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Chapter 16 : Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp.

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Abstract:

This chapter focuses on the biology of the macrophage phagosome with respect to its changing responsibilities, although the data discussed is placed in context with other phagocytic cells. To determine the degradative capacity of the phagosome following its formation, fluorogenic substrates were coupled, along with a calibration fluor, to the surface of beads coated with the phagocytic receptor ligands immunoglobulin G (IgG) or mannosylated BSA. The acidification assay and the fluorescent resonance energy transfer (FRET) assay for phagosome/lysosome fusion both reach an end point equilibrium or maximum value. This contrasts with the hydrolysis assays that progress to substrate limitation because an enzyme, once present, will continue to hydrolyze its substrate until either the enzyme is removed or deactivated or, more likely, the substrate is exhausted. Some of these assays exploited specific substrates processed by single, identified enzymes, whereas other substrates were more generic and were hydrolyzed by several enzymes. Recently, these assays have been employed to probe the modulation of the macrophage phagosomes under differing biological situations such as microbial insult and cytokine-mediated activation. The chapter discusses immune activation and the physiology of the phagosome, and focuses specifically on the interplay between the two bacteria and the changing environments that they will experience in the phagosomes of the macrophage. Microarray analysis appears to afford novel insights into the intraphagosomal environment, with the important caveat that the physiology of these compartments is a reflection of both the host cell biology and its manipulation by the pathogen of interest.

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16

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Figures

Image of FIGURE 1
FIGURE 1

Acidification profiles of phagocytosed IgG-coupled beads labeled with fluorescein. Fluorescent emission at 520 nm was taken every 2 s, using alternating excitation wavelengths of 450 nm and 490 nm. Determination of pH of the lumen of the bead-containing phagosomes was calculated following polynomial regression of the excitation ratio with a standard curve. Inhibition of acidification was achieved with the addition of the V-ATPase specific inhibitor concanamycin A (100 nM) following binding of the beads.

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Image of FIGURE 2
FIGURE 2

Confocal images demonstrating the FRET-based fusion phagosome/lysosome fusion assay. IgG-coupled beads labeled with Alexa Fluor 488-SE were bound to and incubated with bone marrow-derived macrophages that were preloaded with Alexa Fluor 594-hydrazide. Beads were given in two separate pulses 60 min apart and fixed 2 min after the second pulse. (A) Combined confocal images showing a bead in a phagosome that has fused with a lysosome (#2) and a bead in a phagosome that has not in fused with a lysosome (#1). (B) Spectral scan at ex/em ratios 450/520 nm of beads #1 and #2 and 594/620 of the acceptor fluor. Bead #2, in a fused phagolysosome, exhibits a biphasic emission profile, demonstrating quenching of the donor fluor signal coupled with excitation of the acceptor fluor.

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Image of FIGURE 3
FIGURE 3

FRET-based phagosome/lysosome fusion profiles. Diminished phagosome/lysosome fusion was achieved with the calmodulin inhibitor W7 (15 μM) and the V-ATPase inhibitor concanamycin A (100 nM) in comparison with untreated (control) cells. Lysosomal fusion profiles for IgG-coupled bead-containing phagosomes were generated using the equation RFU = F/D – F/D (RFU, relative fluorescent units; F, FRET-generated fluorescent emission in real time; D, donor emission in real time; F, “FRET” signal contribution of the beads alone; D, donor emission of the beads alone). Fluorescent measurements were taken every 2 s for 3 h.

