Manipulation of Host Cholesterol by Obligate Intracellular Bacteria

Abstract

Cholesterol is a multifunctional lipid that plays important metabolic and structural roles in the eukaryotic cell. Despite having diverse lifestyles, the obligate intracellular bacterial pathogens Chlamydia, Coxiella, Anaplasma, Ehrlichia, and Rickettsia all target cholesterol during host cell colonization as a potential source of membrane, as well as a means to manipulate host cell signaling and trafficking. To promote host cell entry, these pathogens utilize cholesterol-rich microdomains known as lipid rafts, which serve as organizational and functional platforms for host signaling pathways involved in phagocytosis. Once a pathogen gains entrance to the intracellular space, it can manipulate host cholesterol trafficking pathways to access nutrient-rich vesicles or acquire membrane components for the bacteria or bacteria-containing vacuole. To acquire cholesterol, these pathogens specifically target host cholesterol metabolism, uptake, efflux, and storage. In this review, we examine the strategies obligate intracellular bacterial pathogens employ to manipulate cholesterol during host cell colonization. Understanding how obligate intracellular pathogens target and use host cholesterol provides critical insight into the host-pathogen relationship.

Keywords: Anaplasma; Chlamydia; Coxiella; Rickettsia; cholesterol; lipid droplet; lipid raft.

Figure 1

Overview of host cholesterol-pathogen interactions. For Rickettsia, Coxiella, Anaplasma, and Ehrlichia, attachment to the host cell plasma membrane and subsequent host cell entry involves cholesterol-rich lipid rafts (red bars). The role of lipid rafts for Chlamydia is unclear, and may be species- or host cell-specific, while Orientia utilizes lipid rafts for exit. Cholesterol (shown as red circles) is found in the pathogen-containing vacuoles, as well as the bacterial membrane of Chlamydia, Anaplasma, and Ehrlichia. Golgi-derived vesicles, multivesicular bodies (MVB), and lipid droplets traffic to the Chlamydia inclusion and serve as source of cholesterol. The source of cholesterol in the Coxiella vacuole is not clear, but may involve MVBs, while Anaplasma and Ehrlichia intercept LDL-derived cholesterol. Chlamydia, Coxiella, and Anaplasma target host gene expression to manipulate cholesterol homeostasis (Dotted arrow pointing to the nucleus).