Transferrin Binding Protein B and Transferrin Binding Protein A2 Expand the Transferrin Recognition Range of Histophilus somni

Abstract

The bacterial bipartite transferrin receptor is an iron acquisition system that several important human and animal pathogens require for survival. It consists of the TonB-dependent transporter transferrin binding protein A (TbpA) and the surface lipoprotein transferrin binding protein B (TbpB). Curiously, the Tbps are only found in host-specific pathogens and are themselves host specific, meaning that they will bind to the transferrin of their host species but not to the transferrins of other animal species. While this phenomenon has long been established, neither the steps in the evolutionary process that led to this exquisite adaptation for the host nor the steps that could alter it are known. We sought to gain insight into these processes by studying Tbp specificity in Histophilus somni, an economically important pathogen of cattle. A past study showed that whole cells of H. somni specifically bind bovine transferrin but not transferrin from sheep and goats, two bovids whose transferrins share 93% amino acid sequence identity with bovine transferrin. To our surprise, we found that H. somni can use sheep and goat transferrins as iron sources for growth and that HsTbpB, but not HsTbpA, has detectable affinity for sheep and goat transferrins. Furthermore, a third transferrin binding protein found in H. somni, HsTbpA2, also showed affinity for sheep and goat transferrins. Our results suggest that H. somni TbpB and TbpA2 may contribute to broadening the host transferrin recognition range of H. somni. IMPORTANCE Host-restricted pathogens infect a single host species or a narrow range of host species. Histophilus somni, a pathogen that incurs severe economic losses for the cattle industry, infects cattle, sheep, and goats but not other mammals. The transferrin binding proteins, TbpA and TbpB, are thought to be a key iron acquisition system in H. somni; however, despite their importance, H. somni TbpA and TbpB were previously shown to be cattle transferrin specific. In our study, we find that H. somni TbpB and another little-studied Tbp, TbpA2, bind sheep and goat transferrins, as well as bovine transferrin. Our results suggest that TbpB and TbpA2 may allow for host range expansion and provide a mechanism for how host specificity in Tbp-encoding pathogens can be altered.

A zero-sum game or an interactive frame? Iron competition between bacteria and humans in infection war

“…In a few cases, TBPs and LBPs of bacteria can directly bind host transferrin or lactoferrin to plunder Fe 3+ into the bacterial cytoplasm under iron stress. The process is also powered by the TonB system [30,31] …”

“…The process is also powered by the TonB system. [30,31] Systems for acquisition of heme and ferrous iron (Fe 2+ ) More than 80% of the iron in the human body is in heme. Therefore, when bacteria infect the human body, obtaining heme is an important strategy for bacteria to uptake iron, including via direct heme transport systems, indirect heme transport systems, and the iron reductase system.…”

Whole-genome sequencing of Histophilus somni strains isolated in Russia

“…One of the mechanisms of iron utilization required by bacterial pathogens is the direct binding of host transferrin by bacterial surface receptors [ 6 ]. The functioning of this mechanism is provided by two outer membrane proteins - transferrin-binding proteins A and B, encoded by the tbpA and tbpB genes, respectively.…”

“…Histophilus somni receptors bind bovine transferrin, which in part accounts for H. somni specificity to cattle [ 7 ]. Recent studies have found that H. somni is also capable of binding sheep and goat transferrins [ 6 ]. Analysis of the complete genomes of H. somni , provided in the GenBank database, revealed that tbpA and tbpB were present in all sequences.…”

The surface lipoproteins of gram-negative bacteria: Protectors and foragers in harsh environments

“…An exception to this can be found in Haemophilus somnus, which has been shown to possess two different systems for the acquisition of iron from transferrins of multiple species (53). It has been recently proposed that two receptors HsTbpA and HsTbpA2 work in conjunction with an SLP, HsTbpB, to broaden the transferrin recognition range to include transferrins from ovine, bovine, and caprine allowing for H. somni infection in these species (54).…”