1. Immunology and Inflammation
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Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster

  1. Naren Srinivasan
  2. Oliver Gordon
  3. Susan Ahrens
  4. Anna Franz
  5. Safia Deddouche
  6. Probir Chakravarty
  7. David Phillips
  8. Ali A Yunus
  9. Michael K Rosen
  10. Rita S Valente
  11. Luis Teixeira
  12. Barry Thompson
  13. Marc S Dionne
  14. Will Wood
  15. Caetano Reis e Sousa  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. Voisin Consulting Life Sciences, United Kingdom
  3. University of Bristol, United Kingdom
  4. Sanofi Strasbourg, France
  5. University of Texas Southwestern Medical Center, United States
  6. Instituto Gulbenkian de Ciência, Portugal
  7. Imperial College London, United Kingdom
Research Article
  • Cited 29
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Cite this article as: eLife 2016;5:e19662 doi: 10.7554/eLife.19662

Abstract

Damage associated molecular patterns (DAMPs) are released by dead cells and can trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to Drosophila melanogaster triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless. Notably, this response requires signalling via Shark, the Drosophila orthologue of Syk, and Src42A, a Drosophila Src-family kinase, and is dependent on Nox activity. Thus, extracellular actin detection via a Src-family kinase-dependent cascade is an ancient means of detecting cell injury that precedes evolution of adaptive immunity.

Data availability

The following data sets were generated
    1. Chakravarty P
    2. Srinivasan N
    (2016) Genome-wide responses to extracellular actin
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE76150).

Article and author information

Author details

  1. Naren Srinivasan

    Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Oliver Gordon

    Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Susan Ahrens

    Voisin Consulting Life Sciences, Camberly, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna Franz

    Department of Biochemistry, Biomedical Sciences, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Safia Deddouche

    Open Innovation Access Platform, Sanofi Strasbourg, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Probir Chakravarty

    Bioinformatics, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. David Phillips

    Genomics-Equipment Park, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Ali A Yunus

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael K Rosen

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0775-7917
  10. Rita S Valente

    Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  11. Luis Teixeira

    Instituto Gulbenkian de Ciência, Oeiras, Portugal
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8326-6645
  12. Barry Thompson

    Epithelial Biology Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Marc S Dionne

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Will Wood

    Department of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Caetano Reis e Sousa

    Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Caetano@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7392-2119

Funding

Wellcome (WT106973MA)

  • Caetano Reis e Sousa

Wellcome (FC001136)

  • Caetano Reis e Sousa

Medical Research Council (FC001136)

  • Caetano Reis e Sousa

Cancer Research UK (FC001136)

  • Caetano Reis e Sousa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Zhijian J Chen, University of Texas Southwestern Medical School, United States

Publication history

  1. Received: July 14, 2016
  2. Accepted: November 14, 2016
  3. Accepted Manuscript published: November 22, 2016 (version 1)
  4. Version of Record published: December 5, 2016 (version 2)
  5. Version of Record updated: December 19, 2016 (version 3)

Copyright

© 2016, Srinivasan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

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    Reliable, robust, large-scale molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for monitoring the ongoing coronavirus disease 2019 (COVID-19) pandemic. We have developed a scalable analytical approach to detect viral proteins based on peptide immuno-affinity enrichment combined with liquid chromatography-mass spectrometry (LC-MS). This is a multiplexed strategy, based on targeted proteomics analysis and read-out by LC-MS, capable of precisely quantifying and confirming the presence of SARS-CoV-2 in phosphate-buffered saline (PBS) swab media from combined throat/nasopharynx/saliva samples. The results reveal that the levels of SARS-CoV-2 measured by LC-MS correlate well with their correspondingreal-time polymerase chain reaction (RT-PCR) read-out (r = 0.79). The analytical workflow shows similar turnaround times as regular RT-PCR instrumentation with a quantitative read-out of viral proteins corresponding to cycle thresholds (Ct) equivalents ranging from 21 to 34. Using RT-PCR as a reference, we demonstrate that the LC-MS-based method has 100% negative percent agreement (estimated specificity) and 95% positive percent agreement (estimated sensitivity) when analyzing clinical samples collected from asymptomatic individuals with a Ct within the limit of detection of the mass spectrometer (Ct ≤ 30). These results suggest that a scalable analytical method based on LC-MS has a place in future pandemic preparedness centers to complement current virus detection technologies.

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    Human serum albumin (HSA) is the frontline antioxidant protein in blood with established anti-inflammatory and anticoagulation functions. Here we report that COVID-19-induced oxidative stress inflicts structural damages to HSA and is linked with mortality outcome in critically ill patients. We recruited 39 patients who were followed up for a median of 12.5 days (1-35 days), among them 23 had died. Analyzing blood samples from patients and healthy individuals (n=11), we provide evidence that neutrophils are major sources of oxidative stress in blood and that hydrogen peroxide is highly accumulated in plasmas of non-survivors. We then analyzed electron paramagnetic resonance (EPR) spectra of spin labelled fatty acids (SLFA) bound with HSA in whole blood of control, survivor, and non-survivor subjects (n=10-11). Non-survivor' HSA showed dramatically reduced protein packing order parameter, faster SLFA correlational rotational time, and smaller S/W ratio (strong-binding/weak-binding sites within HSA), all reflecting remarkably fluid protein microenvironments. Following loading/unloading of 16-DSA we show that transport function of HSA maybe impaired in severe patients. Stratified at the means, Kaplan–Meier survival analysis indicated that lower values of S/W ratio and accumulated H2O2 in plasma significantly predicted in-hospital mortality (S/W≤0.15, 81.8% (18/22) vs. S/W>0.15, 18.2% (4/22), p=0.023; plasma [H2O2]>8.6 mM, 65.2% (15/23) vs. 34.8% (8/23), p=0.043). When we combined these two parameters as the ratio ((S/W)/[H2O2]) to derive a risk score, the resultant risk score lower than the mean (< 0.019) predicted mortality with high fidelity (95.5% (21/22) vs. 4.5% (1/22), logrank c2 = 12.1, p=4.9x10-4). The derived parameters may provide a surrogate marker to assess new candidates for COVID-19 treatments targeting HSA replacements and/or oxidative stress.