| dc.description.abstract | A critical feature of the pathogenesis of B. pseudomallei is its ability to invade,
survive and replicate in both phagocytic and non-phagocytic cells, hence a
thorough understanding of this intracellular stage is essential in order to develop
novel therapeutic strategies.
Bioinformatics analysis on B. pseudomallei and B. thailandensis has revealed the
presence of two distinct putative sphingosine-1-phosphate lyases (S1PLs). The
human S1PL homolog is responsible for the irreversible degradation of
sphingosine-1-phosphate (S1P), a critical regulator of immune responses. It was
hypothesised whether Burkholderia-encoded S1PLs could represent a strategy
employed by the bacteria to subvert the normal cellular functions of the host cells
and contribute to B. pseudomallei pathogenesis.
Using B. thailandensis as a model, we confirmed that both bacteria-encoded
S1PLs orthologues are functionally equivalent to eukaryotic S1PL and are
secreted in a pH-dependent manner, with secretion being observed during
intracellular infection in macrophages. S1PL-deficient B. thailandensis mutants
exhibited increased sensitivity to the antimicrobial sphingosine, attenuation in the
Galleria mellonella infection model, impaired intracellular replication in
macrophages, and inefficient phagosomal escape. Moreover, treatment of B.
thailandensis-infected macrophages with S1P enhanced bacterial colocalisation
with LAMP-1. Furthermore, either single or double deletion of S1PLs in B.
pseudomallei displayed similar defective intracellular growth. Additionally, single
deletion of S1PL displayed attenuation in BALB/c infection model. Macrophages
infected with B. pseudomallei or B. thailandensis treated either with S1P or a
specific agonist of S1P receptor 1 significantly enhanced phagocytic killing of
intracellular bacteria.
This study has highlighted the role of B. pseudomallei-encoded S1PL as a critical
virulence determinant for intracellular survival, further establishing S1P-axis
modulation as a strategy employed by Burkholderia to overcome the host immune
response. In addition, herein has been demonstrated the potential therapeutic
value of S1P pathway modulation for the treatment of intracellular infection. | en_GB |
