Are lactoferrin receptors in Gram-negative bacteria viable vaccine targets? Clement Chan . Vahid F. Andisi . Dixon Ng . Nick Ostan . Warren K. Yunker . Anthony B. Schryvers Received: 2 January 2018 / Accepted: 28 April 2018 / Published online: 16 May 2018 Ó Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract A number of important Gram-negative pathogens that reside exclusively in the upper respi- ratory 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 vaccina- tion 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 Mo- raxella 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 lipopro- tein targets, thus this should not exclude lactoferrin binding protein B as a target. Keywords Lactoferrin-binding protein Á Transferrin binding protein Á Vaccine Á Antimicrobial peptides Introduction A number of Gram-negative bacterial pathogens responsible for important diseases in humans and food production animals reside exclusively in the upper respiratory or genitourinary tract of their vertebrate host and rely on surface receptors capable of specifically binding the host iron-binding glyco- proteins transferrin (Tf) or lactoferrin (Lf) to acquire iron for growth (Table 1). The typical bipartite Tf receptor is comprised of a surface anchored lipopro- tein, TbpB (transferrin binding protein B), responsible for initial capture of Tf and delivering it to the integral outer membrane protein TbpA (transferrin binding protein A), which extracts iron and transports it across the outer membrane (Morgenthau et al. 2013) (Fig. 1). The energy for the outer membrane transport process is derived from interaction with the TonB protein, a C. Chan Á V. F. Andisi Á D. Ng Á A. B. Schryvers (&) Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada e-mail: schryver@ucalgary.ca N. Ostan Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada W. K. Yunker Department of Surgery, University of Calgary, Calgary, AB T2N 4N1, Canada 123 Biometals (2018) 31:381–398 https://doi.org/10.1007/s10534-018-0105-7