Details

Autor(en) / Beteiligte

• Custódio, Rafael
• McLean, Christopher J.
• Scott, Andrew E.
• Lowther, Jonathan
• Kennedy, Amanda
• Clarke, David J.
• Campopiano, Dominic J.
• Sarkar‐Tyson, Mitali
• Brown, Alan R.

Titel

Characterization of secreted sphingosine‐1‐phosphate lyases required for virulence and intracellular survival of Burkholderia pseudomallei

Ist Teil von

• Molecular microbiology, 2016-12, Vol.102 (6), p.1004-1019

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Wiley Online Library

Beschreibungen/Notizen

• Summary Sphingosine‐1‐phosphate (S1P), a bioactive sphingolipid metabolite, plays a critical role in the orchestration of immune responses. S1P levels within the mammalian host are tightly regulated, in part through the activity of S1P lyase (S1PL) which catalyses its irreversible degradation. Herein, we describe the identification and characterization of secreted S1PL orthologues encoded by the facultative intracellular bacteria Burkholderia pseudomallei and Burkholderia thailandensis. These bacterial orthologues exhibited S1PL enzymatic activity, functionally complemented an S1PL‐deficient yeast strain and conferred resistance to the antimicrobial sphingolipid D‐erythro‐sphingosine. We report that secretion of these bacterial S1PLs is pH‐dependent, and is observed during intracellular infection. S1PL‐deficient mutants displayed impaired intracellular replication in murine macrophages (associated with an inability to evade the maturing phagosome) and were significantly attenuated in murine and larval infection models. Furthermore, treatment of Burkholderia‐infected macrophages with either S1P or a selective agonist of S1P receptor 1 enhanced bacterial colocalisation with LAMP‐1 and reduced their intracellular survival. In summary, our studies confirm bacterial‐encoded S1PL as a critical virulence determinant of B. pseudomallei and B. thailandensis, further highlighting the pivotal role of S1P in host‐pathogen interactions. In addition, our data suggest that S1P pathway modulators have potential for the treatment of intracellular infection. Following phagocytosis, sphingosine‐1‐phosphate (S1P) lyases are secreted by Burkholderia pseudomallei (1). These S1P lyases catalyse the irreversible degradation of S1P, a bioactive sphingolipid metabolite that promotes phagosome maturation (2). These bacterial S1P lyases promote escape from endocytic vacuoles and subsequent intracellular replication (3). S1P lyase‐deficient Burkholderia are unable to evade the maturing phagosome and display attenuated virulence. Treatment of infected macrophages with exogenous S1P circumvents the activity of the bacterial S1P lyases, enhancing bacterial killing.