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

Abstract

While developing vaccines targeting surface transferrin receptor proteins in Gram-negative pathogens of humans and food production animals, the common features derived from their evolutionary origins has provided us with insights on how improvements could be implemented in the various stages of research and vaccine development. These pathogens are adapted to live exclusively on the mucosal surfaces of the upper respiratory or genitourinary tract of their host and rely on their receptors to acquire iron from transferrin for survival, indicating that there likely are common mechanisms for delivering transferrin to the mucosal surfaces that should be explored. The modern-day receptors are derived from those present in bacteria that lived over 320 million years ago. The pathogens represent the most host adapted members of their bacterial lineages and may possess factors that enable them to have strong association with the mucosal epithelial cells, thus likely reside in a different niche than the commensal members of the bacterial lineage. The bacterial pathogens normally lead a commensal lifestyle which presents challenges for development of relevant infection models as most infection models either exclude the early stages of colonization or subsequent disease development, and the immune mechanisms at the mucosal surface that would prevent disease are not evident. Development of infection models emulating natural horizontal disease transmission are also lacking. Our aim is to share our insights from the study of pathogens of humans and food production animals with individuals involved in vaccine development, maintaining health or regulation of products in the human and animal health sectors.

Keywords: TBDT; evolution; host specifity; iron acquisition systems; microbioal community; transferrin; vaccine.

Figure 1

The evolution of iron acquisition systems in bacteria and multicellular animals. The timeline for appearance of microbial communities (stromatolite), proteins involved in acquisition of iron by Gram-negative bacteria (TBDTs, Tf receptors, Lf receptors) and in multicellular animals is illustrated in the left panel. Red arrows indicate evolutionary ancestors. The process for capture and iron removal from the two-component receptor is illustrated in the right panel.

Figure 2

Does transferrin availability vary in the upper respiratory tract for pathogens and commensals? The concentration of transferrin (Tf) would be expected to be highest in the subepithelial space and decrease the further away from the epithelial cell layer the biofilm extends. In contrast, the concentration of iron from environmental sources would be highest at the air-liquid interface. 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. H. parahaemolyticus strains possess Tf receptors whereas only some strains of H. haemolyticus do. However, the demonstrated competition between H. haemolyticus and H. influenzae (Atto et al., 2021) and similarity in adhesins (Singh et al., 2013) suggests that at least some strains of H. haemolyticus occupy the same niche. All strains of Glaesserella parasuis possess Tf receptors, with more virulent serovars possessing genes involved in binding to the mucosal surface. (Created with Biorender.com).