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Manipulation of Host Cell Organelles by Intracellular Pathogens

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  • Authors: Titilayo O. Omotade1, Craig R. Roy2
  • Editors: Pascale Cossart3, Craig R. Roy4, Philippe Sansonetti5
    Affiliations: 1: Department of Microbial Pathogenesis, Yale University, New Haven, CT; 2: Department of Microbial Pathogenesis, Yale University, New Haven, CT; 3: Institut Pasteur, Paris, France; 4: Yale University School of Medicine, New Haven, Connecticut; 5: Institut Pasteur, Paris, France
  • Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0022-2019
  • Received 10 January 2019 Accepted 28 January 2019 Published 26 April 2019
  • Craig R. Roy, [email protected]
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  • Abstract:

    In this article, we explore the unique adaptations of intracellular bacterial pathogens that manipulate conserved cellular pathways, organelles, and cargo to convert the phagosome into a pathogen-containing vacuole (PCV). The phagosome is a degradative organelle that rapidly acidifies as it delivers cargo to the lysosome to destroy microbes and cellular debris. However, to avoid this fate, intracellular bacterial pathogens hijack the key molecular modulators of intracellular traffic: small GTPases, phospholipids, SNAREs, and their associated effectors. Following uptake, pathogens that reside in the phagosome either remain associated with the endocytic pathway or rapidly diverge from the preprogrammed route to the lysosome. Both groups rely on effector-mediated mechanisms to meet the common challenges of intracellular life, such as nutrient acquisition, vacuole expansion, and evasion of the host immune response. , , and serve as a lens through which we explore regulators of the canonical endocytic route and pathogens that seek to subvert it. On the other hand, pathogens such as , , and disconnect from the canonical endocytic route. This bifurcation is linked to extensive hijacking of the secretory pathway and repurposing of the PCV into specialized compartments that resemble organelles in the secretory network. Finally, each pathogen devises specific strategies to counteract host immune responses, such as autophagy, which aim to destroy these aberrant organelles. Collectively, each unique intracellular niche and the pathogens that construct them reflect the outcome of an aggressive and ongoing molecular arms race at the host-pathogen interface. Improving our understanding of these well-adapted pathogens can help us refine our knowledge of conserved cell biological processes.

  • Citation: Omotade T, Roy C. 2019. Manipulation of Host Cell Organelles by Intracellular Pathogens. Microbiol Spectrum 7(2):BAI-0022-2019. doi:10.1128/microbiolspec.BAI-0022-2019.


1. Doherty GJ, McMahon HT. 2009. Mechanisms of endocytosis. Annu Rev Biochem 78:857–902 http://dx.doi.org/10.1146/annurev.biochem.78.081307.110540. [PubMed][CrossRef]
2. Stenmark H. 2009. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10:513–525 http://dx.doi.org/10.1038/nrm2728. [PubMed][CrossRef]
3. Di Paolo G, De Camilli P. 2006. Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657 http://dx.doi.org/10.1038/nature05185. [PubMed][CrossRef]
4. Hutagalung AH, Novick PJ. 2011. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 91:119–149 http://dx.doi.org/10.1152/physrev.00059.2009. [PubMed][CrossRef]
5. Elkin SR, Lakoduk AM, Schmid SL. 2016. Endocytic pathways and endosomal trafficking: a primer. Wien Med Wochenschr 166:196–204 http://dx.doi.org/10.1007/s10354-016-0432-7. [PubMed][CrossRef]
6. Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B, Zerial M. 1992. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 70:715–728 http://dx.doi.org/10.1016/0092-8674(92)90306-W. [PubMed][CrossRef]
7. Vanlandingham PA, Ceresa BP. 2009. Rab7 regulates late endocytic trafficking downstream of multivesicular body biogenesis and cargo sequestration. J Biol Chem 284:12110–12124 http://dx.doi.org/10.1074/jbc.M809277200. [CrossRef]
8. Kinchen JM, Ravichandran KS. 2008. Phagosome maturation: going through the acid test. Nat Rev Mol Cell Biol 9:781–795 http://dx.doi.org/10.1038/nrm2515. [PubMed][CrossRef]
9. De Camilli P, Emr SD, McPherson PS, Novick P. 1996. Phosphoinositides as regulators in membrane traffic. Science 271:1533–1539 http://dx.doi.org/10.1126/science.271.5255.1533. [PubMed][CrossRef]
