Genome-wide association analyses of invasive pneumococcal isolates identify a missense bacterial mutation associated with meningitis

Yuan Li (), Benjamin J. Metcalf, Sopio Chochua, Zhongya Li, Hollis Walker, Theresa Tran, Paulina A. Hawkins, Ryan Gierke, Tamara Pilishvili, Lesley McGee and Bernard W. Beall
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Yuan Li: U.S. Department of Health and Human Services
Benjamin J. Metcalf: U.S. Department of Health and Human Services
Sopio Chochua: U.S. Department of Health and Human Services
Zhongya Li: U.S. Department of Health and Human Services
Hollis Walker: U.S. Department of Health and Human Services
Theresa Tran: U.S. Department of Health and Human Services
Paulina A. Hawkins: U.S. Department of Health and Human Services
Ryan Gierke: U.S. Department of Health and Human Services
Tamara Pilishvili: U.S. Department of Health and Human Services
Lesley McGee: U.S. Department of Health and Human Services
Bernard W. Beall: U.S. Department of Health and Human Services

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Bacterial mutations predisposing pneumococcus to causing meningitis, a more severe form of invasive pneumococcal disease (IPD), are largely unknown. Knowledge of such mutations may improve our understanding of pathogenesis and inform preventive strategies. Here we report a pneumococcal pbp1b gene mutation (pbp1bA641C causing N214T change in PBP1b transglycosylase domain) that is associated with meningitis in an exploratory cohort of IPD patients (n = 2054, p = 6.8 × 10−6), in an independent confirmatory cohort (n = 2518, p = 2.3 × 10−6), and in a combined analysis (n = 4572, p = 3.0 × 10−10). Patients infected by the pbp1b641C genotype pneumococci show 2.8-fold odds (95% CI 1.7 to 4.8) of meningitis compared to those infected by non-pbp1b641C pneumococci, after controlling for pneumococcal serotype, antibiotic resistance, and patient age. The pbp1bA641C change results in longer time needed for bacterial killing by antibiotic treatment and shows evidence of being under positive selection. Thus, a pneumococcal mutation conferring increased antibiotic tolerance is associated with meningitis among IPD patients.

Date: 2019
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DOI: 10.1038/s41467-018-07997-y

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