Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection

Johanna M. Sweere; Jonas D. Van Belleghem; Heather Ishak; Michelle S. Bach; Medeea Popescu; Vivekananda Sunkari; Gernot Kaber; Robert Manasherob; Gina A. Suh; Xiou Cao; Christiaan R. de Vries; Dung N. Lam; Payton L. Marshall; Maria Birukova; Ethan Katznelson; Daniel V. Lazzareschi; Swathi Balaji; Sundeep G. Keswani; Thomas R. Hawn; Patrick R. Secor; Paul L. Bollyky

doi:10.1126/science.aat9691

Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection

Johanna M. Sweere, Jonas D. Van Belleghem, Heather Ishak, Michelle S. Bach, Medeea Popescu, Vivekananda Sunkari, Gernot Kaber, Robert Manasherob, Gina A. Suh, Xiou Cao, Christiaan R. de Vries, Dung N. Lam, Payton L. Marshall, Maria Birukova, Ethan Katznelson, Daniel V. Lazzareschi, Swathi Balaji, Sundeep G. Keswani, Thomas R. Hawn, Patrick R. SecorPaul L. Bollyky

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

348 Scopus citations

Abstract

Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)– and TIR domain–containing adapter-inducing interferon-b (TRIF)–dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.

Original language	English
Article number	eaat9691
Journal	Science
Volume	363
Issue number	6434
DOIs	https://doi.org/10.1126/science.aat9691
State	Published - Mar 29 2019

Funding

We thank M. Butte, T. Wang, and C. Blish for their critical reading of the manuscript. We are grateful to S. Rice for sharing PAO1DPf4 and its isogenic PAO1 strain. Ifnar−/− and Ifnr−/− mice were gifts from S.-Y. Pu and S. Einav. Cgas−/− and Sting−/− mice were gifts from V. Boehnert and L. Li. RAW64.7 and L929 ISRE reporter cell lines were gifts from S. Brubaker. The pUT-Tn5-EM7-lux-Km1 luminescent construct vector was a gift from J. Hardy. Special thanks to T. Thauland, K. Yadava, and S. M. Ruppert for their technical expertise. This work was supported by grants R21AI133370, R21AI133240, R01AI12492093, and grants from Stanford SPARK and by the Falk Medical Research Trust and the Cystic Fibrosis Foundation (CFF) to P.L.B. A Gabilan Stanford Graduate Fellowship for Science and Engineering and a Lubert Stryer Bio-X Stanford Interdisciplinary Graduate Fellowship supported J.M.S. P.R.S was supported by NIH grants K22AI125282, R01AI138981, and P20GM103546. G.K. was supported by the Stanford Diabetes Research Center (SDRC) under award no. P30DK116074. S.G.K. was supported by NIH grant R01GM111808. The use of the transmission electron microscope was supported, in part, by ARRA award no. 1S10RR026780-F Resources (NCRR).

Funder number
R01GM111808, P20GM103546, K22AI125282, 1S10RR026780-F
R01AI138981
R01AI12492093, R21AI133370, R21AI133240
P30DK116074

UN SDGs

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

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Sweere, J. M., Van Belleghem, J. D., Ishak, H., Bach, M. S., Popescu, M., Sunkari, V., Kaber, G., Manasherob, R., Suh, G. A., Cao, X., de Vries, C. R., Lam, D. N., Marshall, P. L., Birukova, M., Katznelson, E., Lazzareschi, D. V., Balaji, S., Keswani, S. G., Hawn, T. R., ... Bollyky, P. L. (2019). Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science, 363(6434), Article eaat9691. https://doi.org/10.1126/science.aat9691

@article{9140bb4b685140528b4ce5f4b07aaf8d,

title = "Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection",

abstract = "Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)– and TIR domain–containing adapter-inducing interferon-b (TRIF)–dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.",

author = "Sweere, \{Johanna M.\} and \{Van Belleghem\}, \{Jonas D.\} and Heather Ishak and Bach, \{Michelle S.\} and Medeea Popescu and Vivekananda Sunkari and Gernot Kaber and Robert Manasherob and Suh, \{Gina A.\} and Xiou Cao and \{de Vries\}, \{Christiaan R.\} and Lam, \{Dung N.\} and Marshall, \{Payton L.\} and Maria Birukova and Ethan Katznelson and Lazzareschi, \{Daniel V.\} and Swathi Balaji and Keswani, \{Sundeep G.\} and Hawn, \{Thomas R.\} and Secor, \{Patrick R.\} and Bollyky, \{Paul L.\}",

note = "Publisher Copyright: {\textcopyright} The Authors, some rights reserved.",

year = "2019",

month = mar,

day = "29",

doi = "10.1126/science.aat9691",

language = "English",

volume = "363",

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Sweere, JM, Van Belleghem, JD, Ishak, H, Bach, MS, Popescu, M, Sunkari, V, Kaber, G, Manasherob, R, Suh, GA, Cao, X, de Vries, CR, Lam, DN, Marshall, PL, Birukova, M, Katznelson, E, Lazzareschi, DV, Balaji, S, Keswani, SG, Hawn, TR, Secor, PR & Bollyky, PL 2019, 'Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection', Science, vol. 363, no. 6434, eaat9691. https://doi.org/10.1126/science.aat9691

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T1 - Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection

AU - Sweere, Johanna M.

AU - Van Belleghem, Jonas D.

AU - Ishak, Heather

AU - Bach, Michelle S.

AU - Popescu, Medeea

AU - Sunkari, Vivekananda

AU - Kaber, Gernot

AU - Manasherob, Robert

AU - Suh, Gina A.

AU - Cao, Xiou

AU - de Vries, Christiaan R.

AU - Lam, Dung N.

AU - Marshall, Payton L.

AU - Birukova, Maria

AU - Katznelson, Ethan

AU - Lazzareschi, Daniel V.

AU - Balaji, Swathi

AU - Keswani, Sundeep G.

AU - Hawn, Thomas R.

AU - Secor, Patrick R.

AU - Bollyky, Paul L.

PY - 2019/3/29

Y1 - 2019/3/29

N2 - Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)– and TIR domain–containing adapter-inducing interferon-b (TRIF)–dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.

AB - Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)– and TIR domain–containing adapter-inducing interferon-b (TRIF)–dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.

UR - https://www.scopus.com/pages/publications/85064138980

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DO - 10.1126/science.aat9691

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AN - SCOPUS:85064138980

SN - 0036-8075

VL - 363

JO - Science

JF - Science

IS - 6434

M1 - eaat9691

ER -

Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection

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