Zinc Piracy as a Mechanism of Neisseria meningitidis for Evasion of Nutritional Immunity

Abstract

The outer membrane of Gram-negative bacteria functions as a permeability barrier that protects these bacteria against harmful compounds in the environment. Most nutrients pass the outer membrane by passive diffusion via pore-forming proteins known as porins. However, diffusion can only satisfy the growth requirements if the extracellular concentration of the nutrients is high. In the vertebrate host, the sequestration of essential nutrient metals is an important defense mechanism that limits the growth of invading pathogens, a process known as “nutritional immunity.” The acquisition of scarce nutrients from the environment is mediated by receptors in the outer membrane in an energy-requiring process. Most characterized receptors are involved in the acquisition of iron. In this study, we characterized a hitherto unknown receptor from Neisseria meningitidis, a causative agent of sepsis and meningitis. Expression of this receptor, designated CbpA, is induced when the bacteria are grown under zinc limitation. We demonstrate that CbpA functions as a receptor for calprotectin, a protein that is massively produced by neutrophils and other cells and that has been shown to limit bacterial growth by chelating Zn2+ and Mn2+ ions. Expression of CbpA enables N. meningitidis to survive and propagate in the presence of calprotectin and to use calprotectin as a zinc source. Besides CbpA, also the TonB protein, which couples energy of the proton gradient across the inner membrane to receptor-mediated transport across the outer membrane, is required for the process. CbpA was found to be expressed in all N. meningitidis strains examined, consistent with a vital role for the protein when the bacteria reside in the host. Together, our results demonstrate that N. meningitidis is able to subvert an important defense mechanism of the human host and to utilize calprotectin to promote its growth.

Neisseria gonorrhoeae Evades Calprotectin-Mediated Nutritional Immunity and Survives Neutrophil Extracellular Traps by Production of TdfH

“…Instead, our studies demonstrate that gonococcal TdfH binds to CP and enables Zn acquisition. These findings are consistent with a report that CbpA, the meningococcal TdfH homologue, is required for N. meningitidis growth in the presence of CP and for CP binding (35). The present report extends these findings to N. gonorrhoeae and furthermore demonstrates that TdfH contributes to intracellular Zn accumulation in the presence and absence of CP.…”

“…Since both TdfH and TdfJ contribute to growth under Zn-restricted conditions and the meningococcal homologue of TdfH binds to the host Zn-binding protein calprotectin (CP) (34,35), we tested whether these putative transporters are required for the assimilation of Zn from CP. We tested the ability of wild-type or tdfH and tdfJ mutant strains to grow in the presence of CP supplemented with Zn under Zn-restricted conditions.…”

“…Our Zn regulatory and growth data led us to hypothesize that TdfH, a TonB-dependent transporter, and TonB would contribute to Zn internalization by gonococci. While meningococcal CbpA was shown to contribute to growth under Zn limitation, Zn accumulation inside N. meningitis cells was not directly demonstrated (35). To address whether N. gonorrhoeae accumulated intracellular Zn in a TdfH-dependent manner, we grew the wild-type or tdfH and tonB mutants under Zn-replete and Zn-depleted conditions and measured the amount of internalized Zn using inductively coupled plasma optical emission spectrometry (ICP-OES).…”

“…The Neisseria meningitidis homologues of these proteins, CbpA and ZnuD, respectively, have been shown to contribute to growth under Zn-limited conditions (34,35). CbpA was demonstrated to bind to CP and furthermore to enable growth under Zn limitation.…”

Zinc in Infection and Inflammation

“…N.meningitidis effectively undermines an important defense mechanism used by the host and utilized it in its favor [94]. Yersinia pestis utilizes siderophore yersiniabactin (Ybt) as a zincophore and ZnuABC, which are the high -affinity zinc transporter found in bacteria and fungi, to acquire zinc and develop a lethal infection in a septicemic plague mouse model [95].…”