The Zamora Lab seeks to uncover how chronic inflammatory cues reshape the epigenetic and metabolic landscape of the airway, and how these alterations modulate responses to bacterial and viral infections. Our work centers on the respiratory tract of people with cystic fibrosis (pwCF), a genetic disease characterized by persistent airway inflammation, chronic infections, and progressive loss of lung function. By dissecting how epithelial and immune cell responses are reprogrammed in this context, we aim to identify molecular mechanisms that drive host defense alterations. Ultimately, our goal is to inform the development of therapies that restore immune competence and improve respiratory function in chronic airway diseases.
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Focus #1: What are the consequences of repeated inflammatory
stimulation in viral and bacterial infections?
Biofilm aggregates from the sputum of a pwCF.
P. aeruginosa; inflammatory cells
Image obtained from Bjarnsholt, et. al., 2013
P. aeruginosa (green) grown on airway epithelial cells (nuclei, blue; actin, grey) and treated with
bacterial viruses OMKO1 and LPS-5 (red).
Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, which encodes a chloride channel involved in regulating fluid and electrolyte transport across epithelial surfaces. These mutations lead to thick, sticky mucus secretions, particularly in the lungs, impairing mucociliary clearance. This feature creates an environment with the nutritional and physiological qualities to support bacterial infections, which become chronic as individuals age. Over time, these chronic infections contribute to progressive airway damage and decline in lung function. Cystic fibrosis affects approximately 40,000 individuals in the United States. While advances in treatment have significantly improved life expectancy and quality of life, chronic infections remain a major cause of morbidity and mortality in people with CF, with Pseudomonas aeruginosa being a pathogen that correlates with large decreases in lung function.
In pwCF, the lungs are chronically exposed to an hyperinflammatory environment that is intrinsic to the disease pathophysiology. This sustained inflammation not only disrupts normal immune function but also reprograms cellular metabolism within the airway epithelium and resident immune cells. As a result, infections in pwCF tend to be more more severe and harder to clear compared to those in healthy individuals—contributing significantly to disease progression, reduced quality of life, and premature mortality. We hypothesize that repeated cycles of airway inflammation compromise key antimicrobial defenses, ultimately enhancing the pathogenicity of both viral and bacterial infections. Our research aims to dissect the molecular mechanisms underlying this process.
To investigate chronic airway inflammation in a tractable context, we developed an in vitro model using primary human bronchial epithelial cells cultured at the air-liquid interface (ALI), which closely mimics the mucosal architecture of the respiratory tract. This system allows for repeated inflammatory stimulation without compromising epithelial integrity, enabling the study of long-term immune and metabolic adaptations. Using this model, we are examining how chronic inflammation alters airway responses to viral infections, including respiratory syncytial virus (RSV) and rhinovirus, and how it reshapes cellular metabolism and cytokine secretion compared to acute exposures. In parallel, we are exploring inflammation-induced shifts in bacterial phenotypes using a biotic biofilm model of P. aeruginosa. Together, these approaches provide a framework to dissect the complex interplay between chronic inflammation, host responses, and microbial pathogenesis.
Focus #2: What are the epigenetic, transcriptomic, and metabolomic changes in the CF lung that lead to dysregulated responses to pathogens?
It is increasingly clear that phenotypic variation arises from complex interactions between someone's genetic background and environmental exposures, which is mediated by epigenetic and metabolic reprogramming. Epigenetic modifications regulate chromatin structure and gene expression without altering the underlying DNA sequence, playing a critical role in cellular adaptation. In CF, disease severity is influenced by gene modifiers, which are non CFTR genetic variants that influence the clinical presentations of the disease. Even though these genes have been shown to influence the severity of CF, they fall short of fully explaining the clinical heterogeneity observed among individuals with the same CFTR mutations. We hypothesize that chronic inflammatory stimulation in the CF lung induces coordinated changes in the epigenome, transcriptome, and metabolome that compromise host defense that are different from changes associated with acute inflammation. Our research aims to map these changes and identify molecular pathways that drive immune dysfunction.
Focus #3: Can we revert the effects of chronic inflammation to diminish the damage in the CF lung?
Unlike genetic mutations, epigenetic modifications are reversible and do not require genome editing, making them promising targets for therapeutic intervention. While epigenetic therapies are currently being explored in cancer, their potential in CF remains largely untapped. Traditional approaches have focused on broadly acting agents, such as inhibitors of DNA methyltransferases or histone deacetylases, which can affect multiple gene networks. More recent strategies aim to modulate specific epigenetic regulators, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), offering greater precision and reduced off-target effects. In our lab, we will be leveraging a combination of these approaches to investigate whether the transcriptional and epigenetic programs associated with aberrant wound repair and immune dysfunction following recurrent inflammation can be prevented—or even reversed—in the CF airways.
By identifying mechanisms that drive long-term damage in the airway epithelium and testing strategies to reprogram these maladaptive responses, our work has the potential to uncover entirely new classes of treatments that complement existing CF therapies. These insights could lead to interventions that not only preserve lung function but also reduce the frequency and severity of pulmonary exacerbations—ultimately improving quality of life and long-term outcomes for pwCF. Furthermore, because many of the inflammatory pathways and epigenetic signatures we study are shared across other chronic airway diseases, such as asthma and COPD, our research may offer broader therapeutic insights for the larger respiratory disease community.
We are open to new research projects and collaborations. A complete list of publications is available here.
Join us! We are hiring Research Assistants. Are you interested in
tissue culture and infections? You might be a great fit!
Email pzamora@kumc.edu to gain more information.
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