Abstract
Heme is essential for several cellular key functions but is also toxic. Whereas most bacterial pathogens utilize heme as a metabolic cofactor and iron source, the impact of host heme during bacterial infection remains elusive. The opportunist pathogen Streptococcus agalactiae does not synthesize heme but still uses it to activate a respiration metabolism. Concomitantly, heme toxicity is mainly controlled by the HrtBA efflux transporter. Here we investigate how S. agalactiae manages heme toxicity versus benefits in the living host. Using bioluminescent bacteria and heme-responsive reporters for in vivo imaging, we show that the capacity of S. agalactiae to overcome heme toxicity is required for successful infection, particularly in blood-rich organs. Host heme is simultaneously required, as visualized by a generalized infection defect of a respiration-negative mutant. In S. agalactiae, HrtBA expression responds to an intracellular heme signal via activation of the two-component system HssRS. A hssRS promoter-driven intracellular luminescent heme sensor was designed to identify host compartments that supply S. agalactiae with heme. S. agalactiae acquires heme in heart, kidneys, and liver, but not in the brain. We conclude that S. agalactiae response to heme is organ-dependent, and its efflux may be particularly relevant in late stages of infection.
Highlights
A distinct porphyrin efflux network called Pef, for porphyrin efflux, contributes to PPIX and heme homeostasis; this system responds to low PPIX/heme concentrations compared to HrtBA19
GBS depends on exogenous heme to activate a respiration chain that in vitro increases bacterial fitness and survival compared to fermentation metabolism, and is required for full virulence in a neonate rat model[20]
GBS HrtBA was needed to manage environmental heme toxicity, as an in-frame ΔhrtBA deletion mutant (Table S1, strain NEMJ18, Supplementary Methods) exhibited hemin hypersensitivity compared to the WT (Fig. 1B; note that hemin refers to the oxidized molecule as present extracellularly, and heme refers to the reduced form of the molecule)
Summary
GBS depends on exogenous heme to activate a respiration chain that in vitro increases bacterial fitness and survival compared to fermentation metabolism, and is required for full virulence in a neonate rat model[20]. In L. lactis and GBS, respiration gene expression appears to be constitutive, with a slight increase late in growth[20,22,25] This suggests that metabolism can switch efficiently from fermentation to respiration upon availability of the required cofactors in the local environment. Based on the heme sensor, we show that GBS responses to host heme in vivo occur preferentially in specific organs, which contrasts with overall GBS distribution in the host These experiments establish that GBS responses to exogenous heme are required for invasion and growth in the hostile host environment
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