Genome-wide identification of modulators of Chlamydia trachomatis parasitophorous vacuole stability highlights an important role for sphingolipid supply
Fig 8
Model describing how a disruption of both sphingolipid supply routes may destabilize inclusions in a potentially therapeutically beneficial manner.
C. trachomatis can acquire sphingolipids in two ways, by recruiting the host ceramide transfer protein CERT to acquire ceramides (Cer) then converted to sphingomyelin (SM) at the inclusion [48], and by hijacking sphingolipid-laden membrane vesicles and directing them to the inclusion [47]. When CpoS is absent, the vesicular transport of sphingomyelin to the inclusion is compromised [11], leading to inclusion damage at mid stages of infection, followed by premature host cell death. We hypothesize that under conditions of impaired ceramide de novo synthesis, the CERT-mediated transport is compromised, while the bacteria may still be able utilize the already available lipid pool through CpoS-mediated modulation of host vesicular transport, leading to more minor inclusion damage that manifests at late stages of infection. A combination of ceramide synthesis disruption and CpoS deficiency, which should compromise both transport routes, results in early inclusion destabilization and clearance of infection while keeping the host cells alive. Hence, an effective therapeutic targeting of inclusion stability may have to aim for blocking both transport routes simultaneously.