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  1. Evaluation Summary:

    In their study, Rivera-Luogo et al. investigate the main role of respiration in Listeria monocytogenes pathogenicity, whether it is more important for redox balance control (ratio of balance NAD+/NADH) or generation of proton motive force. Drawing on results from an elegant heterologous NOX system supporting regeneration of NAD without producing proton motive force, the authors propose that NAD regeneration, i.e. redox balance, is more important for Listeria than proton motive force as a result of respiration. This is clearly a new way of perceiving respiration that should be of interest broadly to the microbiology community and broader readership.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    Through elegant experimentation (heterologous NOX expression), the authors show that maintaining redox balance is essential for virulence of the pathogen. The experiments are well controlled, and I have only one suggestion regarding the conclusions. Overall, the study represents an important contribution to understanding pathogen metabolism during infection.

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  3. Reviewer #2 (Public Review):

    The study by Rivera-Luogo et al. focuses on the role of respiration in Listeria monocytogenes energetic metabolism and multiplication. In a previous work, the authors had identified two respiratory pathways in L. monocytogenes and here they aim at assessing the contribution of each of them in various phenotypes, both in lab culture and host tissues.

    Respiration provides organisms with two benefits: regeneration of NAD and production of proton motive force (pmf). The former is necessary for oxido-reductases activity and the later powers ATP synthase as well as numerous other processes (transport, secretion, motility ...), as listed by the authors (line 78). Here the authors aim at sorting out which one on the two, redox balance control or pmf production, matters the most for Listeria to multiply. This is both an original and interesting objective, which the authors answer to by using a heterologous NOX system allowing to regenerate NAD, without producing pmf. The provocative outcome is that NAD regeneration, and not pmf production, is what Listeria makes the most out of respiration. This is clearly a new way of perceiving respiration but such a claim needs additional support and reinforced experimental evidences.Experiments are well carried out. Results are convincing. Effects of mutations are analyzed using an impressive battery of tests (phenotype, growth, metabolic products analysis, plaque, macrophage and mouse experiments).

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  4. Reviewer #3 (Public Review):

    The authors show that poor growth, defective intracellular survival, and the reduced ability to expand in tissue of a Listeria strain deficient in aerobic and ferric respiration is partially restored by the heterologous expression of an NADH oxidase (NOX) from Lactobacillus. The investigators conclude that the main role of respiration in Listeria pathogenesis is related to its capacity to balance redox. This is particularly true in spleen tissue. However, the recovery of virulence-associated with the heterologous expression of NOX is more modest in liver, demonstrating that the critical role played by aerobic and ferric respiration in maintaining redox balance is probably tissue specific. Thus, I recommend the claims about the main role of respiration being associated with redox balance be softened in the abstract and elsewhere in the paper. The authors should consider roles for respiration other than redox balance. If the role of the ETC were mainly to maintain redox balance, then the expression of NDH-II, which is uncoupled for proton translocation, would be enough. However, Listeria, as many other organisms, seems to express a proton-couple NDH-I as well. In addition to using O2 and Fe3+, Listeria may utilize other terminal electron acceptors such as nitrate, DMSO or TMAO. This might be especially important in liver parenchyma that receives oxygen-depleted blood from the intestine.

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