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posted by martyb on Wednesday December 02 2020, @06:46PM   Printer-friendly
from the cell-mates'-suicide-pact dept.

Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes:

(From the abstract):

COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by pyroptosis, apoptosis, and necroptosis (PANoptosis). Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD–mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.

View Abstract

TNF-α: Tumor necrosis factor
IFN-γ: Interferon gamma
JAK: Janus kinase
STAT1: transcription 1
IRF1: Interferon regulatory factor 1

Article status is AIP (accepted, peer reviewed articles that are not yet assigned to volumes/issues, but are citable using DOI).

Full pre-print of the article is available for free from the abstract.

Journal Reference:
Rajendra Karki, Bhesh Raj Sharma, Shraddha Tuladhar1, et al. Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes, ScienceDirect, (DOI: 10.1016/j.cell.2020.11.025)


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  • (Score: 3, Insightful) by Fluffeh on Wednesday December 02 2020, @09:51PM (4 children)

    by Fluffeh (954) Subscriber Badge on Wednesday December 02 2020, @09:51PM (#1083397) Journal

    I have zero idea what even this summary is talking about, so lets do a quick barter. You medical nerds keep at it and get a good handle on this so we can all go back to a normal life, while us techie/physicie/otherie nerds keep doing our bit to make the world keep turning. Check in again soon!

    • (Score: 0) by Anonymous Coward on Wednesday December 02 2020, @11:28PM

      by Anonymous Coward on Wednesday December 02 2020, @11:28PM (#1083428)

      AFAICT, it's all about eliminating freedom of speech for cytokines, since they are so inflammatory. This may save the lives of mice and men.

      ---
      Hopefully everyone will be breathing easier in 2021.

    • (Score: 3, Informative) by Taibhsear on Thursday December 03 2020, @09:29AM (2 children)

      by Taibhsear (1464) on Thursday December 03 2020, @09:29AM (#1083559)

      Medical nerd checking in.
      Summary in laymen's terms: Covid causes immune cells to make too many biochemicals that cause inflammation. This causes cells to die if those biochemicals are these two specific ones at the same time. So the scientists created antibodies to stop those biochemicals from working and it stopped the cells from dying. They hope to use these antibodies, or some other drug that has similar effect, in covid patients to stop them from dying.

      • (Score: 0) by Anonymous Coward on Thursday December 03 2020, @01:37PM

        by Anonymous Coward on Thursday December 03 2020, @01:37PM (#1083602)

        They say they used "around 2 x 10^4 PFU" of virus. Why does Figure 7b in their paper look exactly like the mortality curve as seen for the controls when using 10^ 5 PFU, and similar to anti-TNF/IFN when using 10^4 PFU?
          https://www.nature.com/articles/s41586-020-2943-z [nature.com]

      • (Score: 2) by Fluffeh on Monday December 07 2020, @08:41PM

        by Fluffeh (954) Subscriber Badge on Monday December 07 2020, @08:41PM (#1085000) Journal

        Thanks!

        That's completely straightforward and simple and interesting!

  • (Score: 2) by Snospar on Thursday December 03 2020, @09:13AM

    by Snospar (5366) Subscriber Badge on Thursday December 03 2020, @09:13AM (#1083555)

    I'm afraid you have "hemophagocytic lymphohistiocytosis"-expialidocious, but you've won ScrabbleTM

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