Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria

Reinink, Peter and Buter, Jeffrey and Mishra, Vivek K. and Ishikawa, Eri and Cheng, Tan Yun and Willemsen, Peter T.J. and Porwollik, Steffen and Brennan, Patrick J. and Heinz, Eva and Mayfield, Jacob A. and Dougan, Gordon and Van Els, Cécile A. and Cerundolo, Vincenzo and Napolitani, Giorgio and Yamasaki, Sho and Minnaard, Adriaan J. and McClelland, Michael and Branch Moody, D. and Van Rhijn, Ildiko (2019) Discovery of Salmonella trehalose phospholipids reveals functional convergence with mycobacteria. Journal of Experimental Medicine, 216 (4). pp. 757-771. ISSN 0022-1007 (https://doi.org/10.1084/jem.20181812)

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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.

ORCID iDs

Reinink, Peter, Buter, Jeffrey, Mishra, Vivek K., Ishikawa, Eri, Cheng, Tan Yun, Willemsen, Peter T.J., Porwollik, Steffen, Brennan, Patrick J., Heinz, Eva ORCID logoORCID: https://orcid.org/0000-0003-4413-3756, Mayfield, Jacob A., Dougan, Gordon, Van Els, Cécile A., Cerundolo, Vincenzo, Napolitani, Giorgio, Yamasaki, Sho, Minnaard, Adriaan J., McClelland, Michael, Branch Moody, D. and Van Rhijn, Ildiko;
CORE (COnnecting REpositories)