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Enhanced bacteremia in human factor H transgenic rats infected by Neisseria meningitidis.

Authors: Vu, DM  Shaughnessy, J  Lewis, LA  Ram, S  Rice, PA  Granoff, DM 
Citation: Vu DM, etal., Infect Immun. 2012 Feb;80(2):643-50. doi: 10.1128/IAI.05604-11. Epub 2011 Nov 21.
Pubmed: (View Article at PubMed) PMID:22104107
DOI: Full-text: DOI:10.1128/IAI.05604-11

Neisseria meningitidis binds the complement downregulating protein, factor H (fH), which enables the organism to evade host defenses. Two fH ligands, fHbp and NspA, are known to bind specifically to human fH. We developed a human fH transgenic infant rat model to investigate the effect of human fH on meningococcal bacteremia. At 18 h after intraperitoneal challenge with 560 CFU of group B strain H44/76, all 19 human fH-positive rats had positive blood cultures compared to 0 of 7 human fH-negative control littermates (P < 0.0001). Human fH-positive infant rats also developed bacteremia after challenge with isogenic mutants of H44/76 in which genes encoding fHbp and NspA (DeltafHbp DeltaNspA mutant) or the lipooligosaccharide sialyltransferase (Deltalst mutant) had been inactivated. A fully encapsulated DeltafHbp DeltaNspA Deltalst mutant unable to sialylate lipooligosaccharide or bind human fH via the known fH ligands did not cause bacteremia, which argued against global susceptibility to bacteremia resulting from random integration of the transgene into the rat genome. In vitro, the wild-type and DeltafHbp DeltaNspA mutant strains were killed by as little as 20% wild-type infant rat serum. The addition of 3 mug of human fH/ml permitted survival of the wild-type strain in up to 60% infant rat serum, whereas >/=33 mug of human fH/ml was required to rescue the DeltafHbp DeltaNspA mutant. The ability of meningococci lacking expression of fHbp and NspA to cause invasive disease in human fH transgenic rats and to survive in wild-type infant rat serum supplemented with human fH indicates an additional human fH-dependent mechanism of evasion of innate immunity.

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RGD Object Information
RGD ID: 7364945
Created: 2013-10-14
Species: All species
Last Modified: 2013-10-14
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.