Tissue remodeling by an opportunistic pathogen triggers allergic inflammation

Karen Agaronyan; Lokesh Sharma; Bharat Vaidyanathan; Keith Glenn; Shuang Yu; Charles Annicelli; Talia D. Wiggen; Mitchell R. Penningroth; Ryan C. Hunter; Charles S. Dela Cruz; Ruslan Medzhitov

doi:10.1016/j.immuni.2022.04.001

Tissue remodeling by an opportunistic pathogen triggers allergic inflammation

Karen Agaronyan, Lokesh Sharma, Bharat Vaidyanathan, Keith Glenn, Shuang Yu, Charles Annicelli, Talia D. Wiggen, Mitchell R. Penningroth, Ryan C. Hunter, Charles S. Dela Cruz, Ruslan Medzhitov

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

23 Scopus citations

Abstract

Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response—a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This “niche remodeling” by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.

Original language	English (US)
Pages (from-to)	895-911.e10
Journal	Immunity
Volume	55
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2022.04.001
State	Published - May 10 2022

Bibliographical note

Funding Information:
We thank Dr. B. Kazmerciak for providing P. aeruginosa gDNA. We would like to thank all current and former members of Medzhitov lab for helpful discussions. ΔLasB and ΔLasR PA01 strains were obtained from PA01 Mutant Library (NIH P30 DK089507). Work in the R.M. lab was supported by the Howard Hughes Medical Institute , the Blavatnik Family Foundation , the Food Allergy Science Initiative , and a grant from NIH ( AI144152-01 ). C.S.D.C. is supported by NIH HL126094 , a Department of Defense grant, and a Veterans Affairs merit grant. L.S. is supported by Francis B Parker Fellowship and American Lung Association Catalyst Award. R.C.H. is supported by NIH HL136919 . K.A. was supported by the Yale Brown-Coxe Post-Doctoral Fellowship and is a Howard Hughes Medical Institute fellow of the Life Sciences Research Foundation . Images were created with BioRender.com .

Funding Information:
We thank Dr. B. Kazmerciak for providing P. aeruginosa gDNA. We would like to thank all current and former members of Medzhitov lab for helpful discussions. ΔLasB and ΔLasR PA01 strains were obtained from PA01 Mutant Library (NIH P30 DK089507). Work in the R.M. lab was supported by the Howard Hughes Medical Institute, the Blavatnik Family Foundation, the Food Allergy Science Initiative, and a grant from NIH (AI144152-01). C.S.D.C. is supported by NIH HL126094, a Department of Defense grant, and a Veterans Affairs merit grant. L.S. is supported by Francis B Parker Fellowship and American Lung Association Catalyst Award. R.C.H. is supported by NIH HL136919. K.A. was supported by the Yale Brown-Coxe Post-Doctoral Fellowship and is a Howard Hughes Medical Institute fellow of the Life Sciences Research Foundation. Images were created with BioRender.com. K.A. and R.M. designed the study, analyzed the data, and wrote the manuscript with input from the other co-authors. K.A. performed experiments with the assistance from L.S. B.V. S.Y. C.A. T.D.W. M.R.P. C.S.D.C. and R.C.H. and L.S. provided help and advice with bacterial infection experiments and obtaining patient samples. L.S. performed bacterial infection experiments. K.G. recruited patients for collection of tracheal aspirates. K.A. performed all analyses of microbiome composition and metabolic pathways. All authors declare no competing interests. B.V. is currently an employee of EMD Serono. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

LasB
P. aeruginosa
allergic inflammation
amphiregulin
immune deviation
lung
mucin
opportunistic pathogen
type 2 immunity

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10.1016/j.immuni.2022.04.001

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title = "Tissue remodeling by an opportunistic pathogen triggers allergic inflammation",

abstract = "Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response—a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This “niche remodeling” by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.",

keywords = "LasB, P. aeruginosa, allergic inflammation, amphiregulin, immune deviation, lung, mucin, opportunistic pathogen, type 2 immunity",

author = "Karen Agaronyan and Lokesh Sharma and Bharat Vaidyanathan and Keith Glenn and Shuang Yu and Charles Annicelli and Wiggen, {Talia D.} and Penningroth, {Mitchell R.} and Hunter, {Ryan C.} and {Dela Cruz}, {Charles S.} and Ruslan Medzhitov",

note = "Funding Information: We thank Dr. B. Kazmerciak for providing P. aeruginosa gDNA. We would like to thank all current and former members of Medzhitov lab for helpful discussions. ΔLasB and ΔLasR PA01 strains were obtained from PA01 Mutant Library (NIH P30 DK089507). Work in the R.M. lab was supported by the Howard Hughes Medical Institute , the Blavatnik Family Foundation , the Food Allergy Science Initiative , and a grant from NIH ( AI144152-01 ). C.S.D.C. is supported by NIH HL126094 , a Department of Defense grant, and a Veterans Affairs merit grant. L.S. is supported by Francis B Parker Fellowship and American Lung Association Catalyst Award. R.C.H. is supported by NIH HL136919 . K.A. was supported by the Yale Brown-Coxe Post-Doctoral Fellowship and is a Howard Hughes Medical Institute fellow of the Life Sciences Research Foundation . Images were created with BioRender.com . Funding Information: We thank Dr. B. Kazmerciak for providing P. aeruginosa gDNA. We would like to thank all current and former members of Medzhitov lab for helpful discussions. ΔLasB and ΔLasR PA01 strains were obtained from PA01 Mutant Library (NIH P30 DK089507). Work in the R.M. lab was supported by the Howard Hughes Medical Institute, the Blavatnik Family Foundation, the Food Allergy Science Initiative, and a grant from NIH (AI144152-01). C.S.D.C. is supported by NIH HL126094, a Department of Defense grant, and a Veterans Affairs merit grant. L.S. is supported by Francis B Parker Fellowship and American Lung Association Catalyst Award. R.C.H. is supported by NIH HL136919. K.A. was supported by the Yale Brown-Coxe Post-Doctoral Fellowship and is a Howard Hughes Medical Institute fellow of the Life Sciences Research Foundation. Images were created with BioRender.com. K.A. and R.M. designed the study, analyzed the data, and wrote the manuscript with input from the other co-authors. K.A. performed experiments with the assistance from L.S. B.V. S.Y. C.A. T.D.W. M.R.P. C.S.D.C. and R.C.H. and L.S. provided help and advice with bacterial infection experiments and obtaining patient samples. L.S. performed bacterial infection experiments. K.G. recruited patients for collection of tracheal aspirates. K.A. performed all analyses of microbiome composition and metabolic pathways. All authors declare no competing interests. B.V. is currently an employee of EMD Serono. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

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AU - Sharma, Lokesh

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AU - Medzhitov, Ruslan

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N2 - Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response—a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This “niche remodeling” by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.

AB - Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response—a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This “niche remodeling” by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.

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Tissue remodeling by an opportunistic pathogen triggers allergic inflammation

Abstract

Bibliographical note

Keywords

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