Abstract
Staphylococcus aureus is an important human pathogen commonly infecting nearly every host tissue. The ability of S. aureus to resist innate immunity is critical to its success as a pathogen, including its propensity to grow in the presence of host nitric oxide (NO·). Upon exogenous NO· exposure, S. aureus immediately excretes copious amounts of L-lactate to maintain redox balance. However, after prolonged NO·-exposure, S. aureus reassimilates L-lactate specifically and in this work, we identify the enzyme responsible for this L-lactate-consumption as a L-lactate-quinone oxidoreductase (Lqo, SACOL2623). Originally annotated as Mqo2 and thought to oxidize malate, we show that this enzyme exhibits no affinity for malate but reacts specifically with L-lactate (KM = ∼330 μM). In addition to its requirement for reassimilation of L-lactate during NO·-stress, Lqo is also critical to respiratory growth on L-lactate as a sole carbon source. Moreover, Δlqo mutants exhibit attenuation in a murine model of sepsis, particularly in their ability to cause myocarditis. Interestingly, this cardiac-specific attenuation is completely abrogated in mice unable to synthesize inflammatory NO· (iNOS−/−). We demonstrate that S. aureus NO·-resistance is highly dependent on the availability of a glycolytic carbon sources. However, S. aureus can utilize the combination of peptides and L-lactate as carbon sources during NO·-stress in an Lqo-dependent fashion. Murine cardiac tissue has markedly high levels of L-lactate in comparison to renal or hepatic tissue consistent with the NO·-dependent requirement for Lqo in S. aureus myocarditis. Thus, Lqo provides S. aureus with yet another means of replicating in the presence of host NO·.
Highlights
Staphylococcus aureus is a pathogen of tremendous importance to human health (Diekema et al, 2001)
STAPHYLOCOCCUS AUREUS HARBORS AN UNIDENTIFIED L-LACTATE CATABOLIC ENZYME Upon exposure to exogenous NO·, S. aureus evokes fermentative metabolism to contend with the propensity of NO· to block respiration
We reasoned that reversal of the NAD-dependent lactate dehydrogenase 1 (Ldh1), Ldh2, or d-lactate dehydrogenase (Ddh) reactions was not responsible for the observed l-lactateconsumption, because: 1. the reverse reaction would be detrimental to the redox state of the cell and 2. both l-lactate and d-lactate would have been consumed since both reactions are reversible, enzymes for both l-lactate and d-lactate are highly expressed during NO·-stress (Richardson et al, 2006) and both enantiomers can support growth of WT S. aureus
Summary
Staphylococcus aureus is a pathogen of tremendous importance to human health (Diekema et al, 2001). While the most common disease presentations of S. aureus are skin/soft tissue infections, it is a frequent cause of sepsis, endocarditis, and osteomyelitis (Klevens et al, 2007). The latter conditions can be complicated by bacterial spread to cardiac muscle resulting in purulent abscesses or myocarditis (Wasi and Shuter, 2003). While pericarditis and myocarditis are not the most frequent disease presentations associated with S. aureus infections, this organism is the one of the most common causes of both life-threatening conditions (Wasi and Shuter, 2003; Mookadam et al, 2009). This pathogen has a propensity to colonize and thrive in nearly every sterile site in the body, even environments not conducive to supporting most other bacterial pathogens
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