Scientists discover the missing link that causes severe asthma

Scientists have identified a single molecule that would explain how bacteria can trigger one of the most serious types of asthma, a finding that identifies for the first time the “missing link” between exposure to bacterial components and extreme inflammation of the respiratory tract of the lungs. The results of the research were published in Science Translational Medicine.

The new study not only clarifies how a severe form of asthma affects patients, but also highlights how bacterial dysbiosis (alterations in beneficial bacteria amid exposure to pathogenic forms) affect vulnerable lungs.

Asthma is a chronic inflammatory disorder in which the airways narrow, making it difficult to breathe and causing coughing or tightness in the chest. Asthma attacks can range from mild to life-threatening. The causes of asthma are unclear, but a variety of environmental influences, including allergens, bacteria, toxins and viruses, are thought to exacerbate the condition, and genetics may play a role.

According to data from the World Health Organization (WHO), it is estimated that in 2019, asthma affected 262 million people and caused 461,000 deaths. It is a chronic disease characterized by recurrent attacks of shortness of breath and wheezing, and affects people of all ages. It is the most common chronic disease among children.

Doctors once thought that there was only one type of the disease, but research has shown that there are two types of asthma: type 2, which is inflammatory and includes allergic asthma, and not type 2. In a type of allergic asthma, the body also makes a lot of immunoglobulin E in response to triggers such as dust or pet dander, for example.

While there are a variety of treatments for asthma, many of them target inflammation driven by type 2 cytokines that affects about half of asthma patients. There is a lack of treatment for people with other types of asthma. Although asthma has been associated with bacterial infections and dysbiosis (modification of microbiotic flora that reduces beneficial strains in pursuit of an increase in harmful ones), it is not clear exactly how bacteria play a role in the disorder.

It is believed that severe asthma is due to bacterial dysbiosis, but the mechanism that unites them remains unclear. Some previous research sought to understand this mechanism, identifying the protein oncostatin M as a mediator of severe asthma. Its blocking with an antibody reduced severe asthma-related symptoms in mice after exposure to bacterial stimuli. Together, these findings support the further development of antibodies and other drugs targeting oncostatin M as a treatment for severe asthma. New research has now found a mechanical link between germs and asthma.

An important component of bacterial cell membranes is a molecule called lipopolysaccharide (LPS), which can trigger the activity of pro-inflammatory molecules, including a cytokine called oncostatin M (OSM). In the recent study, when researchers analyzed biopsies of asthma patients, they determined that OSM levels were abnormally high. A discovery that has also been associated with other inflammatory disorders.

This work has shown that OSM can have a significant influence on the genetic activity that has been associated with severe asthma; it is the protein that appears to be driving airway inflammation that causes asthma attacks.

When researchers blocked OSM and the biochemical pathways it promotes, asthma symptoms were reduced in a mouse model. Although these pathways involve the immune response to bacterial infection, there was no impairment in the immune system's ability to fight infection.

Sarah Headland, lead author, and a team from the Immunology Division of Genentech in San Francisco, United States, have dedicated themselves to analyzing a form of asthma known as non-type 2 to find out why it is one of the most serious forms that a patient can have.

“Bacterial dysbiosis has been observed in the most severe asthma and can contribute to its onset,” explained Headland. In our paper we show that bacterial lipopolysaccharide induces oncostatin M and that airway biopsies of patients with severe asthma have an OSM-driven profile. This profile correlates with the activation of inflammatory and mucus-producing pathways. By using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that oncostatin M is necessary and sufficient to boost the pathophysiological characteristics seen in severe asthma.”

At this stage in which research has revealed how asthma symptoms can be caused by a bacterial infection, the same team is working on possible new personalized therapies. “A challenge that can improve the lives of many people in situations of severe asthma attacks,” Headland concluded.

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