Molecular and Seroepidemiologic Characteristics of<i>Staphylococcus aureus</i> in Children with Cystic Fibrosis

Abstract Background Cystic fibrosis (CF), through altered sodium and chloride transport across the CF transmembrane receptor (CFTR), is associated with poor mucus clearance, bacterial colonization of the lower airway, chronic pulmonary disease punctuated by acute exacerbations, and chronic inflammation. With increased use of CFTR modulators, changes in the CF pulmonary microbiome have been observed, including decreased prevalence of Pseudomonas colonization; however, overall S. aureus prevalence remains largely unchanged. An important remaining question is whether changes in the CF pulmonary microbiome, while not affecting the overall prevalence of S. aureus colonization, has led to changes in S. aureus diversity or the strain types that are most frequently recovered from children with CF. It is also unknown whether the humoral immune response to S. aureus is altered in the presence of CFTR modulator therapy. Methods Genomic DNA was extracted from S. aureus isolates obtained from two cohorts: a historic cohort, comprised of children not receiving CFTR modulators, and a modern cohort, comprised of children receiving CFTR modulator therapy. Multilocus sequence typing (MLST) and whole genome sequencing (WGS) were used to identify clonotype and characterize virulence factors of interest. Serum was obtained from participants and antibody titers to the extracellular toxins LukAB and LukED were measured. Results One hundred participants were enrolled: 50 in cohort 1 (historic) and 50 in cohort 2 (modern). Compared to cohort 1, isolates identified in cohort 2 were less likely to contain ACME and mecA; similarly, cohort 2 isolates were more likely to contain PVL, sek, and sak. The frequency of specific clonotypes changed over time, with increased prevalence of CC8 and decreased prevalence of CC1, CC5, CC15, and CC30 in cohort 2 compared to cohort 1 (Figure 1A). Serum antibody concentrations to LukAB, a conserved toxin across S. aureus, were similar across cohorts (Figure 1B). Conclusion Over time, the clonotypes responsible for S. aureus colonization in patients receiving CFTR modulators have changed. Despite changes in clonotypes and receipt of CFTR modulators, serum concentrations of LukAB-specific antibodies did not differ. These data suggest that staphylococcal colonization in patients with CF is dynamic over time and may be modified based on the receipt of CFTR modulator therapy. Figure 1. (A) S. aureus clonal complexes, over time, demonstrating a relative increase in CC8 between 2012 and 2022; (B) serum concentrations of LukAB antibodies from 2012 (historic) and 2022 (modern) cohorts. No significant difference was observed in median anti-LukAB concentrations.