Altering lipid droplet homeostasis affects Coxiella burnetii intracellular growth

Mulye, Minal; Zapata, Brianne; Gilk, Stacey D.

doi:10.1371/journal.pone.0192215

Cited by 29 publications

(30 citation statements)

References 59 publications

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“…In order to identify T4BSS-dependent changes in the expression of host genes, we determined the whole transcriptome of murine alveolar (MH-S) macrophages infected with either wild-type (WT) C. burnetii or a C. burnetii mutant lacking icmD, an essential component of the T4BSS (14). We previously found minimal differences in PV size and bacterial replication between the WT and a C. burnetii T4BSS mutant during the first 48 h of infection of MH-S macrophages (28). Thus, to avoid changes in host cell gene expression that could occur due to PV expansion and bacterial replication after 48 h and because C. burnetii T4BSS effector protein secretion occurs by 4 h postinfection (hpi) (29), we analyzed gene expression at 24 and 48 hpi.…”

Section: Resultsmentioning

confidence: 99%

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

et al. 2018

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is an obligate intracellular bacterium and the etiological agent of Q fever. Successful host cell infection requires the type IVB secretion system (T4BSS), which translocates bacterial effector proteins across the vacuole membrane into the host cytoplasm, where they manipulate a variety of cell processes. To identify host cell targets of T4BSS effector proteins, we determined the transcriptome of murine alveolar macrophages infected with a T4BSS effector mutant. We identified a set of inflammatory genes that are significantly upregulated in T4BSS mutant-infected cells compared to mock-infected cells or cells infected with wild-type (WT) bacteria, suggesting that T4BSS effector proteins downregulate the expression of these genes. In addition, the interleukin-17 (IL-17) signaling pathway was identified as one of the top pathways affected by the bacteria. While previous studies demonstrated that IL-17 plays a protective role against several pathogens, the role of IL-17 during infection is unknown. We found that IL-17 kills intracellular in a dose-dependent manner, with the T4BSS mutant exhibiting significantly more sensitivity to IL-17 than WT bacteria. In addition, quantitative PCR confirmed the increased expression of IL-17 downstream signaling genes in T4BSS mutant-infected cells compared to WT- or mock-infected cells, including the proinflammatory cytokine genes ,, and , the chemokine genes and , and the antimicrobial protein gene We further confirmed that the T4BSS downregulates macrophage CXCL2/macrophage inflammatory protein 2 and CCL5/RANTES protein levels following IL-17 stimulation. Together, these data suggest that downregulates IL-17 signaling in a T4BSS-dependent manner in order to escape the macrophage immune response.

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Section: Resultsmentioning

confidence: 99%

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

et al. 2018

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“…Triacsin C, an inhibitor of host-cell ACSLs that are essential for acyl-CoA synthesis (97), significantly blocked E. chaffeensis infection of host cells, suggesting that host de novo synthesized lipids are required for E. chaffeensis proliferation. In contrast to Ehrlichia, Coxiella intracellular growth was enhanced by triacsin C treatment that blocked LD formation (80). E. chaffeensis is more sensitive to triacsin C (∼90% inhibition of growth at 1 μM) than C. trachomatis (56% inhibition at 7.5 μM), or eukaryotic cells (cell type-dependent, but usually IC 50 > 1 μM) (16,75).…”

Section: Discussionmentioning

confidence: 96%

“…However, paradoxically PV formation and intracellular replication of C. burnetii don't require cholesterol, and increasing PV cholesterol, rather, leads to Coxiella death (78,79). In contrast, LD lipolysis, which is likely regulated by Coxiella T4SS, is critical for bacterial growth (80). Coxiella T4SS effector CvpA involved in the regulation of clathrin-mediated vesicular trafficking events, possibly assisting C. burnetii acquisition of lipids and proteins for PV biogenesis (81).…”

Section: Discussionmentioning

confidence: 99%

Host membrane lipids are trafficked to membranes of intravacuolar bacteriumEhrlichia chaffeensis

