Abstract
The obligate intracellular pathogen Chlamydia trachomatis replicates within a membrane-bound inclusion that acquires host sphingomyelin (SM), a process that is essential for replication as well as inclusion biogenesis. Previous studies demonstrate that SM is acquired by a Brefeldin A (BFA)-sensitive vesicular trafficking pathway, although paradoxically, this pathway is dispensable for bacterial replication. This finding suggests that other lipid transport mechanisms are involved in the acquisition of host SM. In this work, we interrogated the role of specific components of BFA-sensitive and BFA-insensitive lipid trafficking pathways to define their contribution in SM acquisition during infection. We found that C. trachomatis hijacks components of both vesicular and non-vesicular lipid trafficking pathways for SM acquisition but that the SM obtained from these separate pathways is being utilized by the pathogen in different ways. We show that C. trachomatis selectively co-opts only one of the three known BFA targets, GBF1, a regulator of Arf1-dependent vesicular trafficking within the early secretory pathway for vesicle-mediated SM acquisition. The Arf1/GBF1-dependent pathway of SM acquisition is essential for inclusion membrane growth and stability but is not required for bacterial replication. In contrast, we show that C. trachomatis co-opts CERT, a lipid transfer protein that is a key component in non-vesicular ER to trans-Golgi trafficking of ceramide (the precursor for SM), for C. trachomatis replication. We demonstrate that C. trachomatis recruits CERT, its ER binding partner, VAP-A, and SM synthases, SMS1 and SMS2, to the inclusion and propose that these proteins establish an on-site SM biosynthetic factory at or near the inclusion. We hypothesize that SM acquired by CERT-dependent transport of ceramide and subsequent conversion to SM is necessary for C. trachomatis replication whereas SM acquired by the GBF1-dependent pathway is essential for inclusion growth and stability. Our results reveal a novel mechanism by which an intracellular pathogen redirects SM biosynthesis to its replicative niche.
Highlights
Chlamydia species are obligate intracellular pathogens that cause a wide range of diseases in humans, including sexually transmitted, ocular, and respiratory tract infections [1]
We propose that C. trachomatis utilizes separate lipid trafficking pathways to acquire SM for distinct roles during infection: SM acquired by the GBF1dependent pathway is essential for inclusion growth and stability while CERT-dependent transport of ceramide and subsequent conversion to SM is necessary for C. trachomatis replication
We found that GBF1 and BIG1 were localized to the fragmented Golgi around the inclusion in C. trachomatis-infected cells and appeared to maintain their cis and trans polarity, as observed in uninfected cells (Figure 1A)
Summary
Chlamydia species are obligate intracellular pathogens that cause a wide range of diseases in humans, including sexually transmitted, ocular, and respiratory tract infections [1]. All Chlamydia species share a dimorphic developmental cycle that allows them to survive within the hostile environment of the host cell (reviewed in [3]). Infection is initiated by binding of the EB to the host cell where it is taken up by an actin and Rho family GTPase-dependent process and sequestered within a unique membrane bound compartment called the inclusion [4].
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