By Better Predicting Asthma Risk, Preventive Treatments Could Bypass Disease Development

Two University of Arizona College of Medicine – Tucson scientists are one step closer to developing a predictive test to assess a baby's risk for asthma, which would allow parents to take steps to thwart the disease's development, and in the future could guide doctors to prescribe preventive treatments. Their research was recently published in Frontiers of Immunology.

Genetics and family history influence a baby's risk for developing asthma during the earliest years of life, but they don't tell the whole story. What happens during those formative years can tip the balance, with allergies and respiratory viral infections increasing risk. But where some see danger, Anthony Bosco, PhD, associate professor of immunobiology and associate research scientist with the Asthma and Airway Disease Research Center, sees opportunity.

"The first thousand days of life shape how the immune system develops in response to the outside world," he said. "There's a window of opportunity to go in there with interventions that can strengthen the immune system and reduce the risk of asthma."

Predicting asthma risk at birth

Asthma is an inflammatory disorder in which the airways narrow as they become inflamed, making it difficult to breathe. Dr. Bosco and his colleague James Read, a data scientist with the Department of Immunobiology and the Asthma and Airway Disease Research Center, studied a cohort of 50 babies at high risk for asthma and found that those who went on to develop asthma exhibited an exaggerated inflammatory response after being exposed to certain pathogenic, or disease-causing, bacteria.

Investigators studied the unusually intense immune response and identified a likely driver: a network controlled by a gene called IRF1.

"The internet is a bunch of information that's connected through web links. Gene networks work in much the same way," Dr. Bosco said. "If gene A interacts with gene B, we connect it with a link, constructing a 'wiring diagram' of hundreds of genes that control the immune response."

The researchers saw that the "wiring" of the IRF1 gene network in children who develop asthma is different than in children who do not develop asthma. They believe that conditioning the body to pathogenic bacteria at an early age could "reprogram" the immune systems in asthma-prone children to respond more appropriately to asthma-attack triggers, such as fungi, dust mites and viral infections.

"Our research suggests you can minimize asthma risk by treating the immune system in a way that avoids this excessive inflammatory response," Dr. Bosco said. "Our long-term goal is to roll out a predictive test at scale, start testing babies to predict their risk, and put them on therapies that promote a healthy immune system."

Nipping asthma in the bud

The investigators are hopeful that at-risk babies can overcome their genetic predisposition to asthma through controlled exposure to bacterial extracts that have been attenuated, or weakened, to make them safe to administer to babies and young children.

"In the womb, you're protected from infections. All of a sudden, you're in the outside world, surrounded by bacteria, viruses and molds," Dr. Bosco said. "As your immune system is exposed to different pathogens, it starts to learn how to respond."

They believe training a baby's immune system through exposure to certain microbes may be the key to reducing their risk of developing asthma.

"At birth, your brain can function, but you don't know how to read or write. You need to learn by being educated. The immune system is the same," Dr. Bosco said. "The immune system has to be educated, or trained, by being exposed to things in the environment to figure out how to respond."

If infections with pathogenic bacteria cause an exaggerated inflammatory response, , the researchers reasoned that exposure to attenuated forms of bacteria could nurture a healthy relationship between the immune system and the microbial world, "teaching" the immune system not to respond so aggressively to subsequent asthma triggers.

"If your exposure to bacteria happens early on and you develop a healthy microbiome, the way your immune system responds to pathogens will be more fine-tuned," Dr. Bosco said. The microbiome is the community of bacteria and other microbes that take up residence in the body, where they mostly live in symbiosis.

The investigators believe we can potentially bypass the need for lifelong asthma medications by giving at-risk children microbial products that can train the immune system. Microbial products are already being studied for their ability to reduce asthma risk, including at the Asthma and Airways Disease Research Center, where Fernando Martinez, MD, is principal investigator of the ORBEX trial to measure the efficacy of bacterial extracts in preventing asthma-like symptoms.

'Moving away from the reactive'

In addition to using microbial products, Read says a test revealing babies' faulty genetic wiring can motivate parents to make healthier choices for their children.

"If parents are informed that their child is more likely to have asthma, they can make changes, like monitoring time outside during certain periods of the year, such as when outdoor airborne fungal spore concentrations are at their highest levels in spring," Read said. "Our work is moving away from the reactive, where you wait until a disease is present and treat it, to an earlier timepoint where we can take actions to reduce risk and lower disease burden."

When possible, parents can take other steps to reduce their babies' asthma risk.

"If you have a natural birth, breastfeed your baby, avoid smoking and avoid the unnecessary use of antibiotics, that will help build up healthy bacteria in your baby's microbiome and stimulate the development of a healthy immune system. That resilient immune system will protect your baby's lungs from infections," Dr. Bosco said.

Dr. Bosco came to the College of Medicine – Tucson from Australia earlier this year, bringing Read with him. He was drawn here by the opportunity to join forces with Dr. Martinez, for whom he was a postdoctoral researcher more than a decade ago.

"Fernando is leading some large clinical trials and cohort studies, which can take our research to that next level," Dr. Bosco said. "We got very exciting data in these smaller cohorts. Now we want to do the large-scale research, which will generate the evidence needed to change clinical practice."