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Chapter 6 : Establishing Intracellular Infection: Modulation of Host Cell Functions ()

Author: Jason A. Carlyon1
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Affiliations: 1: Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298-0678
Content Type: Monograph
Publication Year: 2012

Category: Bacterial Pathogenesis

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Abstract:

Studies of representative members, primarily and , have shed much light on the exquisite mechanisms by which pathogens manipulate their host cells, and are discussed following overviews of the diseases that they cause, their notable genomic features, and their infection and developmental cycles. The secretion of type IV secretion system (T4SS) effectors into host cells is critical for survival of facultative and obligate intracellular bacterial pathogens. Apoptosis is initiated by enzymatic caspases, which are inactive until they are activated by apoptotic signaling pathways. The -occupied vacuole (ApV) excludes fusion with secretory vesicles and specific granules harboring NADPH oxidase and proteolytic enzymes. Preferentially recruiting Rab GTPases that are predominantly found on slow recycling endosomes potentially provides with four intracellular survival advantages. First, is auxotrophic for 16 amino acids. Second, the mechanism by which obtains LDL endocytic pathway-derived cholesterol for incorporation into its cell wall is unknown. Third, continual delivery of recycling endosomes to the ApV would conceivably provide an unlimited supply of host membrane material to allow for expansion of the AVM, which would be necessary to accommodate growing intravacuolar bacterial populations. Fourth, by coating the AVM with recycling endosome- associated Rab GTPases, the ApV camouflages itself as a recycling endosome, which is likely a means by which it protects itself from fusing with lysosomes. Finally, much of what authors know regarding pathogen manipulation of host cell functions is derived from studies of and .

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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Establishing Intracellular Infection: Modulation of Host Cell Functions (Anaplasmataceae)
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Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
/content/10.1128/9781555817336.chap6.fig6-1
FIGURE 1

infection cycle in a myeloid host cell. This model is based on observations of -infected HL-60 cells. (1 to 3) An dense-cored bacterium binds to the host cell surface and triggers its own uptake to reside within a host cell-derived vacuole. (4) The dense-cored organism transitions to a reticulate cell. Arrowheads in corresponding electron micrograph point to two ApVs in which the bacteria are in the process of differentiating from the dense-cored to reticulate cell stage. The thick arrow denotes a vacuole harboring an bacterium that is still in the dense-cored cell form. (5 and 6) The reticulate cell form divides by binary fission to fill the expanding ApV with bacteria. (7) The reticulate cell bacteria transition to the dense-cored form. (8) The mature ApV opens to release dense-cored organisms into the media. Electron micrographs 8a and 8b present ApVs at different stages of opening. Also, a host cell that is filled with several large morulae can lyse to release bacteria. Similar infection/biphasic developmental cycles have been observed for spp. and spp. cultured in mammalian cell lines. (Electron micrograph in step 2 reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f1

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FIGURE 1

infection cycle in a myeloid host cell. This model is based on observations of -infected HL-60 cells. (1 to 3) An dense-cored bacterium binds to the host cell surface and triggers its own uptake to reside within a host cell-derived vacuole. (4) The dense-cored organism transitions to a reticulate cell. Arrowheads in corresponding electron micrograph point to two ApVs in which the bacteria are in the process of differentiating from the dense-cored to reticulate cell stage. The thick arrow denotes a vacuole harboring an bacterium that is still in the dense-cored cell form. (5 and 6) The reticulate cell form divides by binary fission to fill the expanding ApV with bacteria. (7) The reticulate cell bacteria transition to the dense-cored form. (8) The mature ApV opens to release dense-cored organisms into the media. Electron micrographs 8a and 8b present ApVs at different stages of opening. Also, a host cell that is filled with several large morulae can lyse to release bacteria. Similar infection/biphasic developmental cycles have been observed for spp. and spp. cultured in mammalian cell lines. (Electron micrograph in step 2 reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f1

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 2

morulae. Scanning electron micrograph of a DH82 cell infected with from which the cell membrane and EVM have been removed. Bar, 1 µm. (Courtesy of Sunil Thomas, Vsevolod L. Popov, and David H. Walker, Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch.) doi:10.1128/9781555817336.ch6.f2

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FIGURE 2

morulae. Scanning electron micrograph of a DH82 cell infected with from which the cell membrane and EVM have been removed. Bar, 1 µm. (Courtesy of Sunil Thomas, Vsevolod L. Popov, and David H. Walker, Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch.) doi:10.1128/9781555817336.ch6.f2