10. Lee MC, Orci L, Hamamoto S, Futai E, Ravazzola M, Schekman R. 2005. Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle. Cell 122:605–617 http://dx.doi.org/10.1016/j.cell.2005.07.025. [CrossRef]
11. Beck R, Sun Z, Adolf F, Rutz C, Bassler J, Wild K, Sinning I, Hurt E, Brügger B, Béthune J, Wieland F. 2008. Membrane curvature induced by Arf1-GTP is essential for vesicle formation. Proc Natl Acad Sci USA 105:11731–11736 http://dx.doi.org/10.1073/pnas.0805182105. [CrossRef]
12. D’Souza-Schorey C, Chavrier P. 2006. ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol 7:347–358 http://dx.doi.org/10.1038/nrm1910. [CrossRef]
13. Hong W. 2005. SNAREs and traffic. Biochim Biophys Acta 1744:493–517. [PubMed][CrossRef]
14. Chen YA, Scheller RH. 2001. SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol 2:98–106 http://dx.doi.org/10.1038/35052017. [PubMed][CrossRef]
15. Allan BB, Moyer BD, Balch WE. 2000. Rab1 recruitment of p115 into a cis-SNARE complex: programming budding COPII vesicles for fusion. Science 289:444–448 http://dx.doi.org/10.1126/science.289.5478.444. [CrossRef]
16. Rzomp KA, Scholtes LD, Briggs BJ, Whittaker GR, Scidmore MA. 2003. Rab GTPases are recruited to chlamydial inclusions in both a species-dependent and species-independent manner. Infect Immun 71:5855–5870 http://dx.doi.org/10.1128/IAI.71.10.5855-5870.2003. [PubMed][CrossRef]
17. Capmany A, Damiani MT. 2010. Chlamydia trachomatis intercepts Golgi-derived sphingolipids through a Rab14-mediated transport required for bacterial development and replication. PLoS One 5:e14084 http://dx.doi.org/10.1371/journal.pone.0014084. [PubMed][CrossRef]
18. Dickson EJ, Jensen JB, Hille B. 2014. Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P2 and maintenance of KCNQ2/3 ion channel current. Proc Natl Acad Sci USA 111:E2281–E2290 http://dx.doi.org/10.1073/pnas.1407133111. [PubMed][CrossRef]
19. Clayton EL, Minogue S, Waugh MG. 2013. Mammalian phosphatidylinositol 4-kinases as modulators of membrane trafficking and lipid signaling networks. Prog Lipid Res 52:294–304 http://dx.doi.org/10.1016/j.plipres.2013.04.002. [PubMed][CrossRef]
20. Bishé B, Syed GH, Field SJ, Siddiqui A. 2012. Role of phosphatidylinositol 4-phosphate (PI4P) and its binding protein GOLPH3 in hepatitis C virus secretion. J Biol Chem 287:27637–27647 http://dx.doi.org/10.1074/jbc.M112.346569. [PubMed][CrossRef]
21. Jutras I, Desjardins M. 2005. Phagocytosis: at the crossroads of innate and adaptive immunity. Annu Rev Cell Dev Biol 21:511–527 http://dx.doi.org/10.1146/annurev.cellbio.20.010403.102755. [PubMed][CrossRef]
22. Gruenberg J, van der Goot FG. 2006. Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol 7:495–504 http://dx.doi.org/10.1038/nrm1959. [PubMed][CrossRef]
23. Vieira OV, Botelho RJ, Rameh L, Brachmann SM, Matsuo T, Davidson HW, Schreiber A, Backer JM, Cantley LC, Grinstein S. 2001. Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J Cell Biol 155:19–25 http://dx.doi.org/10.1083/jcb.200107069. [PubMed][CrossRef]
24. Flannagan RS, Jaumouillé V, Grinstein S. 2012. The cell biology of phagocytosis. Annu Rev Pathol 7:61–98 http://dx.doi.org/10.1146/annurev-pathol-011811-132445. [PubMed][CrossRef]
25. Xu M, Liu Y, Zhao L, Gan Q, Wang X, Yang C. 2014. The lysosomal cathepsin protease CPL-1 plays a leading role in phagosomal degradation of apoptotic cells in Caenorhabditis elegans. Mol Biol Cell 25:2071–2083 http://dx.doi.org/10.1091/mbc.e14-01-0015. [CrossRef]
26. Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L, Calafat J, Janssen H, Wubbolts R, Neefjes J. 2001. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol 11:1680–1685 http://dx.doi.org/10.1016/S0960-9822(01)00531-0. [CrossRef]
27. Harrison RE, Bucci C, Vieira OV, Schroer TA, Grinstein S. 2003. Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol Cell Biol 23:6494–6506 http://dx.doi.org/10.1128/MCB.23.18.6494-6506.2003. [CrossRef]
28. Huynh KK, Eskelinen E-L, Scott CC, Malevanets A, Saftig P, Grinstein S. 2007. LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J 26:313–324 http://dx.doi.org/10.1038/sj.emboj.7601511. [PubMed][CrossRef]
29. MacGurn JA, Cox JS. 2007. A genetic screen for Mycobacterium tuberculosis mutants defective for phagosome maturation arrest identifies components of the ESX-1 secretion system. Infect Immun 75:2668–2678 http://dx.doi.org/10.1128/IAI.01872-06. [CrossRef]
30. Vergne I, Chua J, Lee H-H, Lucas M, Belisle J, Deretic V. 2005. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc Natl Acad Sci USA 102:4033–4038 http://dx.doi.org/10.1073/pnas.0409716102. [CrossRef]
