Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts

Sarah L. Price; Viveka Vadyvaloo; Jennifer K. De Marco; Amanda Brady; Phoenix A. Gray; Thomas E. Kehl-Fie; Sylvie Garneau-Tsodikova; Robert D. Perry; Matthew B. Lawrenz

doi:10.1073/pnas.2104073118

Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts

Sarah L. Price, Viveka Vadyvaloo, Jennifer K. De Marco, Amanda Brady, Phoenix A. Gray, Thomas E. Kehl-Fie, Sylvie Garneau-Tsodikova, Robert D. Perry, Matthew B. Lawrenz

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

14 Scopus citations

Abstract

Yersinia pestis causes human plague and colonizes both a mammalian host and a flea vector during its transmission cycle. A key barrier to bacterial infection is the host's ability to actively sequester key biometals (e.g., iron, zinc, and manganese) required for bacterial growth. This is referred to as nutritional immunity. Mechanisms to overcome nutritional immunity are essential virulence factors for bacterial pathogens. Y. pestis produces an iron-scavenging siderophore called yersiniabactin (Ybt) that is required to overcome iron-mediated nutritional immunity and cause lethal infection. Recently, Ybt has been shown to bind to zinc, and in the absence of the zinc transporter ZnuABC, Ybt improves Y. pestis growth in zinc-limited medium. These data suggest that, in addition to iron acquisition, Ybt may also contribute to overcoming zinc-mediated nutritional immunity. To test this hypothesis, we used a mouse model defective in iron-mediated nutritional immunity to demonstrate that Ybt contributes to virulence in an iron-independent manner. Furthermore, using a combination of bacterial mutants and mice defective in zinc-mediated nutritional immunity, we identified calprotectin as the primary barrier for Y. pestis to acquire zinc during infection and that Y. pestis uses Ybt to compete with calprotectin for zinc. Finally, we discovered that Y. pestis encounters zinc limitation within the flea midgut, and Ybt contributes to overcoming this limitation. Together, these results demonstrate that Ybt is a bona fide zinc acquisition mechanism used by Y. pestis to surmount zinc limitation during the infection of both the mammalian and insect hosts.

Original language	English
Article number	e2104073118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	44
DOIs	https://doi.org/10.1073/pnas.2104073118
State	Published - Nov 2 2021

Bibliographical note

Funding Information:
We would like to thank Dr. Thomas Vogl at the University of Muenster for sharing the S100A9-/-mice with the research community. We would also like to thank Dr. Jason Xu and Dr. Lu Cai in the University of Louisville's Department of Pediatrics for ICP-MS analysis, Dr. Amanda Pulsifer, the University of Louisville's Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases Shared Resources and Vivarium Staff, and Kameron Gravelle at Washington State University for technical support during these studies. This work was supported by funding from the NIH T32AI132146 (S.L.P.), F31AI147404 (S.L.P.), R01AI118880 (T.E.K.-F.), R01AI155611 (T.E.K.-F.), R21AI135225 (M.B.L.), R01AI148241 (M.B.L.), P20GM125504 (M.B.L.), and in part from the Jewish Heritage Foundation for Excellence Grant Program at the University of Louisville School ofMedicine (M.B.L.).

Funding Information:
ACKNOWLEDGMENTS. We would like to thank Dr. Thomas Vogl at the University of Muenster for sharing the S100A9−/− mice with the research community. We would also like to thank Dr. Jason Xu and Dr. Lu Cai in the University of Louisville’s Department of Pediatrics for ICP-MS analysis, Dr. Amanda Pulsi-fer, the University of Louisville’s Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases Shared Resources and Vivarium Staff, and Kameron Gravelle at Washington State University for technical support during these studies. This work was supported by funding from the NIH T32AI132146 (S.L.P.), F31AI147404 (S.L.P.), R01AI118880 (T.E.K.-F.), R01AI155611 (T.E.K.-F.), R21AI135225 (M.B.L.), R01AI148241 (M.B.L.), P20GM125504 (M.B.L.), and in part from the Jewish Heritage Foundation for Excellence Grant Program at the University of Louisville School of Medicine (M.B.L.).

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

Insect vectors
Nutritional immunity
Siderophores
Yersinia pestis and plague
Zinc acquisition

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.2104073118

Cite this

Price, S. L., Vadyvaloo, V., De Marco, J. K., Brady, A., Gray, P. A., Kehl-Fie, T. E., Garneau-Tsodikova, S., Perry, R. D., & Lawrenz, M. B. (2021). Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts. Proceedings of the National Academy of Sciences of the United States of America, 118(44), Article e2104073118. https://doi.org/10.1073/pnas.2104073118