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 3

Host cell-free ApV binding to and facilitating its uptake by a host cell. Host cell-free organisms and host cell-free ApVs were liberated from infected HL-60 cells and added to murine bone marrow-derived mast cells. After 40 minutes, unbound bacteria were washed off and the host cells were fixed and examined by transmission electron microscopy. The arrow denotes a host cell-free vacuole filled with reticulate cell organisms that is bound to the surface of and is being internalized by a bone marrow-derived mast cell. Our laboratory has observed similar phenomena demonstrating that ApVs are also infectious for human promyelocytic HL-60 cells and monkey choroidal endothelial RF/6A cells. The arrowhead demarcates an dense-cored cell bound at the host cell surface. doi:10.1128/9781555817336.ch6.f3

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FIGURE 3

Host cell-free ApV binding to and facilitating its uptake by a host cell. Host cell-free organisms and host cell-free ApVs were liberated from infected HL-60 cells and added to murine bone marrow-derived mast cells. After 40 minutes, unbound bacteria were washed off and the host cells were fixed and examined by transmission electron microscopy. The arrow denotes a host cell-free vacuole filled with reticulate cell organisms that is bound to the surface of and is being internalized by a bone marrow-derived mast cell. Our laboratory has observed similar phenomena demonstrating that ApVs are also infectious for human promyelocytic HL-60 cells and monkey choroidal endothelial RF/6A cells. The arrowhead demarcates an dense-cored cell bound at the host cell surface. doi:10.1128/9781555817336.ch6.f3

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 4

Phylogenetic tree showing the relationship, based on predicted amino acid sequences, between the eight paralogs in the HZ strain genome. Four paralogs (, , , and ) are only transcribed during infection of ISE6 tick embryonic cells, while two ( and ) are expressed only during infection of human HL-60 promyelocytic leukemia and HMEC-1 human microvascular endothelial cells. This figure was generated based on data published by . The numbering of paralogs is extrapolated from their relative positions to one another on the chromosome and uses the numerical designations assigned by Rikihisa and Lin, 2010. Full-length VirB2 sequences were bootstrapped ( = 1,000) and an unrooted neighbor-joining tree was created (Clustal-X 2.0.8 using the Gonnet scoring matrix) ( ). The tree was visualized using the TreeView program, and bootstrap support is shown at all nodes (Page, 2002). doi:10.1128/9781555817336.ch6.f4

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FIGURE 4

Phylogenetic tree showing the relationship, based on predicted amino acid sequences, between the eight paralogs in the HZ strain genome. Four paralogs (, , , and ) are only transcribed during infection of ISE6 tick embryonic cells, while two ( and ) are expressed only during infection of human HL-60 promyelocytic leukemia and HMEC-1 human microvascular endothelial cells. This figure was generated based on data published by . The numbering of paralogs is extrapolated from their relative positions to one another on the chromosome and uses the numerical designations assigned by Rikihisa and Lin, 2010. Full-length VirB2 sequences were bootstrapped ( = 1,000) and an unrooted neighbor-joining tree was created (Clustal-X 2.0.8 using the Gonnet scoring matrix) ( ). The tree was visualized using the TreeView program, and bootstrap support is shown at all nodes (Page, 2002). doi:10.1128/9781555817336.ch6.f4

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 5

bacteria induce the formation of and are transported through the filopodia in DH82 cells. Shown are scanning electron micrographs of -infected DH82 cells. Thin arrows indicate filopodia. Thick arrows denote flattened fan-shaped structures at the terminal ends of the filopodia. (A) infection promotes the formation of filopodia by DH82 cells. (B to D) Filopodia and the terminal flattened fan-shaped structures are filled with bacteria, as revealed when cell membranes are removed from filopodia. Similar results have been reported for ( ). (Courtesy of Sunil Thomas, Vsevolod L. Popov, and David H. Walker, Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch.) doi:10.1128/9781555817336.ch6.f 5

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FIGURE 5

bacteria induce the formation of and are transported through the filopodia in DH82 cells. Shown are scanning electron micrographs of -infected DH82 cells. Thin arrows indicate filopodia. Thick arrows denote flattened fan-shaped structures at the terminal ends of the filopodia. (A) infection promotes the formation of filopodia by DH82 cells. (B to D) Filopodia and the terminal flattened fan-shaped structures are filled with bacteria, as revealed when cell membranes are removed from filopodia. Similar results have been reported for ( ). (Courtesy of Sunil Thomas, Vsevolod L. Popov, and David H. Walker, Department of Pathology and Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch.) doi:10.1128/9781555817336.ch6.f 5

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 6

APH_1387 is expressed and localizes to the AVM throughout the course of infection. HL-60 cells were synchronously infected with . At 0.7 (A), 4 (B), 8 (C), 12 (D), 18 (E), 24 (F), and 48 h (G and H) post-bacterial addition, samples were fixed and screened with anti-APH_1387 followed by goat anti-rabbit immunoglobulin G conjugated to 6-nm gold particles and examined by electron microscopy. (A and B) Asterisks denote bound or newly internalized dense-cored organisms. (C to F) Arrowheads denote representative portions of the AVM that are labeled with gold particles. (H) Magnified view of the region in panel G that is demarcated by a hatched box. Bars, 0.5 µm. (Reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f6