31. Vergne I, Chua J, Deretic V. 2003. Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca2+/calmodulin-PI3K hVPS34 cascade. J Exp Med 198:653–659 http://dx.doi.org/10.1084/jem.20030527. [CrossRef]
32. Vieira OV, Harrison RE, Scott CC, Stenmark H, Alexander D, Liu J, Gruenberg J, Schreiber AD, Grinstein S. 2004. Acquisition of Hrs, an essential component of phagosomal maturation, is impaired by mycobacteria. Mol Cell Biol 24:4593–4604 http://dx.doi.org/10.1128/MCB.24.10.4593-4604.2004. [PubMed][CrossRef]
33. Fratti RA, Backer JM, Gruenberg J, Corvera S, Deretic V. 2001. Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J Cell Biol 154:631–644 http://dx.doi.org/10.1083/jcb.200106049. [CrossRef]
34. Gaspar AH, Machner MP. 2014. VipD is a Rab5-activated phospholipase A1 that protects Legionella pneumophila from endosomal fusion. Proc Natl Acad Sci USA 111:4560–4565 http://dx.doi.org/10.1073/pnas.1316376111. [CrossRef]
35. Hubber A, Roy CR. 2010. Modulation of host cell function by Legionella pneumophila type IV effectors. Annu Rev Cell Dev Biol 26:261–283 http://dx.doi.org/10.1146/annurev-cellbio-100109-104034. [PubMed][CrossRef]
36. Campanacci V, Mukherjee S, Roy CR, Cherfils J. 2013. Structure of the Legionella effector AnkX reveals the mechanism of phosphocholine transfer by the FIC domain. EMBO J 32:1469–1477 http://dx.doi.org/10.1038/emboj.2013.82. [PubMed][CrossRef]
37. Puri RV, Reddy PV, Tyagi AK. 2013. Secreted acid phosphatase (SapM) of Mycobacterium tuberculosis is indispensable for arresting phagosomal maturation and growth of the pathogen in guinea pig tissues. PLoS One 8:e70514 http://dx.doi.org/10.1371/journal.pone.0070514. [PubMed][CrossRef]
38. Méresse S, Steele-Mortimer O, Finlay BB, Gorvel JP. 1999. The rab7 GTPase controls the maturation of Salmonella typhimurium-containing vacuoles in HeLa cells. EMBO J 18:4394–4403 http://dx.doi.org/10.1093/emboj/18.16.4394. [CrossRef]
39. Garcia-del Portillo F, Zwick MB, Leung KY, Finlay BB. 1993. Salmonella induces the formation of filamentous structures containing lysosomal membrane glycoproteins in epithelial cells. Proc Natl Acad Sci USA 90:10544–10548 http://dx.doi.org/10.1073/pnas.90.22.10544. [CrossRef]
40. Kubori T, Galán JE. 2003. Temporal regulation of Salmonella virulence effector function by proteasome-dependent protein degradation. Cell 115:333–342 http://dx.doi.org/10.1016/S0092-8674(03)00849-3. [CrossRef]
41. Bakowski MA, Braun V, Lam GY, Yeung T, Heo WD, Meyer T, Finlay BB, Grinstein S, Brumell JH. 2010. The phosphoinositide phosphatase SopB manipulates membrane surface charge and trafficking of the Salmonella-containing vacuole. Cell Host Microbe 7:453–462 http://dx.doi.org/10.1016/j.chom.2010.05.011. [CrossRef]
42. Steele-Mortimer O, Knodler LA, Marcus SL, Scheid MP, Goh B, Pfeifer CG, Duronio V, Finlay BB. 2000. Activation of Akt/protein kinase B in epithelial cells by the Salmonella typhimurium effector sigD. J Biol Chem 275:37718–37724 http://dx.doi.org/10.1074/jbc.M008187200. [CrossRef]
43. Terebiznik MR, Vieira OV, Marcus SL, Slade A, Yip CM, Trimble WS, Meyer T, Finlay BB, Grinstein S. 2002. Elimination of host cell PtdIns(4,5)P(2) by bacterial SigD promotes membrane fission during invasion by Salmonella. Nat Cell Biol 4:766–773 http://dx.doi.org/10.1038/ncb854. [CrossRef]
44. Hernandez LD, Hueffer K, Wenk MR, Galán JE. 2004. Salmonella modulates vesicular traffic by altering phosphoinositide metabolism. Science 304:1805–1807 http://dx.doi.org/10.1126/science.1098188. [CrossRef]
45. Mallo GV, Espina M, Smith AC, Terebiznik MR, Alemán A, Finlay BB, Rameh LE, Grinstein S, Brumell JH. 2008. SopB promotes phosphatidylinositol 3-phosphate formation on Salmonella vacuoles by recruiting Rab5 and Vps34. J Cell Biol 182:741–752 http://dx.doi.org/10.1083/jcb.200804131. [CrossRef]
46. Sherwood RK, Roy CR. 2013. A Rab-centric perspective of bacterial pathogen-occupied vacuoles. Cell Host Microbe 14:256–268 http://dx.doi.org/10.1016/j.chom.2013.08.010. [PubMed][CrossRef]
47. Via LE, Deretic D, Ulmer RJ, Hibler NS, Huber LA, Deretic V. 1997. Arrest of mycobacterial phagosome maturation is caused by a block in vesicle fusion between stages controlled by rab5 and rab7. J Biol Chem 272:13326–13331 http://dx.doi.org/10.1074/jbc.272.20.13326. [CrossRef]
48. Perskvist N, Roberg K, Kulyté A, Stendahl O. 2002. Rab5a GTPase regulates fusion between pathogen-containing phagosomes and cytoplasmic organelles in human neutrophils. J Cell Sci 115:1321–1330.