@article{f1b42df07e1c4d3089547cf633e438e6,

title = "Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts",

abstract = "Yersinia pestis causes human plague and colonizes both a mammalian host and a flea vector during its transmission cycle. A key barrier to bacterial infection is the host's ability to actively sequester key biometals (e.g., iron, zinc, and manganese) required for bacterial growth. This is referred to as nutritional immunity. Mechanisms to overcome nutritional immunity are essential virulence factors for bacterial pathogens. Y. pestis produces an iron-scavenging siderophore called yersiniabactin (Ybt) that is required to overcome iron-mediated nutritional immunity and cause lethal infection. Recently, Ybt has been shown to bind to zinc, and in the absence of the zinc transporter ZnuABC, Ybt improves Y. pestis growth in zinc-limited medium. These data suggest that, in addition to iron acquisition, Ybt may also contribute to overcoming zinc-mediated nutritional immunity. To test this hypothesis, we used a mouse model defective in iron-mediated nutritional immunity to demonstrate that Ybt contributes to virulence in an iron-independent manner. Furthermore, using a combination of bacterial mutants and mice defective in zinc-mediated nutritional immunity, we identified calprotectin as the primary barrier for Y. pestis to acquire zinc during infection and that Y. pestis uses Ybt to compete with calprotectin for zinc. Finally, we discovered that Y. pestis encounters zinc limitation within the flea midgut, and Ybt contributes to overcoming this limitation. Together, these results demonstrate that Ybt is a bona fide zinc acquisition mechanism used by Y. pestis to surmount zinc limitation during the infection of both the mammalian and insect hosts.",

keywords = "Insect vectors, Nutritional immunity, Siderophores, Yersinia pestis and plague, Zinc acquisition",

author = "Price, {Sarah L.} and Viveka Vadyvaloo and {De Marco}, {Jennifer K.} and Amanda Brady and Gray, {Phoenix A.} and Kehl-Fie, {Thomas E.} and Sylvie Garneau-Tsodikova and Perry, {Robert D.} and Lawrenz, {Matthew B.}",

note = "Funding Information: We would like to thank Dr. Thomas Vogl at the University of Muenster for sharing the S100A9-/-mice with the research community. We would also like to thank Dr. Jason Xu and Dr. Lu Cai in the University of Louisville's Department of Pediatrics for ICP-MS analysis, Dr. Amanda Pulsifer, the University of Louisville's Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases Shared Resources and Vivarium Staff, and Kameron Gravelle at Washington State University for technical support during these studies. This work was supported by funding from the NIH T32AI132146 (S.L.P.), F31AI147404 (S.L.P.), R01AI118880 (T.E.K.-F.), R01AI155611 (T.E.K.-F.), R21AI135225 (M.B.L.), R01AI148241 (M.B.L.), P20GM125504 (M.B.L.), and in part from the Jewish Heritage Foundation for Excellence Grant Program at the University of Louisville School ofMedicine (M.B.L.). Funding Information: ACKNOWLEDGMENTS. We would like to thank Dr. Thomas Vogl at the University of Muenster for sharing the S100A9−/− mice with the research community. We would also like to thank Dr. Jason Xu and Dr. Lu Cai in the University of Louisville{\textquoteright}s Department of Pediatrics for ICP-MS analysis, Dr. Amanda Pulsi-fer, the University of Louisville{\textquoteright}s Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases Shared Resources and Vivarium Staff, and Kameron Gravelle at Washington State University for technical support during these studies. This work was supported by funding from the NIH T32AI132146 (S.L.P.), F31AI147404 (S.L.P.), R01AI118880 (T.E.K.-F.), R01AI155611 (T.E.K.-F.), R21AI135225 (M.B.L.), R01AI148241 (M.B.L.), P20GM125504 (M.B.L.), and in part from the Jewish Heritage Foundation for Excellence Grant Program at the University of Louisville School of Medicine (M.B.L.). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",

year = "2021",

month = nov,

day = "2",

doi = "10.1073/pnas.2104073118",

language = "English",

volume = "118",

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}

Price, SL, Vadyvaloo, V, De Marco, JK, Brady, A, Gray, PA, Kehl-Fie, TE, Garneau-Tsodikova, S, Perry, RD & Lawrenz, MB 2021, 'Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 44, e2104073118. https://doi.org/10.1073/pnas.2104073118

Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts. / Price, Sarah L.; Vadyvaloo, Viveka; De Marco, Jennifer K. et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 44, e2104073118, 02.11.2021.

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

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T1 - Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts

AU - Price, Sarah L.

AU - Vadyvaloo, Viveka

AU - De Marco, Jennifer K.

AU - Brady, Amanda

AU - Gray, Phoenix A.

AU - Kehl-Fie, Thomas E.

AU - Garneau-Tsodikova, Sylvie

AU - Perry, Robert D.

AU - Lawrenz, Matthew B.

