Sickle cell disease (SCD) patients are at high risk of contracting

Sickle cell disease (SCD) patients are at high risk of contracting pneumococcal contamination. the general populace and protective capacity of potential antigens was lost over time in SCD. This highlights the importance of understanding bacterial pathogenesis in the context of high-risk individuals. XL147 Introduction (pneumococcus) is usually a major cause of childhood illness worldwide causing approximately 14 million episodes of invasive disease and 1 million deaths per year. The first step in invasive pneumococcal disease (IPD) is usually nasopharyngeal XL147 (NP) colonization but asymptomatic carriage is usually common especially in early child years (~30 – 50%) (Daw et al. 1997 Colonization is usually established by a single pneumococcal strain and persists for 1-2 months before clearance (Ghaffar et al. 1999 Pneumococci lack CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems to protect genomic content and are naturally highly transformable permitting quick genetic response to evolutionary pressures (Bikard et al. 2012 Croucher et al. 2011 For example introduction of the 7-valent pneumococcal conjugate vaccine (Prevnar; PCV7) in the USA in 2000 resulted in near-complete removal of vaccine serotypes and emergence of non-vaccine serotypes (NVT) in colonization and IPD in the general populace (Croucher et al. 2013 Halasa et al. 2013 Sickle cell disease (SCD) a XL147 hemoglobinopathy characterized by chronic hemolysis and sickled reddish blood cells is the most common genetic disorder worldwide with XL147 300 0 affected infants born each year (WHO 2006 Children with SCD have a 600-fold increased risk of potentially fatal IPD compared with the general populace despite comparable colonization rates (Overturf 1999 The increased risk is related to hyposplenism match deficiency and chronic vascular inflammation promoting upregulation of the ligand for pneumococcal invasion (Miller et al. 2007 Rosch et al. 2010 To address this risk children with SCD receive long-term penicillin prophylaxis frequent empiric antibiotic treatment and pneumococcal vaccines. Pneumococci colonizing children with SCD have been previously shown to develop antibiotic resistance in response to the selective antibiotic pressure and demonstrate capsular serotype switching in response to vaccines (Adamkiewicz et al. 2008 Steele et al. 1996 The SCD host and the pneumococcus represents a unique paradigm for understanding how pathogens adapt to both clinical interventions including vaccination and antibiotic pressure as Rabbit Polyclonal to FAS. well as unique aspects of host pathophysiology underlying heightened contamination risk. Due to the combination of clinical and host factors we hypothesized that pneumococci found in the SCD populace would develop unique genomic adaptations from your selective pressures imparted not only XL147 by clinical interventions but also the SCD host environment itself. To characterize the pneumococcus emerging in the pediatric SCD populace between 2004 and 2011 and re-evaluate current disease risk for these vulnerable children we undertook the largest longitudinal study of pneumococcal colonization in children with SCD. We compared the results with a cohort from 1994-5 to ascertain the impact of deployment of the conjugate PCV7 vaccine in 2000. We also acquired a broad range of IPD isolates from healthy and SCD children from across the United States and obtained sequence data for contemporary NP isolates from the general populace (GP) (Croucher et al. 2013 Whole-genome sequencing of 322 isolates one of the largest datasets put together thus far defined overall gene content and recognized genes with differential large quantity between isolates from SCD and the GP as well as between historical and contemporary eras. A murine model of SCD coupled to Tn-seq whole-genome mutagenesis and vaccination experiments were used to identify and evaluate pneumococcal gene networks under selective pressure in this host. These data provide a comprehensive analysis of the influence of both clinical interventions and the SCD host environment around the pneumococcus resulting in unique genetic selection and specialized contribution of genes in virulence in these high-risk patients. Results Modern colonizing SCD strains maintain invasive characteristics and evade interventions Pneumococcal strains were obtained from three sources: A) 63 NP SCD isolates from 1994-5 (Daw et al. 1997 B) 186 IPD SCD isolates from your CDC ABC bacterial surveillance core SJCRH patients and published selections (McCavit.