Emergence of hypervirulent mutants resistant to early clearance during systemic serotype 1 pneumococcal infection in mice and humans

J Infect Dis. 2014 Jul 1;210(1):4-13. doi: 10.1093/infdis/jiu038. Epub 2014 Jan 16.


Background: Streptococcus pneumoniae serotype 1 has a high likelihood of causing invasive disease. Serotype 1 isolates belonging to CC228 are associated with low mortality, while CC217 isolates exhibit high mortality in patients.

Methods: Clinical pneumococcal isolates and mutants were evaluated in wild-type C57BL/6 mice, macrophage-depleted mice, neutrophil-depleted mice, and SIGN-R1 knockout mice. In vitro models included binding and phagocytosis by THP-1 cells, capsule measurements, hydrogen peroxide production, and viability assays.

Results: During early systemic infection in mice with serotype 1, large-colony variants appeared in blood. Similar large colonies were found in blood specimens from patients with invasive disease. Large morphotypes contained higher numbers of viable bacteria, grew faster, produced no or little hydrogen peroxide, and contained mutations in the spxB gene. spxB mutants were considerably more virulent in wild-type mice, less susceptible to early host clearance than wild-type strains after intravenous infection, but impaired in colonization. spxB mutants were less efficiently phagocytosed by macrophages than wild-type bacteria, which, in contrast to spxB mutants, caused more-severe disease when macrophages or SIGN-R1 were depleted.

Conclusions: Hypervirulent spxB mutants are selected in both mice and patients and are resistant to early macrophage-mediated clearance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Typing Techniques
  • Cell Line
  • Humans
  • Immunocompromised Host
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / immunology
  • Mutant Proteins / genetics
  • Phagocytosis
  • Pneumococcal Infections / classification
  • Pneumococcal Infections / immunology*
  • Pneumococcal Infections / microbiology*
  • Serotyping
  • Streptococcus pneumoniae / immunology*
  • Streptococcus pneumoniae / pathogenicity*
  • Virulence


  • Bacterial Proteins
  • Mutant Proteins