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FIGURE 6

APH_1387 is expressed and localizes to the AVM throughout the course of infection. HL-60 cells were synchronously infected with . At 0.7 (A), 4 (B), 8 (C), 12 (D), 18 (E), 24 (F), and 48 h (G and H) post-bacterial addition, samples were fixed and screened with anti-APH_1387 followed by goat anti-rabbit immunoglobulin G conjugated to 6-nm gold particles and examined by electron microscopy. (A and B) Asterisks denote bound or newly internalized dense-cored organisms. (C to F) Arrowheads denote representative portions of the AVM that are labeled with gold particles. (H) Magnified view of the region in panel G that is demarcated by a hatched box. Bars, 0.5 µm. (Reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f6

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 7

APH_0032 is expressed and localizes to the AVM late during infection. HL-60 cells were synchronously infected with . At 0.7 (A), 4 (B), 8 (C), 12 (D), 18 (E), 24 (F), and 48 h (G) post-bacterial addition, samples were fixed and screened with anti-APH_0032 followed by goat anti-rabbit immunoglobulin G conjugated to 6-nm gold particles and examined by transmission electron microscopy. (A and B) Asterisks denote bound or newly internalized dense-cored organisms. (F to H) Arrowheads denote representative portions of the AVM that are labeled with gold particles. (H) Magnified view of the region in panel G that is demarcated by a hatched box. (Reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f7

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FIGURE 7

APH_0032 is expressed and localizes to the AVM late during infection. HL-60 cells were synchronously infected with . At 0.7 (A), 4 (B), 8 (C), 12 (D), 18 (E), 24 (F), and 48 h (G) post-bacterial addition, samples were fixed and screened with anti-APH_0032 followed by goat anti-rabbit immunoglobulin G conjugated to 6-nm gold particles and examined by transmission electron microscopy. (A and B) Asterisks denote bound or newly internalized dense-cored organisms. (F to H) Arrowheads denote representative portions of the AVM that are labeled with gold particles. (H) Magnified view of the region in panel G that is demarcated by a hatched box. (Reprinted from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f7

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 8

Hydropathy and antigenicity profiles of confirmed PVM proteins. Numerical scales correspond to the entire amino acid sequence of each protein. Hydropathy plots were generated using the Kyte-Doolittle algorithm to denote hydrophobic (black filled histogram above the axis) and hydrophilic (black filled histogram below the axis) regions ( ). Antigenicity plots were generated using the Jameson-Wolf algorithm to denote regions that are predicted to be antigenic (unfilled histogram above the axis) and/or nonantigenic (unfilled histogram below the axis) ( ). Analyses were performed using Protean, which is part of the Lasergene software package. doi:10.1128/9781555817336.ch6.f8

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FIGURE 8

Hydropathy and antigenicity profiles of confirmed PVM proteins. Numerical scales correspond to the entire amino acid sequence of each protein. Hydropathy plots were generated using the Kyte-Doolittle algorithm to denote hydrophobic (black filled histogram above the axis) and hydrophilic (black filled histogram below the axis) regions ( ). Antigenicity plots were generated using the Jameson-Wolf algorithm to denote regions that are predicted to be antigenic (unfilled histogram above the axis) and/or nonantigenic (unfilled histogram below the axis) ( ). Analyses were performed using Protean, which is part of the Lasergene software package. doi:10.1128/9781555817336.ch6.f8

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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FIGURE 9

The ApV hijacks Rab GTPases. Rab GTPases that are selectively recruited to the ApV are in bold text. Recycling endosomes that are inferred as being intercepted by the ApV are shaded gray. ER, endoplasmic reticulum; cG, -Golgi; ERC, endocytic recycling center; IC, pre-Golgi intermediate compartment; LE, late endosome; LYS, lysosome; mG, -Golgi; NUC, nucleus; RE, recycling endosome; SG, secretory granule; SV, synaptic vesicle; tG, -Golgi. (Reprinted and modified from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f 9

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FIGURE 9

The ApV hijacks Rab GTPases. Rab GTPases that are selectively recruited to the ApV are in bold text. Recycling endosomes that are inferred as being intercepted by the ApV are shaded gray. ER, endoplasmic reticulum; cG, -Golgi; ERC, endocytic recycling center; IC, pre-Golgi intermediate compartment; LE, late endosome; LYS, lysosome; mG, -Golgi; NUC, nucleus; RE, recycling endosome; SG, secretory granule; SV, synaptic vesicle; tG, -Golgi. (Reprinted and modified from with permission of the publisher.) doi:10.1128/9781555817336.ch6.f 9

Citation: Carlyon J. 2012. Establishing Intracellular Infection: Modulation of Host Cell Functions (), p 175-220. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch6
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