Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality

Dalit Talmi-Frank; Zeev Altboum; Inna Solomonov; Yael Udi; Diego Adhemar Jaitin; Mordehay Klepfish; Eyal David; Alina Zhuravlev; Hadas Keren-Shaul; Deborah R. Winter; Irit Gat-Viks; Michal Mandelboim; Tamar Ziv; Ido Amit; Irit Sagi

doi:10.1016/j.chom.2016.09.005

Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality

Dalit Talmi-Frank, Zeev Altboum, Inna Solomonov, Yael Udi, Diego Adhemar Jaitin, Mordehay Klepfish, Eyal David, Alina Zhuravlev, Hadas Keren-Shaul, Deborah R. Winter, Irit Gat-Viks, Michal Mandelboim, Tamar Ziv, Ido Amit^*, Irit Sagi

^*Corresponding author for this work

Medicine, Rheumatology Division

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

Mounting an effective immune response, while also protecting tissue integrity, is critical for host survival. We used a combined genomic and proteomic approach to investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection. We identified the membrane-tethered matrix metalloprotease MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza infection. Selective inhibition of MT1-MMP protected the tissue from infection-related structural and compositional tissue damage. MT1-MMP inhibition did not significantly alter the immune response or cytokine expression. The available flu therapeutic Oseltamivir did not prevent lung ECM damage and was less effective than anti-MT1-MMP in influenza virus Streptococcus pneumoniae coinfection paradigms. Combination therapy of Oseltamivir with anti-MT1-MMP showed a strong synergistic effect and resulted in complete recovery of infected mice. This study highlights the importance of tissue resilience in surviving infection and the potential of such host-pathogen therapy combinations for respiratory infections.

Original language	English (US)
Pages (from-to)	458-470
Number of pages	13
Journal	Cell Host and Microbe
Volume	20
Issue number	4
DOIs	https://doi.org/10.1016/j.chom.2016.09.005
State	Published - Oct 12 2016

Keywords

ECM remodeling
Influenza virus
MT1-MMP
host-pathogen gene regulation
immune genomics
matrix metalloproteinase inhibitors
viral-bacterial coinfection

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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Talmi-Frank, D., Altboum, Z., Solomonov, I., Udi, Y., Jaitin, D. A., Klepfish, M., David, E., Zhuravlev, A., Keren-Shaul, H., Winter, D. R., Gat-Viks, I., Mandelboim, M., Ziv, T., Amit, I., & Sagi, I. (2016). Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality. Cell Host and Microbe, 20(4), 458-470. https://doi.org/10.1016/j.chom.2016.09.005

Talmi-Frank, Dalit ; Altboum, Zeev ; Solomonov, Inna ; Udi, Yael ; Jaitin, Diego Adhemar ; Klepfish, Mordehay ; David, Eyal ; Zhuravlev, Alina ; Keren-Shaul, Hadas ; Winter, Deborah R. ; Gat-Viks, Irit ; Mandelboim, Michal ; Ziv, Tamar ; Amit, Ido ; Sagi, Irit. / Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality. In: Cell Host and Microbe. 2016 ; Vol. 20, No. 4. pp. 458-470.

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title = "Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality",

abstract = "Mounting an effective immune response, while also protecting tissue integrity, is critical for host survival. We used a combined genomic and proteomic approach to investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection. We identified the membrane-tethered matrix metalloprotease MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza infection. Selective inhibition of MT1-MMP protected the tissue from infection-related structural and compositional tissue damage. MT1-MMP inhibition did not significantly alter the immune response or cytokine expression. The available flu therapeutic Oseltamivir did not prevent lung ECM damage and was less effective than anti-MT1-MMP in influenza virus Streptococcus pneumoniae coinfection paradigms. Combination therapy of Oseltamivir with anti-MT1-MMP showed a strong synergistic effect and resulted in complete recovery of infected mice. This study highlights the importance of tissue resilience in surviving infection and the potential of such host-pathogen therapy combinations for respiratory infections.",

keywords = "ECM remodeling, Influenza virus, MT1-MMP, host-pathogen gene regulation, immune genomics, matrix metalloproteinase inhibitors, viral-bacterial coinfection",

author = "Dalit Talmi-Frank and Zeev Altboum and Inna Solomonov and Yael Udi and Jaitin, {Diego Adhemar} and Mordehay Klepfish and Eyal David and Alina Zhuravlev and Hadas Keren-Shaul and Winter, {Deborah R.} and Irit Gat-Viks and Michal Mandelboim and Tamar Ziv and Ido Amit and Irit Sagi",

note = "Funding Information: We wish to thank Mrs. Anna Aloshin for technical support. I. Sagi is the Incumbent of the Maurizio Pontecorvo Professorial Chair and has received funding from the Israeli Science Foundation (1226/13), the Ambach fund, and the Kimmelman center at the WIS. I. Sagi has also received funding from the European Research Council AdG(THZCALORIMETRY - DLV-695437) and the USA-Israel Binational Science Foundation (712506-01), the Ambach fund, and the Kimmelman center at the WIS. Research in the I.A. laboratory is supported by the European Research Council (309788), the I-CORE for chromatin and RNA regulation, and grants from the Israel Science foundation (703/15) and the BLUEPRINT FP7 consortium. We thank the members of the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a Minerva Stiftung research grant, and the National Human Genome Research Institute Center for Excellence in Genome Science (1P50HG006193). I.A. is also supported by the Helen and Martin Kimmel award for innovative investigation. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

