Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria

Peter Reinink; Jeffrey Buter; Vivek K. Mishra; Eri Ishikawa; Tan Yun Cheng; Peter T.J. Willemsen; Steffen Porwollik; Patrick J. Brennan; Eva Heinz; Jacob A. Mayfield; Gordon Dougan; Cécile A. Van Els; Vincenzo Cerundolo; Giorgio Napolitani; Sho Yamasaki; Adriaan J. Minnaard; Michael McClelland; D. Branch Moody; Ildiko Van Rhijn

doi:10.1084/jem.20181812

Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria

Peter Reinink, Jeffrey Buter, Vivek K. Mishra, Eri Ishikawa, Tan Yun Cheng, Peter T.J. Willemsen, Steffen Porwollik, Patrick J. Brennan, Eva Heinz, Jacob A. Mayfield, Gordon Dougan, Cécile A. Van Els, Vincenzo Cerundolo, Giorgio Napolitani, Sho Yamasaki, Adriaan J. Minnaard, Michael McClelland, D. Branch Moody, Ildiko Van Rhijn^*

^*Corresponding author for this work

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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Abstract

Salmonella species are among the world's most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,69-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,69-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species.

Original language	English
Pages (from-to)	757-771
Number of pages	15
Journal	Journal of Experimental Medicine
Volume	216
Issue number	4
Early online date	25 Feb 2019
DOIs	https://doi.org/10.1084/jem.20181812
Publication status	Published - 1 Apr 2019

Funding

This work was supported by the Nederlands Weten-schappelijk Onderzoek (grant 824.02.002) and the National Institutes of Health (grant AI116604 to D.B. Moody). P. Reinink was supported by the European Molecular Biology Organization short-term fellowship (16-2015). A.J. Minnaard and V.K. Mishra are supported by the University of Groningen. S. Yamasaki was supported by the Ministry of Education, Culture, Sports, Science and Technology (grants 26293099 and 26110009) and the Japan Agency for Medical Research and Development (grants JP17gm0910010 and JP17ak0101070). V. Cerundolo, G. Napoli-tani, and D.B. Moody were supported by the UK Medical Research Council (grant MR/K021222/1). V. Cerundolo was also supported by Cancer Research UK (grant C399/A2291) and by the National Institute for Health Research Oxford Biomedical Research Centre. S. Porwollik and M. McClelland were supported by the US Department of Agriculture (grants 2017-67017-26180 and 2017-67015-26085) and the National Institutes of Health (R01AI136520 and contract HHSN272200900040C). The authors declare no competing financial interests.

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

infectious disease
inflammation
host defense
innate immunity

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10.1084/jem.20181812Licence: CC BY-NC-SA 4.0

Reinink-etal-JEM-2019-Discovery-of-Salmonella-trehalose-phospholipids-reveals-functional-convergenceFinal published version, 2.94 MBLicence: CC BY-NC-SA 4.0

Cite this

Reinink, P., Buter, J., Mishra, V. K., Ishikawa, E., Cheng, T. Y., Willemsen, P. T. J., Porwollik, S., Brennan, P. J., Heinz, E., Mayfield, J. A., Dougan, G., Van Els, C. A., Cerundolo, V., Napolitani, G., Yamasaki, S., Minnaard, A. J., McClelland, M., Branch Moody, D., & Van Rhijn, I. (2019). Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria. Journal of Experimental Medicine, 216(4), 757-771. https://doi.org/10.1084/jem.20181812

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title = "Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria",

abstract = "Salmonella species are among the world's most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,69-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,69-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species.",

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Reinink, P, Buter, J, Mishra, VK, Ishikawa, E, Cheng, TY, Willemsen, PTJ, Porwollik, S, Brennan, PJ, Heinz, E, Mayfield, JA, Dougan, G, Van Els, CA, Cerundolo, V, Napolitani, G, Yamasaki, S, Minnaard, AJ, McClelland, M, Branch Moody, D & Van Rhijn, I 2019, 'Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria', Journal of Experimental Medicine, vol. 216, no. 4, pp. 757-771. https://doi.org/10.1084/jem.20181812

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AU - Reinink, Peter

AU - Buter, Jeffrey

AU - Mishra, Vivek K.

AU - Ishikawa, Eri

AU - Cheng, Tan Yun

AU - Willemsen, Peter T.J.

AU - Porwollik, Steffen

AU - Brennan, Patrick J.

AU - Heinz, Eva

AU - Mayfield, Jacob A.

AU - Dougan, Gordon

AU - Van Els, Cécile A.

AU - Cerundolo, Vincenzo

AU - Napolitani, Giorgio

AU - Yamasaki, Sho

AU - Minnaard, Adriaan J.

AU - McClelland, Michael

AU - Branch Moody, D.

AU - Van Rhijn, Ildiko

PY - 2019/4/1

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N2 - Salmonella species are among the world's most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,69-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,69-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species.

AB - Salmonella species are among the world's most prevalent pathogens. Because the cell wall interfaces with the host, we designed a lipidomics approach to reveal pathogen-specific cell wall compounds. Among the molecules differentially expressed between Salmonella Paratyphi and S. Typhi, we focused on lipids that are enriched in S. Typhi, because it causes typhoid fever. We discovered a previously unknown family of trehalose phospholipids, 6,69-diphosphatidyltrehalose (diPT) and 6-phosphatidyltrehalose (PT). Cardiolipin synthase B (ClsB) is essential for PT and diPT but not for cardiolipin biosynthesis. Chemotyping outperformed clsB homology analysis in evaluating synthesis of diPT. DiPT is restricted to a subset of Gram-negative bacteria: large amounts are produced by S. Typhi, lower amounts by other pathogens, and variable amounts by Escherichia coli strains. DiPT activates Mincle, a macrophage activating receptor that also recognizes mycobacterial cord factor (6,69-trehalose dimycolate). Thus, Gram-negative bacteria show convergent function with mycobacteria. Overall, we discovered a previously unknown immunostimulant that is selectively expressed among medically important bacterial species.

KW - infectious disease

KW - inflammation

KW - host defense

KW - innate immunity

U2 - 10.1084/jem.20181812

DO - 10.1084/jem.20181812

M3 - Article

C2 - 30804000

AN - SCOPUS:85064198420

SN - 0022-1007

VL - 216

SP - 757

EP - 771

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 4

ER -

Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria

Abstract

Funding

UN SDGs

Keywords

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