Lin

Grandinetti

Hartnell

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Ehrlichia chaffeensis, a cholesterol-rich and cholesterol-dependent obligate intracellular bacterium, partially lacks genes for glycerophospholipid biosynthesis. We found here thatE. chaffeensisis dependent on host glycerolipid biosynthesis, as an inhibitor of host long-chain acyl CoA synthetases, key enzymes for glycerolipid biosynthesis, significantly reduced bacterial proliferation.E. chaffeensiscannot synthesize phosphatidylcholine or cholesterol but encodes enzymes for phosphatidylethanolamine (PE) biosynthesis; however, exogenous NBD-phosphatidylcholine, Bodipy-PE, and TopFluor-cholesterol were rapidly trafficked to ehrlichiae in infected cells. DiI (3,3′-dioctadecylindocarbocyanine)-prelabeled host-cell membranes were unidirectionally trafficked toEhrlichiainclusion and bacterial membranes, but DiI-prelabeledEhrlichiamembranes were not trafficked to host-cell membranes. The trafficking of host-cell membranes toEhrlichiainclusions was dependent on both host endocytic and autophagic pathways, and bacterial protein synthesis, as the respective inhibitors blocked both infection and trafficking of DiI-labeled host membranes toEhrlichia. In addition, DiI-labeled host-cell membranes were trafficked to autophagosomes induced by theE. chaffeensistype IV secretion system effector Etf-1, which traffic to and fuse withEhrlichiainclusions. Cryosections of infected cells revealed numerous membranous vesicles inside inclusions, as well as multivesicular bodies docked on the inclusion surface, both of which were immunogold-labeled by a GFP-tagged 2×FYVE protein that binds to phosphatidylinositol 3-phosphate. Focused ion-beam scanning electron microscopy of infected cells validated numerous membranous structures inside bacteria-containing inclusions. Our results support the notion thatEhrlichiainclusions are amphisomes formed through fusion of early endosomes, multivesicular bodies, and early autophagosomes induced by Etf-1, and they provide host-cell glycerophospholipids and cholesterol that are necessary for bacterial proliferation.

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“…Similarly, C. burnetii ’s formation of foam cells is actively modulated by bacterial effector proteins and is dependent on an increase in fatty acid recruitment to the endoplasmic reticulum for packaging into host LDs [ 82 ]. During C. burnetii infection of macrophages, the expression of host proteins involved in LD breakdown, including patatin-like phospholipase domain containing protein 2 (PNPLA2) or adipose triglyceride lipase (ATGL), acyl-CoA:cholesterol transferase, and fatty acid binding protein (FABP4), is modulated suggesting a requirement of host lipids within LDs, such as cholesterol esters and triacylglycerols, during infection [ 82 , 83 , 84 , 85 ]. The regulation of ATGL and FABP4 indicate a release of free fatty acids and cholesterol from host LDs for C. burnetii nutrient acquisition and membrane production as described previously [ 82 ].…”

Section: Intracellular Bacteria That Replicate Inside a Vacuole Dumentioning

confidence: 99%

Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria

Allen¹,

Martínez²

2020

Pathogens

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Lipids are a broad group of molecules required for cell maintenance and homeostasis. Various intracellular pathogens have developed mechanisms of modulating and sequestering host lipid processes for a large array of functions for both bacterial and host cell survival. Among the host cell lipid functions that intracellular bacteria exploit for infection are the modulation of host plasma membrane microdomains (lipid rafts) required for efficient bacterial entry; the recruitment of specific lipids for membrane integrity of intracellular vacuoles; and the utilization of host lipid droplets for the regulation of immune responses and for energy production through fatty acid β-oxidation and oxidative phosphorylation. The majority of published studies on the utilization of these host lipid pathways during infection have focused on intracellular bacterial pathogens that reside within a vacuole during infection and, thus, have vastly different requirements for host lipid metabolites when compared to those intracellular pathogens that are released into the host cytosol upon infection. Here we summarize the mechanisms by which intracellular bacteria sequester host lipid species and compare the modulation of host lipid pathways and metabolites during host cell infection by intracellular pathogens residing in either a vacuole or within the cytosol of infected mammalian cells. This review will also highlight common and unique host pathways necessary for intracellular bacterial growth that could potentially be targeted for therapeutic intervention.

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Altering lipid droplet homeostasis affects Coxiella burnetii intracellular growth

Cited by 29 publications

References 59 publications

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

Coxiella burnetii Blocks Intracellular Interleukin-17 Signaling in Macrophages

Host membrane lipids are trafficked to membranes of intravacuolar bacteriumEhrlichia chaffeensis

Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria

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