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  1. Evaluation Summary:

    The soluble membrane attack complex (sMAC) is generated from complement activation and contains the complement proteins C5b, C6, C7, C8, C9 together with the regulatory proteins clusterin and vitronectin. Despite intense interest in sMAC, the mechanisms regulating its formation remain poorly understood. In this manuscript the authors demonstrate that sMAC is formed when complement is activated on bacteria that are resistant to killing by MAC pores.

    (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 #2 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The soluble membrane attack complex (sMAC) is generated from complement activation and contains the complement proteins C5b, C6, C7, C8, C9 together with the regulatory proteins clusterin and vitronectin. Despite intense interest in sMAC, the mechanisms regulating its formation remain poorly understood. In this comprehensive manuscript the authors demonstrate that sMAC is formed when complement is activated on bacteria that are resistant to killing by MAC pores.

    The major criticisms of this article relate to no mechanism of action for the proposed inducement of the generation of sMAC. For example, the O-antigen is claimed to be responsible for sMAC generation, however this does not mesh well with data on gram positive bacteria who also produce sMAC. The other major weakness related to the fact that no clinical context is provided by data. For example, it is concluded that sMAC may be used as a biomarker for these certain bacteria but there are no clinical correlations or investigations that would back up that claim and help make the findings here clinically useful.

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  3. Reviewer #2 (Public Review):

    This manuscript describes in some detail the strategies employed by certain bacteria to defend against lytic attack by the membrane attack complex (MAC) of complement. The major new finding is that during complement activation, these MAC-resistant bacteria are able to process and release considerable amounts of C5a as well as large amounts of a soluble form of the MAC (C5b-9) that has less C9 than the active form that promotes cell lysis. This process, possibly mediated by LPS O-Antigen on gram negative bacteria, results in inefficient turnover of much more C5 than when complement-sensitive bacteria are lysed by complement.

    The experimental methods and results are very well-described and the narrative presents a logical and measured approach to investigating an important problem. There is a voluminous amount of data, and it is somewhat difficult to follow each and every point, due to the back and forth between primary manuscript findings and supplementary data. However, the results are indeed compelling and the work has the potential to lead to new and more focused strategies for dealing with bacterial infections that are currently resistant to complement.

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