PPE37 Is Essential for Heme-Iron Acquisition (HIA), and a Defective PPE37 in BCG Prevents HIA.

, one of the world's leading causes of death, must acquire nutrients, such as iron, from the host to multiply and cause disease. Iron is an essential metal and possesses two different systems to acquire iron from its environment: siderophore-mediated iron acquisition (SMIA) and heme-iron acquisition (HIA), involving uptake and degradation of heme to release ferrous iron. We have discovered that BCG, the tuberculosis vaccine strain, is severely deficient in HIA, and we exploited this phenotypic difference between BCG and to identify genes involved in HIA by complementing BCG's defect with a fosmid library. We identified , an iron-regulated PPE family gene, as being essential for HIA. BCG complemented with exhibits HIA as efficient as that of , achieving robust growth with <0.2 µM hemin. Conversely, deletion of from results in a strain severely attenuated in HIA, with a phenotype nearly identical to that of BCG, requiring a 200-fold higher concentration of hemin to achieve growth equivalent to that of its parental strain. A nine-amino-acid deletion near the N terminus of BCG PPE37 (amino acids 31 to 39 of the PPE37 protein) underlies BCG's profound defect in HIA. Significant genetic variability exists in genes across different strains, with more than 60% of sequences from completely sequenced genomes having mutations that result in altered PPE37 proteins; furthermore, these altered PPE37 proteins are nonfunctional in HIA. Our findings should allow delineation of the relative roles of HIA and SMIA in pathogenesis.