Neisseria species are associated with worsening bronchiectasis in patients, study shows

Neisseria species are associated with worsening bronchiectasis in patients, study shows

A team of international scientists led by Nanyang Technological University, Singapore (NTU Singapore) has found that Neisseria - a genus of bacteria that lives in the human body - is not as harmless as previously thought and can cause infections in patients with bronchiectasis. Asthma and chronic obstructive pulmonary disease (COPD).

In a landmark study published today in Cell Host & Microbe, the team showed conclusive evidence that Neisseria species can cause lung disease and are associated with worsening bronchiectasis (a type of lung disease) in patients.

Bronchiectasis is a long-term condition in which the airways of the lungs become abnormally dilated for unknown reasons in up to 50 percent of patients in Singapore. The disease is up to four times more common among Asians compared to their Western counterparts and can occur even after recovery from tuberculosis. In Singapore, research from Tan Tock Seng Hospital in 2017 described 420 hospitalized patients with bronchiectasis. The incidence rate is 10.6 per 100,000 and increases sharply with age.

Despite its prevalence in the elderly, in most cases of bronchiectasis no obvious cause can be found and the disease occurs spontaneously and without warning.

To solve the mystery of why bronchiectasis worsens significantly more frequently in older Asian patients, the international team – consisting of researchers and hospitals in Singapore, Malaysia, China, Australia and the United Kingdom (see appendix) – led by LKCMedicine Associate Professor Sanjay Chotirmall, Provost's Chair in Molecular Medicine, compared disease and infection data from 225 patients with bronchiectasis of Asian origin (Singapore and Malaysia) with those from bronchiectasis patients in Europe.

Neisseria: not so harmless after all

While Neisseria species are known to cause meningitis and gonorrhea, they are not known to infect lungs. Through detailed identification and careful characterization, the research team found that Neisseria dominated the microbiome of Asian patients with worsening bronchiectasis.

In particular, patients with bronchiectasis with predominant levels of a Neisseria subgroup called Neisseria subflava (N. subflava) experienced more severe disease and repeated infections (exacerbations) compared to patients with bronchiectasis without such high levels of Neisseria.

After further investigation using experimental cell and animal models, the research team confirmed that N. subflava causes cell destruction, leading to inflammation and immune dysfunction in bronchiectasis patients with this bacterium.

Prior to this discovery, Neisseria was not considered a cause of lung infections or serious illness in patients with bronchiectasis.

Lead investigator Prof Chotirmall from LKCMedicine said: "Our results have shown for the first time that poorer clinical outcomes such as greater disease severity, poorer lung function and high rates of recurrent infections in bronchiectasis patients are closely associated with the bacterium Neisseria and this finding is particularly important for Asian patients."

"This discovery is significant because it may change the way we treat our patients with bronchiectasis with this bacterium. Doctors must now think about Neisseria as a potential 'culprit' in patients who experience deterioration despite treatment and conduct tests to identify those who may be harboring this type of bacteria in their lungs. We hope that one early identification will lead to personalized therapy and consequently better disease outcomes for Asian patients with this devastating disease,” said Prof. Chotirmall, who is also Associate Dean (Faculty Affairs) at LKC Medicine.

This study reflects NTU's efforts as part of NTU2025, the university's five-year strategic plan that addresses humanity's grand challenges such as human health. Conducted by international researchers from various disciplines, the study also highlights NTU's strength and focus on interdisciplinary research.

Wider relevance of Neisseria

Aside from the link between Neisseria and severe bronchiectasis, the NTU-led research team also discovered the presence of the same bacteria in other more common chronic respiratory diseases such as severe asthma and chronic obstructive pulmonary disease (COPD) - a condition that causes blockage of airflow and breathing-related problems.

Using next-generation sequencing technologies, the team also tried to investigate where this bacterium might have come from, sampling the homes of patients with bronchiectasis who had large amounts of Neisseria in their lungs. The researchers found the presence of the bacteria in the home environment, suggesting that indoor living space and possibly the tropical climate may favor the presence of these bacteria in the Asian environment.

What is Neisseria?

The Neisseria species of bacteria have been widely identified as the cause of sexually transmitted infections such as gonorrhea, as well as meningitis - an inflammation of the fluid and membranes that surround the brain and spinal cord. However, its subspecies N. subflava is known to occur in the oral mucosa, throat and upper respiratory tract of humans, with no known association with lung infections.

This family of bacteria has always been considered harmless to humans; infections caused by them have not yet been described.

It is encouraging to see that we have made progress in identifying the Neisseria species of bacteria as the cause of worsening bronchiectasis, the unlikely culprit that was not initially considered a threat. This is a strong reminder that we should not be too complacent when it comes to conducting research and should be more proactive in exploring different possibilities as any seemingly innocent element could pose a threat to our bodies and our overall health.”

Wang De Yun,co-author, professor,Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore

Co-author Andrew Tan, Associate Professor of Metabolic Disorders from LKCMedicine, said: "The reverse translation approach used in this work was crucial to our success. Starting from the 'bedside', where we examined real patient experiences, we then worked backwards to uncover the biological process of the bacteria. Thanks to the interdisciplinary nature of the study, the team was able to interact with members from different research disciplines, providing an enjoyable experience while gaining unique insights into the disease.”

The researchers now want to conduct further studies and clinical trials on the eradication of Neisseria from the microbiome through the newly established LKCMedicine Center for Microbiome Medicine, which aims to evaluate the benefits of targeting and treating Neisseria with antibiotics at first detection in the hope that it will lead to better clinical outcomes for patients with chronic respiratory diseases.

Source:

Nanyang University of Technology, Singapore

Reference:

Li, L., et al. (2022) Neisseria species as pathobionts in bronchiectasis. Cell host & microbe. doi.org/10.1016/j.chom.2022.08.005.

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