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

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

69 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
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 - 12 Oct 2016

Funding

Funders	Funder number
Helen and Martin Kimmel award for innovative investigation
National Human Genome Research Institute Center for Excellence in Genome Science	1P50HG006193
Horizon 2020 Framework Programme	695437
European Research Council
Minerva Foundation
United States-Israel Binational Science Foundation	712506-01, 309788
Israel Science Foundation	1226/13, 703/15
Israeli Centers for Research Excellence

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chom.2016.09.005

Cite this

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

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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.",

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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

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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

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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.

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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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JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 4

ER -

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

Abstract

Funding

Keywords

UN SDGs

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