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Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

ABSTRACT: Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.

SUBMITTER: Lees JA

PROVIDER: S-EPMC6520353 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Lees John A JA Ferwerda Bart B Kremer Philip H C PHC Wheeler Nicole E NE Serón Mercedes Valls MV Croucher Nicholas J NJ Gladstone Rebecca A RA Bootsma Hester J HJ Rots Nynke Y NY Wijmega-Monsuur Alienke J AJ Sanders Elisabeth A M EAM Trzciński Krzysztof K Wyllie Anne L AL Zwinderman Aeilko H AH van den Berg Leonard H LH van Rheenen Wouter W Veldink Jan H JH Harboe Zitta B ZB Lundbo Lene F LF de Groot Lisette C P G M LCPGM van Schoor Natasja M NM van der Velde Nathalie N Ängquist Lars H LH Sørensen Thorkild I A TIA Nohr Ellen A EA Mentzer Alexander J AJ Mills Tara C TC Knight Julian C JC du Plessis Mignon M Nzenze Susan S Weiser Jeffrey N JN Parkhill Julian J Madhi Shabir S Benfield Thomas T von Gottberg Anne A van der Ende Arie A Brouwer Matthijs C MC Barrett Jeffrey C JC Bentley Stephen D SD van de Beek Diederik D

Nature communications 20190515 1

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, ide ...[more]

PMID: 31092817

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Project description:Invasive pneumococcal disease declined among children and adults after the introduction of the pediatric heptavalent pneumococcal conjugate vaccine (PCV7) in 2000, but its effect on pneumococcal meningitis is unclear.We examined trends in pneumococcal meningitis from 1998 through 2005 using active, population-based surveillance data from eight sites in the United States. Isolates were grouped into PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), PCV7-related serotypes (6A, 9A, 9L, 9N, 18A, 18B, 18F, 19B, 19C, 23A, and 23B), and non-PCV7 serotypes (all others). Changes in the incidence of pneumococcal meningitis were assessed against baseline values from 1998-1999.We identified 1379 cases of pneumococcal meningitis. The incidence declined from 1.13 cases to 0.79 case per 100,000 persons between 1998-1999 and 2004-2005 (a 30.1% decline, P<0.001). Among persons younger than 2 years of age and those 65 years of age or older, the incidence decreased during the study period by 64.0% and 54.0%, respectively (P<0.001 for both groups). Rates of PCV7-serotype meningitis declined from 0.66 case to 0.18 case (a 73.3% decline, P<0.001) among patients of all ages. Although rates of PCV7-related-serotype disease decreased by 32.1% (P=0.08), rates of non-PCV7-serotype disease increased from 0.32 to 0.51 (an increase of 60.5%, P<0.001). The percentages of cases from non-PCV7 serotypes 19A, 22F, and 35B each increased significantly during the study period. On average, 27.8% of isolates were nonsusceptible to penicillin, but fewer isolates were nonsusceptible to chloramphenicol (5.7%), meropenem (16.6%), and cefotaxime (11.8%). The proportion of penicillin-nonsusceptible isolates decreased between 1998 and 2003 (from 32.0% to 19.4%, P=0.01) but increased between 2003 and 2005 (from 19.4% to 30.1%, P=0.03).Rates of pneumococcal meningitis have decreased among children and adults since PCV7 was introduced. Although the overall effect of the vaccine remains substantial, a recent increase in meningitis caused by non-PCV7 serotypes, including strains nonsusceptible to antibiotics, is a concern.

Dataset Information

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Publications

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

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