49. Roberts EA, Chua J, Kyei GB, Deretic V. 2006. Higher order Rab programming in phagolysosome biogenesis. J Cell Biol 174:923–929 http://dx.doi.org/10.1083/jcb.200603026. [PubMed][CrossRef]
50. Garcia-del Portillo F, Finlay BB. 1995. Targeting of Salmonella typhimurium to vesicles containing lysosomal membrane glycoproteins bypasses compartments with mannose 6-phosphate receptors. J Cell Biol 129:81–97 http://dx.doi.org/10.1083/jcb.129.1.81. [PubMed][CrossRef]
51. Hashim S, Mukherjee K, Raje M, Basu SK, Mukhopadhyay A. 2000. Live Salmonella modulate expression of Rab proteins to persist in a specialized compartment and escape transport to lysosomes. J Biol Chem 275:16281–16288 http://dx.doi.org/10.1074/jbc.275.21.16281. [CrossRef]
52. Galán JE. 2001. Salmonella interactions with host cells: type III secretion at work. Annu Rev Cell Dev Biol 17:53–86 http://dx.doi.org/10.1146/annurev.cellbio.17.1.53. [PubMed][CrossRef]
53. Spanò S, Liu X, Galán JE. 2011. Proteolytic targeting of Rab29 by an effector protein distinguishes the intracellular compartments of human-adapted and broad-host Salmonella. Proc Natl Acad Sci USA 108:18418–18423 http://dx.doi.org/10.1073/pnas.1111959108. [CrossRef]
54. Spanò S, Galán JE. 2012. A Rab32-dependent pathway contributes to Salmonella typhi host restriction. Science 338:960–963 http://dx.doi.org/10.1126/science.1229224. [CrossRef]
55. Gerondopoulos A, Langemeyer L, Liang JR, Linford A, Barr FA. 2012. BLOC-3 mutated in Hermansky-Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor. Curr Biol 22:2135–2139 http://dx.doi.org/10.1016/j.cub.2012.09.020. [CrossRef]
56. Bultema JJ, Ambrosio AL, Burek CL, Di Pietro SM. 2012. BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles. J Biol Chem 287:19550–19563 http://dx.doi.org/10.1074/jbc.M112.351908. [CrossRef]
57. Spanò S, Gao X, Hannemann S, Lara-Tejero M, Galán JE. 2016. A bacterial pathogen targets a host Rab-family GTPase defense pathway with a GAP. Cell Host Microbe 19:216–226 http://dx.doi.org/10.1016/j.chom.2016.01.004. [CrossRef]
58. Stein MA, Leung KY, Zwick M, Garcia-del Portillo F, Finlay BB. 1996. Identification of a Salmonella virulence gene required for formation of filamentous structures containing lysosomal membrane glycoproteins within epithelial cells. Mol Microbiol 20:151–164 http://dx.doi.org/10.1111/j.1365-2958.1996.tb02497.x. [CrossRef]
59. Boucrot E, Henry T, Borg JP, Gorvel JP, Méresse S. 2005. The intracellular fate of Salmonella depends on the recruitment of kinesin. Science 308:1174–1178 http://dx.doi.org/10.1126/science.1110225. [PubMed][CrossRef]
60. Dumont A, Boucrot E, Drevensek S, Daire V, Gorvel JP, Poüs C, Holden DW, Méresse S. 2010. SKIP, the host target of the Salmonella virulence factor SifA, promotes kinesin-1-dependent vacuolar membrane exchanges. Traffic 11:899–911 http://dx.doi.org/10.1111/j.1600-0854.2010.01069.x. [PubMed][CrossRef]
61. Beuzón CR, Méresse S, Unsworth KE, Ruíz-Albert J, Garvis S, Waterman SR, Ryder TA, Boucrot E, Holden DW. 2000. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. EMBO J 19:3235–3249 http://dx.doi.org/10.1093/emboj/19.13.3235. [PubMed][CrossRef]
62. Burton PR, Kordová N, Paretsky D. 1971. Electron microscopic studies of the rickettsia Coxiella burnetii: entry, lysosomal response, and fate of rickettsial DNA in L-cells. Can J Microbiol 17:143–150 http://dx.doi.org/10.1139/m71-025. [CrossRef]
63. Voth DE, Heinzen RA. 2007. Lounging in a lysosome: the intracellular lifestyle of Coxiella burnetii. Cell Microbiol 9:829–840 http://dx.doi.org/10.1111/j.1462-5822.2007.00901.x. [PubMed][CrossRef]
