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Pseudomonas aeruginosa acquisition in cystic fibrosis: a role for surfactant protein D and mannose-binding lectin?
Background: Pseudomonas aeruginosa (PSA) infection is one of the most relevant cause of morbidity and mortality in patients with cystic fibrosis (CF). Pulmonary collectins such as surfactant protein D (SP-D) and mannose-binding lectin (MBL) play critical role in local innate immunity and response to bacterial airway infections. Objective: We thus aimed to determine whether serum levels and functional relevant genetic variants of SP-D and MBL are associated with PSA infection susceptibility in patients with CF. Methods: We conducted a retrospective analysis for 42 children with CF and homozygous for DF508 allele. Data on demographics, PSA infection status, percent predicted forced expiratory volume in 1s (FEV1), leucocytes count, C-reactive protein, serum IgG were obtained at visits during follow-up period. Serum levels of SP-D and MBL were measured by ELISA. Common polymorphisms within MBL2 (C-221G, Arg52Cys, Gly54Asp, Gly57Glu) and SP-D gene (Met11Thr, Ala160Thr, Ser270Thr) were identified by TaqMan PCR technology. Haplotypes were estimated by HPlus v3.1 program using expectation-maximization algorithm. The association with PSA susceptibility was analyzed using Cox regression with time to first positive PSA culture as outcome. Results: Mean age at CF diagnosis was 1.3 (±2.6) years. A total of 22 (52.4%) subjects were infected with PSA after a mean age of 6.7 (±4.5) years. Serum levels of SP-D and MBL were higher in infected children compared to uninfected subjects, but this was not statistically significant [MBL: 183±135 vs. 144±130ng/ml, P=0.22; SP-D: 964±479 vs. 844±398ng/ml, P=0.42]. MBL serum concentrations were influenced by MBL haplotypes. Significant negative correlation was found between SP-D serum level and FEV1 [r=-0.63, P<0.02] in CF children irrespective of PSA infection. Gender adjusted cox regression analysis resulted in a increased hazard ratio to PSA acquisition for carriers of SP-D haplotype Thr/Ala/Ser compared to carriers of most common haplotype Met/Thr/Ser [3.01; 95%CI 1.1–8.6; P=0.04]. Conclusion: Our findings indicate that susceptibility to PSA acquisition in CF is modified by SP-D genetic variants with Thr/Ala/Ser as risk haplotype for early PSA infection. This is probably due to the presence of the polymorphism Met11Thr, which is associated with oligomeric structure of SP-D protein and binding ability to bacterial ligands.