Referee 2's review:

The authors rightly identify the relationship between the hypoxic microenvironment and latency as an area with needs thorough and rigorous analysis. In an ambitious but well executed study the compare 3 in vitro hypoxia models, 3 mouse strains for in vivo experiments and dosR wild type and mutant strains. This results in a substantial amount of data but unfortunately compressing this information into the format of a single paper leads to 2 broad brush conclusions with little opportunity for the author (or reader) to dissect out the detail.

The authors make 2 key points, firstly that the dosR response is early, not sustained and not essential for virulence. Secondly they describe the enduring hypoxic response of the title. Although these conclusions are linked I feel that conflating the 2 aspects into a single manuscript has led to a lack of useful detail. Surely this would be best separated into 2 manuscripts? I feel that the data presented, by necessity, represents snap shots. I would like to see a fuller description of the dosR response with critical comparison between the various models, the points of difference between these models will inform our understanding of the significance of the dosR response.

Similarly, I feel that there is a substantial lack of detail missing in the EHR, is this really a response? What is the evidence that it is induced across the board. What sentinel genes define the EHR. I would suggest that at present we have an observed phenomenon but not a defined response.

The manuscript contains what to the reader appears as speculation, but I imagine this is founded on the data the authors have but have not presented in this manuscript. If this data is available this would make a useful and important contribution to our understanding of the hypoxic response.

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.