64. Berón W, Gutierrez MG, Rabinovitch M, Colombo MI. 2002. Coxiella burnetii localizes in a Rab7-labeled compartment with autophagic characteristics. Infect Immun 70:5816–5821 http://dx.doi.org/10.1128/IAI.70.10.5816-5821.2002. [CrossRef]
65. Romano PS, Gutierrez MG, Berón W, Rabinovitch M, Colombo MI. 2007. The autophagic pathway is actively modulated by phase II Coxiella burnetii to efficiently replicate in the host cell. Cell Microbiol 9:891–909 http://dx.doi.org/10.1111/j.1462-5822.2006.00838.x. [PubMed][CrossRef]
66. McDonough JA, Newton HJ, Klum S, Swiss R, Agaisse H, Roy CR. 2013. Host pathways important for Coxiella burnetii infection revealed by genome-wide RNA interference screening. mBio 4:e00606-12 http://dx.doi.org/10.1128/mBio.00606-12. [PubMed][CrossRef]
67. Newton HJ, McDonough JA, Roy CR. 2013. Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole. PLoS One 8:e54566 http://dx.doi.org/10.1371/journal.pone.0054566. [PubMed][CrossRef]
68. Beare PA, Gilk SD, Larson CL, Hill J, Stead CM, Omsland A, Cockrell DC, Howe D, Voth DE, Heinzen RA. 2011. Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages. mBio 2:e00175-11 http://dx.doi.org/10.1128/mBio.00175-11. [PubMed][CrossRef]
69. Howe D, Melnicáková J, Barák I, Heinzen RA. 2003. Maturation of the Coxiella burnetii parasitophorous vacuole requires bacterial protein synthesis but not replication. Cell Microbiol 5:469–480 http://dx.doi.org/10.1046/j.1462-5822.2003.00293.x. [PubMed][CrossRef]
70. Heinzen RA, Scidmore MA, Rockey DD, Hackstadt T. 1996. Differential interaction with endocytic and exocytic pathways distinguish parasitophorous vacuoles of Coxiella burnetii and Chlamydia trachomatis. Infect Immun 64:796–809. [PubMed]
71. Ghigo E, Capo C, Tung CH, Raoult D, Gorvel JP, Mege JL. 2002. Coxiella burnetii survival in THP-1 monocytes involves the impairment of phagosome maturation: IFN-gamma mediates its restoration and bacterial killing. J Immunol 169:4488–4495 http://dx.doi.org/10.4049/jimmunol.169.8.4488. [CrossRef]
72. He C, Klionsky DJ. 2009. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93 http://dx.doi.org/10.1146/annurev-genet-102808-114910. [PubMed][CrossRef]
73. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T. 2000. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19:5720–5728 http://dx.doi.org/10.1093/emboj/19.21.5720. [CrossRef]
74. Gutierrez MG, Vázquez CL, Munafó DB, Zoppino FC, Berón W, Rabinovitch M, Colombo MI. 2005. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell Microbiol 7:981–993 http://dx.doi.org/10.1111/j.1462-5822.2005.00527.x. [CrossRef]
75. Kohler LJ, Reed SC, Sarraf SA, Arteaga DD, Newton HJ, Roy CR. 2016. Effector protein Cig2 decreases host tolerance of infection by directing constitutive fusion of autophagosomes with the Coxiella-containing vacuole. mBio 17:e01127-16. [CrossRef]
76. Munafó DB, Colombo MI. 2002. Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24. Traffic 3:472–482 http://dx.doi.org/10.1034/j.1600-0854.2002.30704.x. [CrossRef]
77. Gutierrez MG, Saka HA, Chinen I, Zoppino FC, Yoshimori T, Bocco JL, Colombo MI. 2007. Protective role of autophagy against Vibrio cholerae cytolysin, a pore-forming toxin from V. cholerae. Proc Natl Acad Sci USA 104:1829–1834 http://dx.doi.org/10.1073/pnas.0601437104. [CrossRef]
78. Campoy EM, Zoppino FC, Colombo MI. 2011. The early secretory pathway contributes to the growth of the Coxiella-replicative niche. Infect Immun 79:402–413 http://dx.doi.org/10.1128/IAI.00688-10. [CrossRef]
79. Pappas G, Akritidis N, Bosilkovski M, Tsianos E. 2005. Brucellosis. N Engl J Med 352:2325–2336 http://dx.doi.org/10.1056/NEJMra050570. [PubMed][CrossRef]
