Emergence of hypervirulent mutants resistant to early clearance during systemic serotype 1 pneumococcal infection in mice and humans
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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.
Insights
Certain Streptococcus pneumoniae serotype 1 strains with spxB mutations are hypervirulent and evade early immune clearance by macrophages in both mice and patients.
Area of Science:
- Microbiology
- Infectious Diseases
- Bacterial Pathogenesis
Background:
- Streptococcus pneumoniae serotype 1 is a significant cause of invasive disease.
- Specific clonal complexes (CCs) of serotype 1 are linked to differing mortality rates, with CC217 associated with high mortality.
Purpose of the Study:
- To investigate the mechanisms behind the high mortality associated with certain Streptococcus pneumoniae serotype 1 isolates.
- To identify genetic factors contributing to virulence and host immune evasion.
Main Methods:
- Evaluation of clinical isolates and mutants in various mouse models (wild-type, macrophage-depleted, neutrophil-depleted, SIGN-R1 knockout).
- In vitro assays including THP-1 cell binding and phagocytosis, capsule measurements, hydrogen peroxide production, and viability.
- Genetic analysis of large-colony variants identified mutations in the spxB gene.
Main Results:
- Large-colony variants with spxB mutations were observed in invasive disease cases in both mice and patients.
- spxB mutants exhibited increased virulence in wild-type mice and resistance to early host clearance.
- spxB mutants were less efficiently phagocytosed by macrophages and caused more severe disease upon immune cell depletion.
Conclusions:
- Hypervirulent spxB mutants of Streptococcus pneumoniae serotype 1 are selected during infection in both hosts and animal models.
- These mutants possess resistance to early clearance mechanisms mediated by macrophages.
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