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

Abstract

c Neisseria gonorrhoeae successfully overcomes host strategies to limit essential nutrients, termed nutritional immunity, by production of TonB-dependent transporters (TdTs)-outer membrane proteins that facilitate nutrient transport in an energy-dependent manner. Four gonococcal TdTs facilitate utilization of iron or iron chelates from host-derived proteins, including transferrin (TbpA), lactoferrin (LbpA), and hemoglobin (HpuB), in addition to xenosiderophores from other bacteria (FetA). The roles of the remaining four uncharacterized TdTs (TdfF, TdfG, TdfH, and TdfJ) remain elusive. Regulatory data demonstrating that production of gonococcal TdfH and TdfJ are unresponsive to or upregulated under iron-replete conditions led us to evaluate the role of these TdTs in the acquisition of nutrients other than iron. In this study, we found that production of gonococcal TdfH is both Zn and Zur repressed. We also found that TdfH confers resistance to calprotectin, an immune effector protein highly produced in neutrophils that has antimicrobial activity due to its ability to sequester Zn and Mn. We found that TdfH directly binds calprotectin, which enables gonococcal Zn accumulation in a TdfH-dependent manner and enhances bacterial survival after exposure to neutrophil extracellular traps (NETs). These studies highlight Zn sequestration by calprotectin as a key functional arm of NET-mediated killing of gonococci. We demonstrate for the first time that N. gonorrhoeae exploits this host strategy in a novel defense mechanism, in which TdfH production hijacks and directly utilizes the host protein calprotectin as a zinc source and thereby evades nutritional immunity.

Dietary Manganese Promotes Staphylococcal Infection of the Heart

“…Neisseria species scavenge Zn from calprotectin in vitro, a process termed ‘zinc piracy’ (Jean et al, 2016; Stork et al, 2013). We assessed whether S. aureus can utilize calprotectin as a source for nutrient Mn by disc diffusion assay.…”

Transition metals at the host–pathogen interface: howNeisseriaexploit human metalloproteins for acquiring iron and zinc

“…In particular, Neisseria employ TBDTs to extract nutrient metal ions from human transferrin (hTF) [23], lactoferrin (hLF) [24], hemoglobin (hHb) [25], and calprotectin (hCP) [7,8]. Among the different TBDTs employed by pathogenic Neisseria for metal uptake, the iron acquisition systems are the most well characterized to date and are discussed in several extensive reviews [6,26–28].…”

“…hCP is a component of neutrophil extracellular traps (NETs), which form when neutrophils release proteins and chromatin to capture and kill microbes [81–82]. In this section, we consider the competition between the host and Neisseria for zinc by highlighting two recent studies reporting that Neisseria overcome zinc limitation by expressing TBDTs that capture Zn(II)-hCP and use this innate immune factor as a zinc source [7,8]. …”

“…N. gonorrhoeae have a homologous TBDT, hereafter called CbpA [8]. This transporter is also expressed under condition of Zn(II) limitation and allows N. gonorrhoeae to use Zn(II)-CP as a Zn(II) source.…”

“…In particular, several bacterial pathogens, including Neisseria spp. [6–8] and Staphylococcus spp. [9], capture host metalloproteins and use these biomolecules as sources of nutrient metals (Figure 1).…”