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.
Enterococcus faecalis is a commensal Gram-positive pathogen found in the intestines of mammals and is also a leading cause of severe infections occurring mainly among antibiotic-treated dysbiotic hospitalized patients. Like most intestinal bacteria, E. faecalis does not synthesize heme (in this report, heme refers to iron protoporphyrin IX regardless of the iron redox state). Nevertheless, environmental heme can improve E. faecalis fitness by activating respiration metabolism and a catalase that limits hydrogen peroxide stress. Since free heme also generates toxicity, its intracellular levels need to be strictly controlled. Here, we describe a unique transcriptional regulator, FhtR (named FhtR for faecalis heme transport regulator), which manages heme homeostasis by controlling an HrtBA-like efflux pump (named HrtBAEf for the HrtBA from E. faecalis). We show that FhtR, by managing intracellular heme concentration, regulates the functional expression of the heme-dependent catalase A (KatA), thus participating in heme detoxification. The biochemical features of FhtR binding to DNA, and its interaction with heme that induces efflux, are characterized. The FhtR-HrtBAEf system is shown to be relevant in a mouse intestinal model. We further show that FhtR senses heme from blood and hemoglobin but also from crossfeeding by Escherichia coli. These findings bring to light the central role of heme sensing by FhtR in response to heme fluctuations within the gastrointestinal tract, which allow this pathogen to limit heme toxicity while ensuring expression of an oxidative defense system. IMPORTANCE Enterococcus faecalis, a normal and harmless colonizer of the human intestinal flora can cause severe infectious diseases in immunocompromised patients, particularly those that have been heavily treated with antibiotics. Therefore, it is important to understand the factors that promote its resistance and its virulence. E. faecalis, which cannot synthesize heme, an essential but toxic metabolite, needs to scavenge this molecule from the host to respire and fight stress generated by oxidants. Here, we report a new mechanism used by E. faecalis to sense heme and trigger the synthesis of a heme efflux pump that balances the amount of heme inside the bacteria. We show in a mouse model that E. faecalis uses this mechanisms within the gastrointestinal tract.
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