Emergence of hypervirulent mutants resistant to early clearance during systemic serotype 1 pneumococcal infection in mice and humans.
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.
Anna
A
Syk
Martin
M
Norman
Jenny
J
Fernebro
Marilena
M
Gallotta
Susan
S
Farmand
Andreas
A
Sandgren
Staffan
S
Normark
Birgitta
B
Henriques-Normark
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D015373:Bacterial Typing Techniques; D002460:Cell Line; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D050505:Mutant Proteins / Q000235:genetics; D010587:Phagocytosis; D011008:Pneumococcal Infections / Q000145:classification / Q000276:immunology* / Q000382:microbiology*; D012703:Serotyping; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000472:pathogenicity*; D014774:Virulence
D001426:Bacterial Proteins; D050505:Mutant Proteins