When I tell people that I presented cystic fibrosis research at an infectious disease conference back in March, I often get the same question:

"What does cystic fibrosis have to do with infectious diseases?"

At first glance, it is a fair question. Cystic fibrosis (CF) is widely recognized as a genetic disease caused by mutations in the CFTR gene. Most discussions of CF focus on thick mucus, breathing difficulties, and progressive lung damage. So why would CF research belong alongside discussions of emerging pathogens, antimicrobial resistance, and infectious disease outbreaks?

As it turns out, answering that question completely changed the way I think about cystic fibrosis.

The Cystic Fibrosis Most People Know

Like many students entering the field, I initially learned about CF as a genetic disease. Mutations in the CFTR gene disrupt the movement of chloride and water across cell membranes, leading to thick, sticky mucus that accumulates in the lungs and other organs. This mucus creates an environment where bacteria can thrive, resulting in recurrent infections and progressive lung damage.

For decades, this framework shaped our understanding of CF. The genetic mutation caused abnormal mucus, the mucus promoted infection, and infection drove disease progression.

While this model remains fundamentally true, researchers are increasingly recognizing that it may not tell the whole story. What if chronic infection is not only a consequence of CF, but also a force that shapes the disease itself?

More Than a Lung Disease

One of the defining features of CF is chronic infection. Unlike many infections that are cleared within days or weeks, individuals with CF can experience years, or even decades, of persistent bacterial colonization. Microorganisms such as Pseudomonas aeruginosa establish long-term residence within the lungs, creating a continuous battle between microbes and the immune system.

As I became more involved in CF research, I found myself asking the same question:

What happens to an immune system that spends a lifetime fighting the same infections?

Surprisingly, we still do not have a complete answer.

Historically, most CF immune research focused on innate immune cells such as neutrophils and macrophages. These cells are among the first responders to infection and play important roles in the chronic inflammation observed in CF airways.

However, a growing body of evidence suggests that adaptive immune cells, including T cells and B cells, may also be altered in CF.

Looking Through an Immune Lens

The adaptive immune system is responsible for developing targeted, long-term responses against pathogens. It allows the body to remember previous infections and coordinate highly specialized immune responses.

In recent years, researchers have begun observing changes in adaptive immune populations in people with CF. Some studies suggest altered T-cell activation, imbalances in immune regulation, and signs of chronic immune stimulation. These findings raise an intriguing possibility: the immune system may not simply be responding to CF-related infections, it may also be reshaped by them.

The more I learned about chronic infection in CF, the more I found myself drawn to a question that seemed surprisingly underexplored: what happens to the adaptive immune system after years, or even decades, of fighting the same pathogens? 

Working in the Microbe-Host Dynamics Lab, I became interested in a molecule called CD28, which plays a critical role in T-cell activation. In many chronic inflammatory and infectious diseases, loss of CD28 expression is associated with altered T-cell function and prolonged immune stimulation.

We wondered whether similar changes might be occurring in cystic fibrosis.

Using a combination of published datasets, mouse models, and patient samples, our preliminary findings suggest that CD28-negative T-cell populations may be expanded in CF, particularly within CD8+ T cells. Even more interestingly, these alterations appeared to persist despite treatment with CFTR modulators.

While this work remains ongoing, it raises an important question: if we can improve CFTR function and dramatically improve lung health, what happens to the immune system after years of chronic infection and inflammation?

Why This Matters in the Modulator Era

The development of CFTR modulators has transformed the lives of many people with CF. Lung function has improved, hospitalizations have declined, and life expectancy continues to increase.

Yet infections have not disappeared entirely.

Many individuals continue to experience persistent microbial colonization and inflammation despite remarkable clinical improvements. This has prompted researchers to look beyond mucus abnormalities alone and consider whether long-standing changes within the immune system may contribute to ongoing disease processes.

As people with CF live longer and healthier lives, understanding these immune changes may become increasingly important.

A New Conversation

When I presented this work at the conference, I realized that the original question, "What does cystic fibrosis have to do with infectious diseases?", has a much more interesting answer than I initially thought.

Cystic fibrosis is still a genetic disease. It is still a disease of mucus dysfunction. But it is also a disease shaped by lifelong interactions between microbes and the immune system.

When I first began studying cystic fibrosis, I saw it primarily as a genetic disease. Today, I still see the genetics, but I also see the microbes, the immune system, and the complex interactions between them. That shift in perspective has changed how I think about CF, and perhaps it is why CF research belongs in infectious disease conversations after all.