80. Celli J, de Chastellier C, Franchini DM, Pizarro-Cerda J, Moreno E, Gorvel JP. 2003. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J Exp Med 198:545–556 http://dx.doi.org/10.1084/jem.20030088. [CrossRef]
81. Comerci DJ, Martínez-Lorenzo MJ, Sieira R, Gorvel JP, Ugalde RA. 2001. Essential role of the VirB machinery in the maturation of the Brucella abortus-containing vacuole. Cell Microbiol 3:159–168 http://dx.doi.org/10.1046/j.1462-5822.2001.00102.x. [CrossRef]
82. Delrue RM, Martinez-Lorenzo M, Lestrate P, Danese I, Bielarz V, Mertens P, De Bolle X, Tibor A, Gorvel JP, Letesson JJ. 2001. Identification of Brucella spp. genes involved in intracellular trafficking. Cell Microbiol 3:487–497 http://dx.doi.org/10.1046/j.1462-5822.2001.00131.x. [CrossRef]
83. Pizarro-Cerdá J, Moreno E, Sanguedolce V, Mege JL, Gorvel JP. 1998. Virulent Brucella abortus prevents lysosome fusion and is distributed within autophagosome-like compartments. Infect Immun 66:2387–2392.
84. Starr T, Ng TW, Wehrly TD, Knodler LA, Celli J. 2008. Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment. Traffic 9:678–694 http://dx.doi.org/10.1111/j.1600-0854.2008.00718.x. [CrossRef]
85. Bellaire BH, Roop RM II, Cardelli JA. 2005. Opsonized virulent Brucella abortus replicates within nonacidic, endoplasmic reticulum-negative, LAMP-1-positive phagosomes in human monocytes. Infect Immun 73:3702–3713 http://dx.doi.org/10.1128/IAI.73.6.3702-3713.2005. [CrossRef]
86. Boschiroli ML, Ouahrani-Bettache S, Foulongne V, Michaux-Charachon S, Bourg G, Allardet-Servent A, Cazevieille C, Liautard JP, Ramuz M, O’Callaghan D. 2002. The Brucella suis virB operon is induced intracellularly in macrophages. Proc Natl Acad Sci USA 99:1544–1549 http://dx.doi.org/10.1073/pnas.032514299. [CrossRef]
87. Fraser DW, Tsai TR, Orenstein W, Parkin WE, Beecham HJ, Sharrar RG, Harris J, Mallison GF, Martin SM, McDade JE, Shepard CC, Brachman PS. 1977. Legionnaires’ disease: description of an epidemic of pneumonia. N Engl J Med 297:1189–1197 http://dx.doi.org/10.1056/NEJM197712012972201. [CrossRef]
88. Berger KH, Isberg RR. 1993. Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Mol Microbiol 7:7–19 http://dx.doi.org/10.1111/j.1365-2958.1993.tb01092.x. [PubMed][CrossRef]
89. Horwitz MA. 1987. Characterization of avirulent mutant Legionella pneumophila that survive but do not multiply within human monocytes. J Exp Med 166:1310–1328 http://dx.doi.org/10.1084/jem.166.5.1310. [PubMed][CrossRef]
90. Clemens DL, Horwitz MA. 1995. Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J Exp Med 181:257–270 http://dx.doi.org/10.1084/jem.181.1.257. [CrossRef]
91. Roy CR, Berger KH, Isberg RR. 1998. Legionella pneumophila DotA protein is required for early phagosome trafficking decisions that occur within minutes of bacterial uptake. Mol Microbiol 28:663–674 http://dx.doi.org/10.1046/j.1365-2958.1998.00841.x. [CrossRef]
92. Horwitz MA, Maxfield FR. 1984. Legionella pneumophila inhibits acidification of its phagosome in human monocytes. J Cell Biol 99:1936–1943 http://dx.doi.org/10.1083/jcb.99.6.1936. [CrossRef]
93. Horwitz MA. 1983. Formation of a novel phagosome by the Legionnaires’ disease bacterium ( Legionella pneumophila) in human monocytes. J Exp Med 158:1319–1331 http://dx.doi.org/10.1084/jem.158.4.1319. [CrossRef]
94. Ingmundson A, Roy CR. 2008. Analyzing association of the endoplasmic reticulum with the Legionella pneumophila-containing vacuoles by fluorescence microscopy. Methods Mol Biol 445:379–387 http://dx.doi.org/10.1007/978-1-59745-157-4_24. [CrossRef]
