Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth

Aria Eshraghi; Jungyun Kim; Alexandra C. Walls; Hannah E. Ledvina; Cheryl N. Miller; Kathryn M. Ramsey; John C. Whitney; Matthew C. Radey; S. Brook Peterson; Brittany R. Ruhland; Bao Q. Tran; Young Ah Goo; David R. Goodlett; Simon L. Dove; Jean Celli; David Veesler; Joseph D. Mougous

doi:10.1016/j.chom.2016.10.008

Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth

Aria Eshraghi, Jungyun Kim, Alexandra C. Walls, Hannah E. Ledvina, Cheryl N. Miller, Kathryn M. Ramsey, John C. Whitney, Matthew C. Radey, S. Brook Peterson, Brittany R. Ruhland, Bao Q. Tran, Young Ah Goo, David R. Goodlett, Simon L. Dove, Jean Celli, David Veesler, Joseph D. Mougous^*

^*Corresponding author for this work

PCE - Proteomics Center of Excellence

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

54 Scopus citations

Abstract

The intracellular bacterial pathogen Francisella tularensis causes tularemia, a zoonosis that can be fatal. The type VI secretion system (T6SS) encoded by the Francisella pathogenicity island (FPI) is critical for the virulence of this organism. Existing studies suggest that the complete repertoire of T6SS effectors delivered to host cells is encoded by the FPI. Using a proteome-wide approach, we discovered that the FPI-encoded T6SS exports at least three effectors encoded outside of the island. These proteins share features with virulence determinants of other pathogens, and we provide evidence that they can contribute to intramacrophage growth. The remaining proteins that we identified are encoded within the FPI. Two of these FPI-encoded proteins constitute effectors, whereas the others form a unique complex required for core function of the T6SS apparatus. The discovery of secreted effectors mediating interactions between Francisella and its host significantly advances our understanding of the pathogenesis of this organism.

Original language	English (US)
Pages (from-to)	573-583
Number of pages	11
Journal	Cell Host and Microbe
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.chom.2016.10.008
State	Published - Nov 9 2016

Funding

The authors would like to thank Tamir Gonen and Hongjin Zheng for preliminary EM analyses, Adelle McFarland for technical advice, Josh Woodward for critical review of the manuscript, Dan Stetson and Brad Cookson for sharing reagents, and members of the J.D.M. lab for helpful discussions. J.C.W. was supported by a postdoctoral research fellowship from CIHR , training grants from the NIH supported A.E. and H.E.L. ( AI055396 ), A.C.W. ( GM008268 ), and K.M.R. ( HD055148 ), and J.D.M. holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund ( BWF 1010010 ) and is an HHMI investigator. The work was supported by The University of Maryland Baltimore School of Pharmacy Mass Spectrometry Center ( SOP1841-IQB2014 to Y.A.G. and D.R.G.), the Paul G. Allen School for Global Health, Washington State University (to J.C.), and National Institutes of Health grants AI081693 (to S.L.D.) and AI080609 (to J.D.M.).

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2016.10.008

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Eshraghi, A., Kim, J., Walls, A. C., Ledvina, H. E., Miller, C. N., Ramsey, K. M., Whitney, J. C., Radey, M. C., Peterson, S. B., Ruhland, B. R., Tran, B. Q., Goo, Y. A., Goodlett, D. R., Dove, S. L., Celli, J., Veesler, D., & Mougous, J. D. (2016). Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth. Cell Host and Microbe, 20(5), 573-583. https://doi.org/10.1016/j.chom.2016.10.008

@article{f5114ca3859a4d388259b77d0ad495ba,

title = "Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth",

abstract = "The intracellular bacterial pathogen Francisella tularensis causes tularemia, a zoonosis that can be fatal. The type VI secretion system (T6SS) encoded by the Francisella pathogenicity island (FPI) is critical for the virulence of this organism. Existing studies suggest that the complete repertoire of T6SS effectors delivered to host cells is encoded by the FPI. Using a proteome-wide approach, we discovered that the FPI-encoded T6SS exports at least three effectors encoded outside of the island. These proteins share features with virulence determinants of other pathogens, and we provide evidence that they can contribute to intramacrophage growth. The remaining proteins that we identified are encoded within the FPI. Two of these FPI-encoded proteins constitute effectors, whereas the others form a unique complex required for core function of the T6SS apparatus. The discovery of secreted effectors mediating interactions between Francisella and its host significantly advances our understanding of the pathogenesis of this organism.",

author = "Aria Eshraghi and Jungyun Kim and Walls, {Alexandra C.} and Ledvina, {Hannah E.} and Miller, {Cheryl N.} and Ramsey, {Kathryn M.} and Whitney, {John C.} and Radey, {Matthew C.} and Peterson, {S. Brook} and Ruhland, {Brittany R.} and Tran, {Bao Q.} and Goo, {Young Ah} and Goodlett, {David R.} and Dove, {Simon L.} and Jean Celli and David Veesler and Mougous, {Joseph D.}",

