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

Yuan Li1, Benjamin J Metcalf2, Sopio Chochua2

  • 1Respiratory Diseases Branch, Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, 30333, Georgia, USA. yqh8@cdc.gov.

Nature Communications
|January 16, 2019
PubMed

Insights

A newly identified pneumococcal mutation in the pbp1b gene is linked to meningitis, a severe form of invasive pneumococcal disease (IPD). This bacterial mutation also increases antibiotic tolerance, potentially impacting treatment outcomes.

Area of Science:

  • Microbiology
  • Genetics
  • Infectious Diseases

Background:

  • Invasive pneumococcal disease (IPD) can lead to severe outcomes like meningitis.
  • The genetic factors predisposing Streptococcus pneumoniae to cause meningitis are not well understood.
  • Identifying such factors is crucial for understanding pathogenesis and developing preventive strategies.

Purpose of the Study:

  • To identify bacterial mutations associated with meningitis in IPD patients.
  • To investigate the functional impact of identified mutations on antibiotic tolerance and pathogenesis.

Main Methods:

  • Retrospective analysis of two independent cohorts of IPD patients (total n=4572).
  • Genotyping of Streptococcus pneumoniae isolates for pbp1b gene mutations.
  • Statistical analysis to determine the association between pbp1b mutations and meningitis, controlling for confounders.
  • Assessment of antibiotic killing time in vitro for mutant strains.

Main Results:

  • A specific pbp1b gene mutation (pbp1bA641C) was significantly associated with meningitis in both exploratory and confirmatory cohorts (p < 10^-6).
  • Patients infected with pbp1b641C pneumococci had a 2.8-fold increased odds of developing meningitis.
  • The pbp1bA641C mutation was associated with increased antibiotic tolerance, showing longer bacterial killing times.
  • Evidence suggests the pbp1bA641C mutation is under positive selection.

Conclusions:

  • A pneumococcal pbp1b gene mutation is a significant risk factor for meningitis in IPD patients.
  • This mutation confers increased antibiotic tolerance, potentially contributing to more severe disease.
  • Findings highlight the role of specific bacterial genetic alterations in disease severity and inform potential therapeutic targets.

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