Bacillus anthracis Secretes Proteins That Mediate Heme Acquisition from Hemoglobin

Abstract

Acquisition of iron is necessary for the replication of nearly all bacterial pathogens; however, iron of vertebrate hosts is mostly sequestered by heme and bound to hemoglobin within red blood cells. In Bacillus anthracis, the spore-forming agent of anthrax, the mechanisms of iron scavenging from hemoglobin are unknown. We report here that B. anthracis secretes IsdX1 and IsdX2, two NEAT domain proteins, to remove heme from hemoglobin, thereby retrieving iron for bacterial growth. Unlike other Gram-positive bacteria, which rely on cell wall anchored Isd proteins for heme scavenging, B. anthracis seems to have also evolved NEAT domain proteins in the extracellular milieu and in the bacterial envelope to provide for the passage of heme. Iron is an essential nutrient used by almost all organisms. Bacterial pathogens must acquire iron in order to grow inside mammalian hosts. The host, however, limits the availability of free iron, thereby providing an effective defense strategy against infection. In response, bacteria have evolved clever ways to subvert host sequestration of iron. In this work, we report that the causative agent of anthrax disease, Bacillus anthracis, produces two proteins (IsdX1 and IsdX2), which act to acquire iron complexed to heme, a co-factor of host hemoproteins such as hemoglobin. This activity is dependent on a conserved protein domain found in many Gram-positive bacterial pathogens and is necessary for growth of B. anthracis in low-iron environments. Our results yield a greater understanding of the mechanisms used by bacterial pathogens to subvert host defenses and provide an avenue for the development of antiinfectives that aim to block these strategies.