A Novel Heme Transporter from the Energy Coupling Factor Family Is Vital for Group A Streptococcus Colonization and Infections

Abstract

Group A streptococcus (GAS) produces millions of infections worldwide, including mild mucosal infections, postinfection sequelae, and life-threatening invasive diseases. During infection, GAS readily acquires nutritional iron from host heme and hemoproteins. Here, we identified a new heme importer, named SiaFGH, and investigated its role in GAS pathophysiology. The SiaFGH proteins belong to a group of transporters with an unknown ligand from the recently described family of energy coupling factors (ECFs). A siaFGH deletion mutant exhibited high streptonigrin resistance compared to the parental strain, suggesting that iron ions or an iron complex is the likely ligand. Iron uptake and inductively coupled plasma mass spectrometry (ICP-MS) studies showed that the loss of siaFGH did not impact GAS import of ferric or ferrous iron, but the mutant was impaired in using hemoglobin iron for growth. Analysis of cells growing on hemoglobin iron revealed a substantial decrease in the cellular heme content in the mutant compared to the complemented strain. The induction of the siaFGH genes in trans resulted in the induction of heme uptake. The siaFGH mutant exhibited a significant impairment in murine models of mucosal colonization and systemic infection. Together, the data show that SiaFGH is a new type of heme importer that is key for GAS use of host hemoproteins and that this system is imperative for bacterial colonization and invasive infection. IMPORTANCE ECF systems are new transporters that take up various vitamins, cobalt, or nickel with a high affinity. Here, we establish the GAS SiaFGH proteins as a new ECF module that imports heme and demonstrate its importance in virulence. SiaFGH is the first heme ECF system described in bacteria. We identified homologous systems in the genomes of related pathogens from the Firmicutes phylum. Notably, GAS and other pathogens that use a SiaFGH-type importer rely on host hemoproteins for a source of iron during infection. Hence, recognizing the function of this noncanonical ABC transporter in heme acquisition and the critical role that it plays in disease has broad implications.

Insights into the bilayer-mediated toppling mechanism of a folate-specific ECF transporter by cryo-EM

“…Moreover, it lays the foundations to further explore the influence of membrane deformations on the transport cycle in ECF transporter complexes within a near native environment. ECF transporter complexes have recently gained renewed attention with the identification of a novel haem transporter belonging to the family of ECF-type ABC transporters (34)(35)(36). As various ECF transporters complexes are encoded in the genome of various human pathogens but not in humans (37,38), it makes them attractive targets for newly designed antimicrobial compounds, for which this work represents a stepping stone towards studying their means of action on a structural level.…”

Genome‐wide identification of Streptococcus sanguinis fitness genes in human serum and discovery of potential selective drug targets

“…We also characterized a mutant lacking the common components of an ECF transport system. As far as we are aware, this is only the second such system to have been identified as important for virulence, with the first being an apparent heme transporter in S. pyogenes (Chatterjee et al, 2020). This is also the first ECF system shown to be important for IE virulence in any bacterium.…”

The Regulatory Protein ChuP Connects Heme and Siderophore-Mediated Iron Acquisition Systems Required for Chromobacterium violaceum Virulence

“…Several investigations have found that genes encoding heme uptake systems are upregulated in vivo ( Cook et al., 2019 ; Rivera-Chávez and Mekalanos, 2019 ) and required for colonization and virulence of many bacterial pathogens ( Skaar et al., 2004 ; Si et al., 2017 ; Abdelhamed et al., 2018 ; Cook et al., 2019 ; Rivera-Chávez and Mekalanos, 2019 ; Chatterjee et al., 2020 ). In many cases, bacteria explore multiple host iron sources, employing both heme and siderophore-based iron acquisition systems ( Contreras et al., 2014 ; Huang and Wilks, 2017 ).…”