95. Robinson CG, Roy CR. 2006. Attachment and fusion of endoplasmic reticulum with vacuoles containing Legionella pneumophila. Cell Microbiol 8:793–805 http://dx.doi.org/10.1111/j.1462-5822.2005.00666.x. [PubMed][CrossRef]
96. Kagan JC, Stein MP, Pypaert M, Roy CR. 2004. Legionella subvert the functions of Rab1 and Sec22b to create a replicative organelle. J Exp Med 199:1201–1211 http://dx.doi.org/10.1084/jem.20031706. [PubMed][CrossRef]
97. Derré I, Isberg RR. 2004. Legionella pneumophila replication vacuole formation involves rapid recruitment of proteins of the early secretory system. Infect Immun 72:3048–3053 http://dx.doi.org/10.1128/IAI.72.5.3048-3053.2004. [CrossRef]
98. Murata T, Delprato A, Ingmundson A, Toomre DK, Lambright DG, Roy CR. 2006. The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nat Cell Biol 8:971–977 http://dx.doi.org/10.1038/ncb1463. [CrossRef]
99. Kagan JC, Roy CR. 2002. Legionella phagosomes intercept vesicular traffic from endoplasmic reticulum exit sites. Nat Cell Biol 4:945–954 http://dx.doi.org/10.1038/ncb883. [CrossRef]
100. Machner MP, Isberg RR. 2006. Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev Cell 11:47–56 http://dx.doi.org/10.1016/j.devcel.2006.05.013. [PubMed][CrossRef]
101. Zhu Y, Hu L, Zhou Y, Yao Q, Liu L, Shao F. 2010. Structural mechanism of host Rab1 activation by the bifunctional Legionella type IV effector SidM/DrrA. Proc Natl Acad Sci USA 107:4699–4704 http://dx.doi.org/10.1073/pnas.0914231107. [PubMed][CrossRef]
102. Schoebel S, Oesterlin LK, Blankenfeldt W, Goody RS, Itzen A. 2009. RabGDI displacement by DrrA from Legionella is a consequence of its guanine nucleotide exchange activity. Mol Cell 36:1060–1072 http://dx.doi.org/10.1016/j.molcel.2009.11.014. [CrossRef]
103. Müller MP, Peters H, Blümer J, Blankenfeldt W, Goody RS, Itzen A. 2010. The Legionella effector protein DrrA AMPylates the membrane traffic regulator Rab1b. Science 329:946–949 http://dx.doi.org/10.1126/science.1192276. [CrossRef]
104. Hardiman CA, Roy CR. 2014. AMPylation is critical for Rab1 localization to vacuoles containing Legionella pneumophila. mBio 5:e01035-13 http://dx.doi.org/10.1128/mBio.01035-13. [PubMed][CrossRef]
105. Pan X, Lührmann A, Satoh A, Laskowski-Arce MA, Roy CR. 2008. Ankyrin repeat proteins comprise a diverse family of bacterial type IV effectors. Science 320:1651–1654 http://dx.doi.org/10.1126/science.1158160. [CrossRef]
106. Tan Y, Arnold RJ, Luo ZQ. 2011. Legionella pneumophila regulates the small GTPase Rab1 activity by reversible phosphorylcholination. Proc Natl Acad Sci USA 108:21212–21217 http://dx.doi.org/10.1073/pnas.1114023109. [CrossRef]
107. Mukherjee S, Liu X, Arasaki K, McDonough J, Galán JE, Roy CR. 2011. Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature 477:103–106 http://dx.doi.org/10.1038/nature10335. [CrossRef]
108. Tan Y, Luo ZQ. 2011. Legionella pneumophila SidD is a deAMPylase that modifies Rab1. Nature 475:506–509 http://dx.doi.org/10.1038/nature10307. [PubMed][CrossRef]
109. Neunuebel MR, Chen Y, Gaspar AH, Backlund PS Jr, Yergey A, Machner MP. 2011. De-AMPylation of the small GTPase Rab1 by the pathogen Legionella pneumophila. Science 333:453–456 http://dx.doi.org/10.1126/science.1207193. [CrossRef]
110. Seto S, Tsujimura K, Koide Y. 2011. Rab GTPases regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. Traffic 12:407–420 http://dx.doi.org/10.1111/j.1600-0854.2011.01165.x. [CrossRef]
111. Ingmundson A, Delprato A, Lambright DG, Roy CR. 2007. Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature 450:365–369 http://dx.doi.org/10.1038/nature06336. [CrossRef]
