Acclimation to Nutritional Immunity and Metal Intoxication Requires Zinc, Manganese, and Copper Homeostasis in the Pathogenic Neisseriae

Abstract

Neisseria gonorrhoeae and Neisseria meningitidis are human-specific pathogens in the Neisseriaceae family that can cause devastating diseases. Although both species inhabit mucosal surfaces, they cause dramatically different diseases. Despite this, they have evolved similar mechanisms to survive and thrive in a metal-restricted host. The human host restricts, or overloads, the bacterial metal nutrient supply within host cell niches to limit pathogenesis and disease progression. Thus, the pathogenic Neisseria require appropriate metal homeostasis mechanisms to acclimate to such a hostile and ever-changing host environment. This review discusses the mechanisms by which the host allocates and alters zinc, manganese, and copper levels and the ability of the pathogenic Neisseria to sense and respond to such alterations. This review will also discuss integrated metal homeostasis in N. gonorrhoeae and the significance of investigating metal interplay.

Keywords: Neisseria gonorrhoeae; Neisseria meningitidis; copper; integrated metal homeostasis; manganese; metal intoxication; nutritional immunity; zinc.

Figure 1

Neisseria gonorrhoeae and Neisseria meningitidis experience host-driven nutritional immunity and metal intoxication. The host exerts nutritional immunity on the pathogenic Neisseriae by exposing the bacteria to calprotectin and S100A7. Calprotectin sequesters both zinc (Zn) and manganese (Mn) from the extracellular environment to limit Zn and Mn availability. N. gonorrhoeae in turn expresses TdfH, which has been shown to strip Zn from calprotectin and subsequently import the ion. TdfH is able bind Mn-loaded calprotectin suggesting a role for Mn import across the outer membrane. TdfH is referred to as CbpA in N. meningitidis. S100A7 also sequesters Zn from the extracellular environment. Gonococcal TdfJ binds S100A7 to pirate and import the Zn payload. Lipooligosaccharide (LOS) is shown in the outer membrane for reference. Once in the periplasm, Zn and Mn are chaperoned by the periplasmic binding protein, ZnuA (MntC) to the permease in the cytoplasmic membrane, ZnuB (MntB). Transport across the cytoplasmic membrane is energized by the ATPase, ZnuC (MntA). The host also exerts metal intoxication, specifically copper (Cu) intoxication on N. gonorrhoeae and Mn intoxication in N. meningitidis through unknown mechanisms. In response, these efflux proteins export excess cytoplasmic Cu or Mn from to the periplasmic space.

Figure 2

The genome of Neisseria gonorrhoeae and Neisseria meningitidis encodes the znuCBA/mntABC operon. The znuCBA operon in N. gonorrhoeae is indicated by the locus numbers NGO_0170, NGO_0169, and NGO_0168. The operon is named in order of predicted transcriptional direction. NGO_0170 encodes an ATPase named ZnuC which provides energy from zinc (Zn) transport into the cytoplasm. NGO_0169 encodes a permease named ZnuB which serves as a channel for transporting Zn through the cytoplasmic membrane. NGO_0160 encodes ZnuA, which chaperones Zn from the periplasm and delivers it to ZnuB. A simplified image of the znuCBA gene products is depicted. The gene products of the NGO_0170, NGO_0169, and NGO_0168 have been implicated in both Zn and manganese (Mn) binding and transport. Thus, znuCBA is also referred to as mntABC in reference to Mn transport. znuCBA and mntABC are two different names to identify the same genetic sequence indicated by the locus numbers NGO_0170, NGO_0169, and NGO_0168. The znuCBA operon including the intergenic regions in N. gonorrhoeae is 92% identical to that in N. meningitidis (Accession number AE002098.2), in which znuCBA is also responsible for Zn and Mn import.