This paper reviews how cystic fibrosis (CF) lungs get damaged by a stubborn bug called Pseudomonas aeruginosa and how the body’s own defenses, especially a natural antibiotic called LL‑37, try to fight it. It explains that the disease gets worse because the immune system overreacts and the bacteria develop tricks to avoid being killed, but it doesn’t give new treatment steps for everyday use.

In human pathophysiology, the clash between microbial infection and host immunity contributes to multiple diseases. Cystic fibrosis (CF) is a classical example of this phenomenon, wherein a dysfunctional, hyperinflammatory immune response combined with chronic pulmonary infections wreak havoc upon the airway, leading to a disease course of substantial morbidity and shortened life span. <i>Pseudomonas aeruginosa</i> is an opportunistic pathogen that commonly infects the CF lung, promoting an accelerated decline of pulmonary function. Importantly, <i>P. aeruginosa</i> exhibits significant resistance to innate immune effectors and to antibiotics, in part, by expressing specific virulence factors (e.g., antioxidants and exopolysaccharides) and by acquiring adaptive mutations during chronic infection. In an effort to review our current understanding of the host-pathogen interface driving CF pulmonary disease, we discuss (i) the progression of disease within the primitive CF lung, specifically focusing on the role of host versus bacterial factors; (ii) critical, neutrophil-derived innate immune effectors that are implicated in CF pulmonary disease, including reactive oxygen species (ROS) and antimicrobial peptides (e.g., LL-37); (iii) <i>P. aeruginosa</i> virulence factors and adaptive mutations that enable evasion of the host response; and (iv) ongoing work examining the distribution and colocalization of host and bacterial factors within distinct anatomical niches of the CF lung.