 percent more likely to die from any cause.

Researchers found risks were higher for certain women. Heavy intake of diet drinks, defined as two or more times daily, more than doubled stroke risk in:

  • women without previous heart disease or diabetes, who were 2.44 times as likely to have a common type of stroke caused by blockage of one of the very small arteries within the brain;
  • obese women without previous heart disease or diabetes, who were 2.03 times as likely to have a clot-caused stroke; and
  • African-American women without previous heart disease or diabetes, who were 3.93 times as likely to have a clot-caused stroke.

“Many well-meaning people, especially those who are overweight or obese, drink low-calorie sweetened drinks to cut calories in their diet. Our research and other observational studies have shown that artificially sweetened beverages may not be harmless and high consumption is associated with a higher risk of stroke and heart disease,” said Yasmin Mossavar-Rahmani, Ph.D., lead author of the study and associate professor of clinical epidemiology and population health at the Albert Einstein College of Medicine in the Bronx, New York.

Researchers analyzed data on 81,714 postmenopausal women (age 50-79 years at the start) participating in the Women’s Health Initiative study that tracked health outcomes for an average of 11.9 years after they enrolled between 1993 and 1998. At their three-year evaluation, the women reported how often in the previous three months they had consumed diet drinks such as low calorie, artificially sweetened colas, sodas and fruit drinks. The data collected did not include information about the specific artificial sweetener the drinks contained.

The results were obtained after adjusting for various stroke risk factors such as age, high blood pressure, and smoking. These results in postmenopausal women may not be generalizable to men or younger women. The study is also limited by having only the women’s self-report of diet drink intake.

“We don’t know specifically what types of artificially sweetened beverages they were consuming, so we don’t know which artificial sweeteners may be harmful and which may be harmless,” Mossavar-Rahmani said.

The American Heart Association recently published a science advisory that found there was inadequate scientific research to conclude that low-calorie sweetened beverages do – or do not – alter risk factors for heart disease and stroke in young children, teens or adults. The Association recognizes diet drinks may help replace high calorie, sugary beverages, but recommends water (plain, carbonated and unsweetened flavored) as the best choice for a no calorie drink.

“Unfortunately, current research simply does not provide enough evidence to distinguish between the effects of different low-calorie sweeteners on heart and brain health. This study adds to the evidence that limiting use of diet beverages is the most prudent thing to do for your health,” said Rachel K. Johnson, Ph.D., R.D., professor of nutrition emeritus, University of Vermont and the chair of the writing group for the American Heart Association’s science advisory, Low-Calorie Sweetened Beverages and Cardiometabolic Health.

“The American Heart Association suggests water as the best choice for a no-calorie beverage. However, for some adults, diet drinks with low calorie sweeteners may be helpful as they transition to adopting water as their primary drink. Since long-term clinical trial data are not available on the effects of low-calorie sweetened drinks and cardiovascular health, given their lack of nutritional value, it may be prudent to limit their prolonged use” said Johnson.

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