Inhibition of the Alternative Pathway of Nonhuman Infant Complement by Porin B2 Contributes to Virulence of Neisseria meningitidis in the Infant Rat Model
Year: 2014
Type: article
Abstract: Neisseria meningitidis utilizes capsular polysaccharide, lipooligosaccharide (LOS) sialic acid, factor H binding protein (fHbp), and neisserial surface protein A (NspA) to regulate the alternative pathway (AP) of complement. Using meningococcal mutants that lacked all four of the above-mentioned molecules (quadruple mutants), we recently identified a role for PorB2 in attenuating the human AP; inhibition was mediated by human fH, a key downregulatory protein of the AP. Previous studies showed that fH downregulation of the AP via fHbp or NspA is specific for human fH. Here, we report that PorB2-expressing quadruple mutants also regulate the AP of baby rabbit and infant rat complement. Blocking a human fH binding region on PorB2 of the quadruple mutant of strain 4243 with a chimeric protein that comprised human fH domains 6 and 7 fused to murine IgG Fc enhanced AP-mediated baby rabbit C3 deposition, which provided evidence for an fH-dependent mechanism of nonhuman AP regulation by PorB2. Using isogenic mutants of strain H44/76 that differed only in their PorB molecules, we confirmed a role for PorB2 in resistance to killing by infant rat serum. The PorB2-expressing strain also caused higher levels of bacteremia in infant rats than its isogenic PorB3-expressing counterpart, thus providing a molecular basis for increased survival of PorB2 isolates in this model. These studies link PorB2 expression with infection of infant rats, which could inform the choice of meningococcal strains for use in animal models, and reveals, for the first time, that PorB2-expressing strains of N. meningitidis regulate the AP of baby rabbits and rats.
Source: Infection and Immunity
DOI: 10.1128/iai.01517-14
Institution: University of Massachusetts Chan Medical School
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1429770987, G159632509, IMMUNOLOGY OF INFECTION WITH NEISSERIA GONORRHOEAE, G205759073, Meningococcal and gonococcal vaccine to prevent invasive disease and carriage, Novel immunotherapeutics against multi-drug resistant Neisseria gonorrhoeae, Immunology of Infection with Neisseria gonorrhoeae, Immunology of Infection with Neisseria gonorrhoeae, G4237008422, An engineered meningococcal OMV vaccine for Africa against all capsular groups, CONSTRUCTION OF THE VACCINE CENTER, G5998862441, Complement Activation on Neisseria meningitidis, G7360200138, Innate and Adaptive Immunity in Experimental and Human Gonoccocal Infection
OpenAlex ID: W2144014919