Abstract
Chlamydiae are obligate intracellular pathogens that must coordinate the acquisition of host cell-derived biosynthetic constituents essential for bacterial survival. Purified chlamydiae contain several lipids that are typically found in eukaryotes, implying the translocation of host cell lipids to the chlamydial vacuole. Acquisition and incorporation of sphingomyelin occurs subsequent to transport from Golgi-derived exocytic vesicles, with possible intermediate transport through endosomal multivesicular bodies. Eukaryotic host cell-derived sphingomyelin is essential for intracellular growth of Chlamydia trachomatis, but the precise role of this lipid in development has not been delineated. The present study identifies specific phenotypic effects on inclusion membrane biogenesis and stability consequent to conditions of sphingomyelin deficiency. Culturing infected cells in the presence of inhibitors of serine palmitoyltransferase, the first enzyme in the biosynthetic pathway of host cell sphingomyelin, resulted in loss of inclusion membrane integrity with subsequent disruption in normal chlamydial inclusion development. Surprisingly, this was accompanied by premature redifferentiation to and release of infectious elementary bodies. Homotypic fusion of inclusions was also disrupted under conditions of sphingolipid deficiency. In addition, host cell sphingomyelin synthesis was essential for inclusion membrane stability and expansion that is vital to reactivation of persistent chlamydial infection. The present study implicates both the Golgi apparatus and multivesicular bodies as key sources of host-derived lipids, with multivesicular bodies being essential for normal inclusion development and reactivation of persistent C. trachomatis infection.
Highlights
The genus Chlamydia is composed of obligate intracellular prokaryotic pathogens that cause a range of clinical sequelae in humans encompassing ocular, genital, and respiratory tract infections
The genus Chlamydia is composed of a group of obligate intracellular bacterial pathogens that cause several human diseases of medical significance
This study identifies a requirement for the lipid sphingomyelin from the infected host cell for bacterial replication during infection, and for long-term subsistence in persistent chlamydial infection
Summary
The genus Chlamydia is composed of obligate intracellular prokaryotic pathogens that cause a range of clinical sequelae in humans encompassing ocular, genital, and respiratory tract infections. Consequences of subsequent chronic disease include blindness, infertility, arthritis, and possible coronary heart disease [1,2]. Despite their notoriety clinically, the molecular interactions between Chlamydia and its host cell that allow for propagation, persistence, and subsequent pathology, remain elusive. The defining biological characteristic of these successful pathogens is a unique process of intracellular development, with an infectious elementary body (EB) initiating uptake into a target host cell. Successive growth and replication, giving rise to a large inclusion body containing a multitude of infectious EBs, is contingent upon the acquisition of biosynthetic constituents from the nutrient-rich host cell cytosol. The cellular biosynthetic constituents that sustain persistent chlamydiae, and allow for emergence from a persistent state, are poorly understood
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