Are lactoferrin receptors in Gram-negative bacteria viable vaccine targets?

Abstract

A number of important Gram-negative pathogens that reside exclusively in the upper respiratory or genitourinary tract of their mammalian host rely on surface receptors that specifically bind host transferrin and lactoferrin as a source of iron for growth. The transferrin receptors have been targeted for vaccine development due to their critical role in acquiring iron during invasive infection and for survival on the mucosal surface. In this study, we focus on the lactoferrin receptors, determining their prevalence in pathogenic bacteria and comparing their prevalence in commensal Neisseria to other surface antigens targeted for vaccines; addressing the issue of a reservoir for vaccine escape and impact of vaccination on the microbiome. Since the selective release of the surface lipoprotein lactoferrin binding protein B by the NalP protease in Neisseria meningitidis argues against its utility as a vaccine target, we evaluated the release of outer membrane vesicles, and transferrin and lactoferrin binding in N. meningitidis and Moraxella catarrhalis. The results indicate that the presence of NalP reduces the binding of transferrin and lactoferrin by cells and native outer membrane vesicles, suggesting that NalP may impact all lipoprotein targets, thus this should not exclude lactoferrin binding protein B as a target.

Structural and functional insights into iron acquisition from lactoferrin and transferrin in Gram-negative bacterial pathogens

“…Previous studies have described or compared the Tf and Lf receptors in Neisseria and Moraxella species (Ostan et al 2021 ; Chan et al 2018 ) but there is little information comparing the repertoire of other iron acquisition proteins in these genera. FetA in Neisseria , CopB in M. catarrhalis and IrpA in M. bovis are reasonable homologues of each other (44% identity, Table 1 ) and their structural models preserve the overall canonical features.…”

Insights from targeting transferrin receptors to develop vaccines for pathogens of humans and food production animals

“…The Trumemba vaccine, which contains two lipidated factor H binding protein (fHbp) variants, is predicted to provide broad crossprotection from infection (Wang et al, 2011) and the absence offHbp in N. lactamica (Chan et al, 2018) indicates that it would not interfere with the natural protection it provides (Dale et al, 2022). However, the property of binding factor H is not unique to FhBP, strains lacking FhBP are still capable of inhibiting killing by the alternate complement pathway and invasive disease is possible without the ability to bind factor H (Lewis et al, 2013).…”

“…The availability of transferrin on the mucosal surface will likely be greater closer to the epithelial cells, thus commensal species that usually possess transferrin receptors such as N. lactamica, N. polysacchareae and N. cinerea may tend to grow more effectively if located closer to the mucosal surface. The commensal species that are variable in the possession of transferrin receptors such as N. sicca, N. mucosa, N. subflava and N. flavescens (Chan et al, 2018) clearly are capable of surviving without accessing transferrin, thus likely can use alternate environmental iron sources, including iron complexed by siderophores available within the microbial community, and their distribution within the biofilm may reflect that (Figure 2). Recent genomic studies indicate that the phylogeny of human-colonizing Neisseria species is more complex with seven additional species (Diallo et al, 2019), which could provide a more comprehensive picture of the relationship between iron acquisition mechanisms and biogeographic distribution.…”

“…The rationale for the proposed localization for Neisseria species is described in the text. The determination of the prevalence of receptors in Neisseria species has been described previously (Chan et al, 2018) and the same approach was used to evaluate the presence of receptors in the bacteria from the Pasteurellaceae. Access to Tf would not provide a tendency for H. parainfluenzae, A. aphrophilus and A. segnis to localize near the mucosal surface since they do not possess Tf receptors.…”

Stealthy microbes: How Neisseria gonorrhoeae hijacks bulwarked iron during infection

“…TDTs have been suggested as vaccine candidates because they are highly conserved, present in pathogenic Neisseria , and most are not subject to high-frequency antigenic variation ( Cornelissen et al., 2000 ; Cornelissen, 2008 ; Martinez-Martinez et al., 2011 ; Noinaj et al., 2012a ; Cash et al., 2015 ; Frandoloso et al., 2015 ; Martínez-Martínez et al., 2016 ; Martinez-Martinez et al., 2016 ; Rice et al., 2017 ; Chan et al., 2018 ; Russell et al., 2019 ). This review summarizes the important iron metalloproteins and tissue specialization involved in neisserial pathogenesis.…”