year = "2016",

month = oct,

day = "12",

doi = "10.1016/j.chom.2016.09.005",

language = "English (US)",

volume = "20",

pages = "458--470",

journal = "Cell Host and Microbe",

issn = "1931-3128",

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Talmi-Frank, D, Altboum, Z, Solomonov, I, Udi, Y, Jaitin, DA, Klepfish, M, David, E, Zhuravlev, A, Keren-Shaul, H, Winter, DR, Gat-Viks, I, Mandelboim, M, Ziv, T, Amit, I & Sagi, I 2016, 'Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality', Cell Host and Microbe, vol. 20, no. 4, pp. 458-470. https://doi.org/10.1016/j.chom.2016.09.005

Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality. / Talmi-Frank, Dalit; Altboum, Zeev; Solomonov, Inna; Udi, Yael; Jaitin, Diego Adhemar; Klepfish, Mordehay; David, Eyal; Zhuravlev, Alina; Keren-Shaul, Hadas; Winter, Deborah R.; Gat-Viks, Irit; Mandelboim, Michal; Ziv, Tamar; Amit, Ido; Sagi, Irit.

In: Cell Host and Microbe, Vol. 20, No. 4, 12.10.2016, p. 458-470.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality

AU - Talmi-Frank, Dalit

AU - Altboum, Zeev

AU - Solomonov, Inna

AU - Udi, Yael

AU - Jaitin, Diego Adhemar

AU - Klepfish, Mordehay

AU - David, Eyal

AU - Zhuravlev, Alina

AU - Keren-Shaul, Hadas

AU - Winter, Deborah R.

AU - Gat-Viks, Irit

AU - Mandelboim, Michal

AU - Ziv, Tamar

AU - Amit, Ido

AU - Sagi, Irit

N1 - Funding Information: We wish to thank Mrs. Anna Aloshin for technical support. I. Sagi is the Incumbent of the Maurizio Pontecorvo Professorial Chair and has received funding from the Israeli Science Foundation (1226/13), the Ambach fund, and the Kimmelman center at the WIS. I. Sagi has also received funding from the European Research Council AdG(THZCALORIMETRY - DLV-695437) and the USA-Israel Binational Science Foundation (712506-01), the Ambach fund, and the Kimmelman center at the WIS. Research in the I.A. laboratory is supported by the European Research Council (309788), the I-CORE for chromatin and RNA regulation, and grants from the Israel Science foundation (703/15) and the BLUEPRINT FP7 consortium. We thank the members of the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a Minerva Stiftung research grant, and the National Human Genome Research Institute Center for Excellence in Genome Science (1P50HG006193). I.A. is also supported by the Helen and Martin Kimmel award for innovative investigation. Publisher Copyright: © 2016 Elsevier Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2016/10/12

Y1 - 2016/10/12

N2 - Mounting an effective immune response, while also protecting tissue integrity, is critical for host survival. We used a combined genomic and proteomic approach to investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection. We identified the membrane-tethered matrix metalloprotease MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza infection. Selective inhibition of MT1-MMP protected the tissue from infection-related structural and compositional tissue damage. MT1-MMP inhibition did not significantly alter the immune response or cytokine expression. The available flu therapeutic Oseltamivir did not prevent lung ECM damage and was less effective than anti-MT1-MMP in influenza virus Streptococcus pneumoniae coinfection paradigms. Combination therapy of Oseltamivir with anti-MT1-MMP showed a strong synergistic effect and resulted in complete recovery of infected mice. This study highlights the importance of tissue resilience in surviving infection and the potential of such host-pathogen therapy combinations for respiratory infections.

AB - Mounting an effective immune response, while also protecting tissue integrity, is critical for host survival. We used a combined genomic and proteomic approach to investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection. We identified the membrane-tethered matrix metalloprotease MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza infection. Selective inhibition of MT1-MMP protected the tissue from infection-related structural and compositional tissue damage. MT1-MMP inhibition did not significantly alter the immune response or cytokine expression. The available flu therapeutic Oseltamivir did not prevent lung ECM damage and was less effective than anti-MT1-MMP in influenza virus Streptococcus pneumoniae coinfection paradigms. Combination therapy of Oseltamivir with anti-MT1-MMP showed a strong synergistic effect and resulted in complete recovery of infected mice. This study highlights the importance of tissue resilience in surviving infection and the potential of such host-pathogen therapy combinations for respiratory infections.

KW - ECM remodeling

KW - Influenza virus

KW - MT1-MMP

KW - host-pathogen gene regulation

KW - immune genomics

KW - matrix metalloproteinase inhibitors

KW - viral-bacterial coinfection

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AN - SCOPUS:84992365498

VL - 20

SP - 458

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JO - Cell Host and Microbe

JF - Cell Host and Microbe

SN - 1931-3128

IS - 4

ER -

Extracellular Matrix Proteolysis by MT1-MMP Contributes to Influenza-Related Tissue Damage and Mortality

Abstract

Keywords

ASJC Scopus subject areas

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