N1 - Funding Information: We would like to thank Dr. Thomas Vogl at the University of Muenster for sharing the S100A9-/-mice with the research community. We would also like to thank Dr. Jason Xu and Dr. Lu Cai in the University of Louisville's Department of Pediatrics for ICP-MS analysis, Dr. Amanda Pulsifer, the University of Louisville's Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases Shared Resources and Vivarium Staff, and Kameron Gravelle at Washington State University for technical support during these studies. This work was supported by funding from the NIH T32AI132146 (S.L.P.), F31AI147404 (S.L.P.), R01AI118880 (T.E.K.-F.), R01AI155611 (T.E.K.-F.), R21AI135225 (M.B.L.), R01AI148241 (M.B.L.), P20GM125504 (M.B.L.), and in part from the Jewish Heritage Foundation for Excellence Grant Program at the University of Louisville School ofMedicine (M.B.L.). Funding Information: ACKNOWLEDGMENTS. We would like to thank Dr. Thomas Vogl at the University of Muenster for sharing the S100A9−/− mice with the research community. We would also like to thank Dr. Jason Xu and Dr. Lu Cai in the University of Louisville’s Department of Pediatrics for ICP-MS analysis, Dr. Amanda Pulsi-fer, the University of Louisville’s Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases Shared Resources and Vivarium Staff, and Kameron Gravelle at Washington State University for technical support during these studies. This work was supported by funding from the NIH T32AI132146 (S.L.P.), F31AI147404 (S.L.P.), R01AI118880 (T.E.K.-F.), R01AI155611 (T.E.K.-F.), R21AI135225 (M.B.L.), R01AI148241 (M.B.L.), P20GM125504 (M.B.L.), and in part from the Jewish Heritage Foundation for Excellence Grant Program at the University of Louisville School of Medicine (M.B.L.). Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.

PY - 2021/11/2

Y1 - 2021/11/2

N2 - Yersinia pestis causes human plague and colonizes both a mammalian host and a flea vector during its transmission cycle. A key barrier to bacterial infection is the host's ability to actively sequester key biometals (e.g., iron, zinc, and manganese) required for bacterial growth. This is referred to as nutritional immunity. Mechanisms to overcome nutritional immunity are essential virulence factors for bacterial pathogens. Y. pestis produces an iron-scavenging siderophore called yersiniabactin (Ybt) that is required to overcome iron-mediated nutritional immunity and cause lethal infection. Recently, Ybt has been shown to bind to zinc, and in the absence of the zinc transporter ZnuABC, Ybt improves Y. pestis growth in zinc-limited medium. These data suggest that, in addition to iron acquisition, Ybt may also contribute to overcoming zinc-mediated nutritional immunity. To test this hypothesis, we used a mouse model defective in iron-mediated nutritional immunity to demonstrate that Ybt contributes to virulence in an iron-independent manner. Furthermore, using a combination of bacterial mutants and mice defective in zinc-mediated nutritional immunity, we identified calprotectin as the primary barrier for Y. pestis to acquire zinc during infection and that Y. pestis uses Ybt to compete with calprotectin for zinc. Finally, we discovered that Y. pestis encounters zinc limitation within the flea midgut, and Ybt contributes to overcoming this limitation. Together, these results demonstrate that Ybt is a bona fide zinc acquisition mechanism used by Y. pestis to surmount zinc limitation during the infection of both the mammalian and insect hosts.

AB - Yersinia pestis causes human plague and colonizes both a mammalian host and a flea vector during its transmission cycle. A key barrier to bacterial infection is the host's ability to actively sequester key biometals (e.g., iron, zinc, and manganese) required for bacterial growth. This is referred to as nutritional immunity. Mechanisms to overcome nutritional immunity are essential virulence factors for bacterial pathogens. Y. pestis produces an iron-scavenging siderophore called yersiniabactin (Ybt) that is required to overcome iron-mediated nutritional immunity and cause lethal infection. Recently, Ybt has been shown to bind to zinc, and in the absence of the zinc transporter ZnuABC, Ybt improves Y. pestis growth in zinc-limited medium. These data suggest that, in addition to iron acquisition, Ybt may also contribute to overcoming zinc-mediated nutritional immunity. To test this hypothesis, we used a mouse model defective in iron-mediated nutritional immunity to demonstrate that Ybt contributes to virulence in an iron-independent manner. Furthermore, using a combination of bacterial mutants and mice defective in zinc-mediated nutritional immunity, we identified calprotectin as the primary barrier for Y. pestis to acquire zinc during infection and that Y. pestis uses Ybt to compete with calprotectin for zinc. Finally, we discovered that Y. pestis encounters zinc limitation within the flea midgut, and Ybt contributes to overcoming this limitation. Together, these results demonstrate that Ybt is a bona fide zinc acquisition mechanism used by Y. pestis to surmount zinc limitation during the infection of both the mammalian and insect hosts.

KW - Insect vectors

KW - Nutritional immunity

KW - Siderophores

KW - Yersinia pestis and plague

KW - Zinc acquisition

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Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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