title: Inhibition of the alternative pathway of nonhuman infant complement by porin B2 contributes to virulence of Neisseria meningitidis in the infant rat model.
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.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lewis
authors.forename: David M
authors.initials: DM
authors.lastname: Vu
authors.forename: Dan M
authors.initials: DM
authors.lastname: Granoff
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology; D001426:Bacterial Proteins / Q000502:physiology; D003176:Complement C3 / Q000378:metabolism; D050578:Complement C3-C5 Convertases, Alternative Pathway / Q000502:physiology*; D004195:Disease Models, Animal; D008589:Meningococcal Infections / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D009345:Neisseria meningitidis / Q000472:pathogenicity / Q000502:physiology*; D018272:Porins / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D044967:Serum / Q000382:microbiology; D014774:Virulence
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D003176:Complement C3; D018272:Porins; C484699:factor H-binding protein, Neisseria meningitidis; C057699:porin protein, Neisseria; D050578:Complement C3-C5 Convertases, Alternative Pathway