note = "Funding Information: The authors would like to thank Tamir Gonen and Hongjin Zheng for preliminary EM analyses, Adelle McFarland for technical advice, Josh Woodward for critical review of the manuscript, Dan Stetson and Brad Cookson for sharing reagents, and members of the J.D.M. lab for helpful discussions. J.C.W. was supported by a postdoctoral research fellowship from CIHR , training grants from the NIH supported A.E. and H.E.L. ( AI055396 ), A.C.W. ( GM008268 ), and K.M.R. ( HD055148 ), and J.D.M. holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund ( BWF 1010010 ) and is an HHMI investigator. The work was supported by The University of Maryland Baltimore School of Pharmacy Mass Spectrometry Center ( SOP1841-IQB2014 to Y.A.G. and D.R.G.), the Paul G. Allen School for Global Health, Washington State University (to J.C.), and National Institutes of Health grants AI081693 (to S.L.D.) and AI080609 (to J.D.M.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = nov,

day = "9",

doi = "10.1016/j.chom.2016.10.008",

language = "English (US)",

volume = "20",

pages = "573--583",

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Eshraghi, A, Kim, J, Walls, AC, Ledvina, HE, Miller, CN, Ramsey, KM, Whitney, JC, Radey, MC, Peterson, SB, Ruhland, BR, Tran, BQ, Goo, YA, Goodlett, DR, Dove, SL, Celli, J, Veesler, D & Mougous, JD 2016, 'Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth', Cell Host and Microbe, vol. 20, no. 5, pp. 573-583. https://doi.org/10.1016/j.chom.2016.10.008

TY - JOUR

T1 - Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth

AU - Eshraghi, Aria

AU - Kim, Jungyun

AU - Walls, Alexandra C.

AU - Ledvina, Hannah E.

AU - Miller, Cheryl N.

AU - Ramsey, Kathryn M.

AU - Whitney, John C.

AU - Radey, Matthew C.

AU - Peterson, S. Brook

AU - Ruhland, Brittany R.

AU - Tran, Bao Q.

AU - Goo, Young Ah

AU - Goodlett, David R.

AU - Dove, Simon L.

AU - Celli, Jean

AU - Veesler, David

AU - Mougous, Joseph D.

N1 - Funding Information: The authors would like to thank Tamir Gonen and Hongjin Zheng for preliminary EM analyses, Adelle McFarland for technical advice, Josh Woodward for critical review of the manuscript, Dan Stetson and Brad Cookson for sharing reagents, and members of the J.D.M. lab for helpful discussions. J.C.W. was supported by a postdoctoral research fellowship from CIHR , training grants from the NIH supported A.E. and H.E.L. ( AI055396 ), A.C.W. ( GM008268 ), and K.M.R. ( HD055148 ), and J.D.M. holds an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund ( BWF 1010010 ) and is an HHMI investigator. The work was supported by The University of Maryland Baltimore School of Pharmacy Mass Spectrometry Center ( SOP1841-IQB2014 to Y.A.G. and D.R.G.), the Paul G. Allen School for Global Health, Washington State University (to J.C.), and National Institutes of Health grants AI081693 (to S.L.D.) and AI080609 (to J.D.M.). Publisher Copyright: © 2016 Elsevier Inc.

PY - 2016/11/9

Y1 - 2016/11/9

N2 - The intracellular bacterial pathogen Francisella tularensis causes tularemia, a zoonosis that can be fatal. The type VI secretion system (T6SS) encoded by the Francisella pathogenicity island (FPI) is critical for the virulence of this organism. Existing studies suggest that the complete repertoire of T6SS effectors delivered to host cells is encoded by the FPI. Using a proteome-wide approach, we discovered that the FPI-encoded T6SS exports at least three effectors encoded outside of the island. These proteins share features with virulence determinants of other pathogens, and we provide evidence that they can contribute to intramacrophage growth. The remaining proteins that we identified are encoded within the FPI. Two of these FPI-encoded proteins constitute effectors, whereas the others form a unique complex required for core function of the T6SS apparatus. The discovery of secreted effectors mediating interactions between Francisella and its host significantly advances our understanding of the pathogenesis of this organism.

AB - The intracellular bacterial pathogen Francisella tularensis causes tularemia, a zoonosis that can be fatal. The type VI secretion system (T6SS) encoded by the Francisella pathogenicity island (FPI) is critical for the virulence of this organism. Existing studies suggest that the complete repertoire of T6SS effectors delivered to host cells is encoded by the FPI. Using a proteome-wide approach, we discovered that the FPI-encoded T6SS exports at least three effectors encoded outside of the island. These proteins share features with virulence determinants of other pathogens, and we provide evidence that they can contribute to intramacrophage growth. The remaining proteins that we identified are encoded within the FPI. Two of these FPI-encoded proteins constitute effectors, whereas the others form a unique complex required for core function of the T6SS apparatus. The discovery of secreted effectors mediating interactions between Francisella and its host significantly advances our understanding of the pathogenesis of this organism.

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UR - http://www.scopus.com/inward/citedby.url?scp=84994752046&partnerID=8YFLogxK

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DO - 10.1016/j.chom.2016.10.008

M3 - Article

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AN - SCOPUS:84994752046

SN - 1931-3128

VL - 20

SP - 573

EP - 583

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 5

ER -

Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth

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