Host response to Staphylococcus aureus cytotoxins in children with cystic fibrosis.

BACKGROUND: Staphylococcus aureus is one of the earliest bacterial pathogens to colonize the lungs of children with cystic fibrosis and is an important contributor to pulmonary exacerbations. The adaptive host response to S. aureus in cystic fibrosis remains inadequately defined and has important implications for pathogenesis and potential interventions. The objectives of this study were to determine the functional antibody response to select staphylococcal exotoxins (LukAB, alpha-hemolysin, and PVL) in children with cystic fibrosis and to evaluate the relationship of this response with pulmonary exacerbations. METHODS: Fifty children with cystic fibrosis were enrolled and followed prospectively for 12months. Clinical characteristics and serologic profiles were assessed at routine visits and during pulmonary exacerbations, and functional antibody assessments were performed to measure neutralization of LukAB-mediated cytotoxicity. RESULTS: For each antigen, geometric mean titers were significantly higher if S. aureus was detected at the time of exacerbation. For LukAB, geometric mean titers were significantly higher at exacerbation follow-up compared to titers during the exacerbation, consistent with expression during human disease, and the humoral response capably neutralized LukAB-mediated cytotoxicity. Moreover, the presence of a positive S. aureus culture during a pulmonary exacerbation was associated with 31-fold higher odds of having a LukA titer ≥1:160, suggesting potential diagnostic capability of this assay. CONCLUSIONS: The leukotoxin LukAB is expressed by S. aureus and recognized by the human adaptive immune response in the setting of pulmonary infection in cystic fibrosis. Anti-LukAB antibodies were not only predictive of positive staphylococcal culture during exacerbation, but also functional in the neutralization of this toxin.

Unusual progression and subsequent improvement in cystic lung disease in a child with radiation-induced lung injury.

Radiation-induced lung disease is a known complication of therapeutic lung irradiation, but the features have not been well described in children. We report the clinical, radiologic and histologic features of interstitial lung disease (ILD) in a 4-year-old child who had previously received lung irradiation as part of successful treatment for metastatic Wilms tumor. Her radiologic abnormalities and clinical symptoms developed in an indolent manner. Clinical improvement gradually occurred with corticosteroid therapy. However, the observed radiologic progression from interstitial and reticulonodular opacities to diffuse cystic lung disease, with subsequent improvement, is striking and has not been previously described in children.

Inter- and intraspecies metabolite exchange promotes virulence of antibiotic-resistant Staphylococcus aureus.

Adaptations that enable antimicrobial resistance often pose a fitness cost to the microorganism. Resistant pathogens must therefore overcome such fitness decreases to persist within their hosts. Here we demonstrate that the reduced fitness associated with one resistance-conferring mutation can be offset by community interactions with microorganisms harboring alternative mutations or via interactions with the human microbiota. Mutations that confer antibiotic resistance in the human pathogen Staphylococcus aureus led to decreased fitness, whereas coculture or coinfection of two distinct mutants resulted in collective recovery of fitness comparable to that of wild-type. Such fitness enhancements result from the exchange of metabolites between distinct mutants, leading to enhanced growth, virulence factor production, and pathogenicity. Interspecies fitness enhancements were also identified, as members of the human microbiota can promote growth of antibiotic-resistant S. aureus. Thus, inter- and intraspecies community interactions offset fitness costs and enable S. aureus to develop antibiotic resistance without loss of virulence.

Respiratory syncytial virus morbidity and outpatient palivizumab dosing in South Carolina, 2004-2009.

OBJECTIVE: Respiratory syncytial virus (RSV) has been identified as an important cause of lower respiratory tract disease in infants. In patients at high risk, prevention is attempted through immunoprophylaxis with palivizumab. In 2008, as a result of revisions to the American Academy of Pediatrics' guidelines, South Carolina Medicaid reduced the number of approved palivizumab doses from six to five. This study attempted to determine whether the reduction of approved doses would affect hospitalization and emergency department visits and to characterize dose administration. METHODS: We obtained data for all South Carolina Medicaid reimbursed births from November 2004 through March 2009. For each RSV season, infants who should have received palivizumab were identified. Rates of outpatient palivizumab dosing and hospitalizations and emergency department visits because of RSV also were identified. RESULTS: In the seasons sampled, 1956 infants met eligibility criteria for our study. Infants younger than 29 weeks' gestation received 34% to 48% of their total eligible palivizumab doses, whereas infants 29 to 31 weeks' gestation received 36% to 46% of their doses. The rate of emergency department visits and inpatient admissions because of RSV did not differ significantly across years. DISCUSSION: In evaluating our primary outcome, there was no increase in hospitalizations or emergency department visits. Overall, we did note a poor dosing rate in all of the groups. A statistically significant decline in dosing per eligible month was noted following the dose reductions. Despite solid evidence of the benefits of palivizumab in high-risk groups, we are doing an inadequate job of dosing these patients. CONCLUSIONS: We believe adherence to current recommendations for palivizumab dosing is suboptimal in preterm infants insured by the South Carolina Medicaid program. Healthcare professionals must work harder to identify and follow-up with patients who qualify for palivizumab dosing, including infants who meet criteria for a second season.

A mutation in the STN1 gene triggers an alternative lengthening of telomere-like runaway recombinational telomere elongation and rapid deletion in yeast.

Some human cancer cells achieve immortalization by using a recombinational mechanism termed ALT (alternative lengthening of telomeres). A characteristic feature of ALT cells is the presence of extremely long and heterogeneous telomeres. The molecular mechanism triggering and maintaining this pathway is currently unknown. In Kluyveromyces lactis, we have identified a novel allele of the STN1 gene that produces a runaway ALT-like telomeric phenotype by recombination despite the presence of an active telomerase pathway. Additionally, stn1-M1 cells are synthetically lethal in combination with rad52 and display chronic growth and telomere capping defects including extensive 3' single-stranded telomere DNA and highly elevated subtelomere gene conversion. Strikingly, stn1-M1 cells undergo a very high rate of telomere rapid deletion (TRD) upon reintroduction of STN1. Our results suggest that the protein encoded by STN1, which protects the terminal 3' telomere DNA, can regulate both ALT and TRD.