Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
mBio. 2013 Oct 15;4(5):e00339-13. doi: 10.1128/mBio.00339-13.
The identification of "factor H binding protein (fHbp)-null" invasive meningococcal isolates and the realization that widespread use of fHbp-based vaccines could herald selection of such strains prompted us to characterize novel mechanisms of alternative pathway (AP) inhibition on meningococci. Of seven strains engineered to lack four known AP-inhibiting molecules, capsular polysaccharide, lipooligosaccharide sialic acid, fHbp, and neisserial surface protein A (quadruple mutants), four strains inhibited human AP-mediated C3 deposition. All four expressed the porin B2 (PorB2) molecule, and three strains belonged to the hypervirulent ST-11 lineage. Consistent with reduced C3 deposition, the rate of C3a generation by a PorB2 isolate was lower than that by a PorB3 strain. Allelic replacement of PorB3 with PorB2, in both encapsulated and unencapsulated strains, confirmed the role of PorB2 in AP inhibition. Expression of PorB2 increased resistance to complement-dependent killing relative to that seen in an isogenic PorB3-expressing strain. Adult rabbit and mouse APs were unimpeded on all mutants, and human fH inhibited nonhuman C3 deposition on PorB2-expressing strains, which provided functional evidence for human fH-dependent AP regulation by PorB2. Low-affinity binding of full-length human fH to quadruple mutants expressing PorB2 was demonstrated. fH-like protein 1 (FHL-1; contains fH domains 1 through 7) and fH domains 6 and 7 fused to IgG Fc bound to one PorB2-expressing quadruple mutant, which suggested that fH domains 6 and 7 may interact with PorB2. These results associate PorB2 expression with serum resistance and presage the appearance of fHbp-null and hypervirulent ST-11 isolates that may evade killing by fHbp-based vaccines.
The widespread use of antimeningococcal vaccines based on factor H (fH) binding protein (fHbp) is imminent. Meningococci that lack fHbp were recently isolated from persons with invasive disease, and these fHbp-null strains could spawn vaccine failure. Our report provides a molecular basis for an explanation of how fHbp-null strains may evade the host immune system. Meningococci possess several mechanisms to subvert killing by the alternative pathway (AP) of complement, including production of the fHbp and NspA fH binding proteins. Here we show that a meningococcal protein called porin B2 (PorB2) contributes to inhibition of the AP on the bacterial surface. A majority of the "fHbp-null" isolates identified, as well as all members of a "hypervirulent" lineage (called ST-11), express PorB2. Our findings highlight the potential for the emergence of fHbp-negative strains that are able to regulate the AP and may be associated with fHbp vaccine failure.
基于因子 H（fH）结合蛋白（fHbp）的抗脑膜炎球菌疫苗即将广泛应用。最近从患有侵袭性疾病的患者中分离到缺乏 fHbp 的脑膜炎球菌，这些 fHbp 缺失株可能导致疫苗失效。本报告为解释 fHbp 缺失株如何逃避宿主免疫系统提供了分子基础。脑膜炎球菌具有多种逃避补体替代途径（AP）杀伤的机制，包括产生 fHbp 和 NspA fH 结合蛋白。在这里，我们表明一种称为 PorB2（PorB2）的脑膜炎球菌蛋白有助于抑制细菌表面的 AP。大多数鉴定的“fHbp 缺失”分离株，以及称为 ST-11 的“高毒力”谱系的所有成员，都表达 PorB2。我们的研究结果强调了出现能够调节 AP 的 fHbp 阴性菌株的潜力，并且可能与 fHbp 疫苗失效有关。
