Review 2: "SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade"

RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

This report extends a recent publication from the same group (in JMCB, Dec 2020, vol 12, issue 12) in which the group demonstrated that CoV-2 spike protein binds to bacterial LPS, causing a strong proinflammatory response, both in mice and in humans with COVID-19. The current submission contains a great deal of additional information describing the binding of LPS to the spike protein, together with the subsequent inflammatory responses in mice. It appears that the S2 subunit of spike protein is the most proinflammatory product. Such information may have important relevance to COVID-19 infection in humans. The authors have extended their evidence related to the interaction between COVID-19 and LPS. The data presented suggest new studies that should be pursued in humans.

While I believe this report should promote further studies of spike protein binding to LPS and a strong inflammatory response, the authors need to be cautious in their generalizations. In the past five years, patients with “infectious sepsis” were studied with novel inhibitors that prevent LPS from reacting with TLR4, resulting in a strong inflammatory response. Two large international clinical trials were stopped after 6 months, due to lack of efficacy of either eritoran or TAK242, which block TLR4 binding to LPS. It is true that the authors have shown LPS presence in some COVID-19 patients, but these failed clinical trials indicate that caution should be used in the studies. Certainly, the information about physical-chemical interactions of spike protein with LPS is important, since some COVID-19 patients had endotoxemia. The detailed data on spike protein interactions with LPS should spur new studies in COVID-19 humans.