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Image of FIGURE 4
FIGURE 4

Measurement of the hydrolytic activities in macrophage phagosomes following the internalization of substrate-bearing particles. (A) Bulk proteinase activity was measured with the substrate DQ Green BSA linked to Man-BSA-coated beads. Manipulation of hydrolytic rates was achieved with inhibitors concanamycin A (100 nM) and leupeptin (100 μg/ml). (B) Cysteine proteinase activity was measured with Biotin-FR-Rhodamine 110 beads. Manipulation of hydrolytic rates was achieved with inhibitors concanamycin A (100 nM) and leupeptin (100 μg/ml). (C) β-Galactosidase activity was measured with beads bearing the substrate 5-dodecanoylaminofluorescein di-β-D-galactopyranoside. Manipulation of hydrolytic rates was achieved with inhibitors concanamycin A (100 nM) and PETG (phenylethyl thiogalactopyranoside) (10 μg/ml). (D) Lipolysis was measured with the quenched pyrene-containing substrate 1-trinitrophenyl-amino-dodecanoyl-2-pyrenedecanoyl-3--hexadecyl--glycerol. Manipulation of hydrolytic rates was achieved with inhibitors concanamycin A (100 nM) and tetrahydrolipstatin (10 μg/ml). Traces were generated using the equation FU = substrate fluorescence/calibration fluor emission (where FU = arbitrary fluorescent units). Measurements were taken every second for 30 min.

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Image of FIGURE 5
FIGURE 5

Phagosomes containing , formed in the presence or absence of TLR2 or TLR4 signaling, exhibit comparable phagosome/lysosome fusion profiles, indicating that the stimulation of either TLR2 or TLR4 does not have an impact on phagosome maturation. (A) The FRET-based assay was used to quantify phagosome/lysosome mixing following uptake of formalinfixed +/– LPS in wild-type (WT) (C57BL/6) and TLR2 macrophages. Data are presented as an average over four individual sets of data. (B) Degradation of IκBα and phosphorylation of p38 mitogen-activated protein kinase in the macrophage were examined by immuno-blotting following phagocytosis of particles with or without incorporated LPS in WT (C57BL/6) and TLR2 macrophages. Reproduced with permission from Elsevier ( ).

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Image of FIGURE 6
FIGURE 6

Specific hydrolase activities of phagosomes containing mannosylated beads bearing fluorogenic substrates along with a calibration fluor were measured in resting and macrophage monolayers activated by overnight incubation with LPS (10 ng/ml) and/or IFN-γ (100 U/ml). The increase in substrate fluorescence relative to the calibration fluor (relative reporter fluorescence) correlates to substrate hydrolysis and was plotted against time. (A) Phagosomal proteolysis was measured through incorporation of the generic protease substrate DQ Green Bodipy BSA. (B) Phagosomal lipolysis was measured through incorporation of the triglyceride analogue 1-trinitrophenyl-amino-dodecanoyl-2-pyrenedecanoyl-3--hexadecyl--glycerol. (C) Phagosomal β-galactosidase activity was measured through the incorporation of the β-galactosidase substrate 5-dodecanoylaminofluorescein di-β-D-galactopyranoside. Reproduced with permission ( ).

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Image of FIGURE 7
FIGURE 7

(Left) Transcriptional profile of 2 h postinternalization compared with bacteria in the medium control. Genes upregulated beyond the 1.6X cutoff are shown in gray. (Right) Kinetics of the transcriptional response to the transition to an intraphagosomal environment. A rapid, time-dependent induction of a gene subset is triggered within minutes of internalization in response to intracellular cues. Reproduced with permission from Elsevier ( ).

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Image of FIGURE 8
FIGURE 8

Phagosome acidification modulates gene expression. Prior to infection, macrophages were treated with 100 nM concanamycin A (CcA) to inhibit acidification of -containing phagosome from pH 7 to pH 6.4. Transcriptional profiling showed that 24 of the 64 genes that were upregulated in untreated macrophages were not upregulated in cells treated with CcA (>1.5-fold, < 0.05). The Venn diagram shows the overlap of these 24 genes compared with those genes induced by in vitro acid stress at pH 6.5 and 5.5. Genes induced >1.5-fold ( < 0.05) in at least one condition and whose array signals passed quality filters in all three conditions were included. Reproduced with permission from Elsevier ( ).

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16
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Tables

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TABLE 1

Substrates used and activities assayed

Citation: Yates R, Rohde K, Abramovitch R, Russell D. 2009. Functional Analysis of the Intraphagosomal Environment of the Macrophage: Fluorogenic Reporters and the Transcriptional Responses of and spp., p 249-264. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch16

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