112. Nagai H, Kagan JC, Zhu X, Kahn RA, Roy CR. 2002. A bacterial guanine nucleotide exchange factor activates ARF on Legionella phagosomes. Science 295:679–682 http://dx.doi.org/10.1126/science.1067025. [CrossRef]
113. Amor JC, Swails J, Zhu X, Roy CR, Nagai H, Ingmundson A, Cheng X, Kahn RA. 2005. The structure of RalF, an ADP-ribosylation factor guanine nucleotide exchange factor from Legionella pneumophila, reveals the presence of a cap over the active site. J Biol Chem 280:1392–1400 http://dx.doi.org/10.1074/jbc.M410820200. [CrossRef]
114. Dorer MS, Kirton D, Bader JS, Isberg RR. 2006. RNA interference analysis of Legionella in Drosophila cells: exploitation of early secretory apparatus dynamics. PLoS Pathog 2:e34 http://dx.doi.org/10.1371/journal.ppat.0020034. [PubMed][CrossRef]
115. Celli J, Salcedo SP, Gorvel J-P. 2005. Brucella coopts the small GTPase Sar1 for intracellular replication. Proc Natl Acad Sci USA 102:1673–1678 http://dx.doi.org/10.1073/pnas.0406873102. [PubMed][CrossRef]
116. Fugier E, Salcedo SP, de Chastellier C, Pophillat M, Muller A, Arce-Gorvel V, Fourquet P, Gorvel JP. 2009. The glyceraldehyde-3-phosphate dehydrogenase and the small GTPase Rab 2 are crucial for Brucella replication. PLoS Pathog 5:e1000487 http://dx.doi.org/10.1371/journal.ppat.1000487. [PubMed][CrossRef]
117. de Barsy M, Jamet A, Filopon D, Nicolas C, Laloux G, Rual JF, Muller A, Twizere JC, Nkengfac B, Vandenhaute J, Hill DE, Salcedo SP, Gorvel JP, Letesson JJ, De Bolle X. 2011. Identification of a Brucella spp. secreted effector specifically interacting with human small GTPase Rab2. Cell Microbiol 13:1044–1058 http://dx.doi.org/10.1111/j.1462-5822.2011.01601.x. [CrossRef]
118. Xu D, Joglekar AP, Williams AL, Hay JC. 2000. Subunit structure of a mammalian ER/Golgi SNARE complex. J Biol Chem 275:39631–39639 http://dx.doi.org/10.1074/jbc.M007684200. [PubMed][CrossRef]
119. Arasaki K, Roy CR. 2010. Legionella pneumophila promotes functional interactions between plasma membrane syntaxins and Sec22b. Traffic 11:587–600 http://dx.doi.org/10.1111/j.1600-0854.2010.01050.x. [PubMed][CrossRef]
120. Arasaki K, Toomre DK, Roy CR. 2012. The Legionella pneumophila effector DrrA is sufficient to stimulate SNARE-dependent membrane fusion. Cell Host Microbe 11:46–57 http://dx.doi.org/10.1016/j.chom.2011.11.009. [PubMed][CrossRef]
121. Menon S, Timms P, Allan JA, Alexander K, Rombauts L, Horner P, Keltz M, Hocking J, Huston WM. 2015. Human and pathogen factors associated with Chlamydia trachomatis-related infertility in women. Clin Microbiol Rev 28:969–985 http://dx.doi.org/10.1128/CMR.00035-15. [CrossRef]
122. Elwell C, Mirrashidi K, Engel J. 2016. Chlamydia cell biology and pathogenesis. Nat Rev Microbiol 14:385–400 http://dx.doi.org/10.1038/nrmicro.2016.30. [PubMed][CrossRef]
123. Fields KA, Hackstadt T. 2002. The chlamydial inclusion: escape from the endocytic pathway. Annu Rev Cell Dev Biol 18:221–245 http://dx.doi.org/10.1146/annurev.cellbio.18.012502.105845. [PubMed][CrossRef]
124. Rejman Lipinski A, Heymann J, Meissner C, Karlas A, Brinkmann V, Meyer TF, Heuer D. 2009. Rab6 and Rab11 regulate Chlamydia trachomatis development and golgin-84-dependent Golgi fragmentation. PLoS Pathog 5:e1000615 http://dx.doi.org/10.1371/journal.ppat.1000615. [PubMed][CrossRef]
125. Moorhead AM, Jung JY, Smirnov A, Kaufer S, Scidmore MA. 2010. Multiple host proteins that function in phosphatidylinositol-4-phosphate metabolism are recruited to the chlamydial inclusion. Infect Immun 78:1990–2007 http://dx.doi.org/10.1128/IAI.01340-09. [PubMed][CrossRef]
126. Ronzone E, Wesolowski J, Bauler LD, Bhardwaj A, Hackstadt T, Paumet F. 2014. An α-helical core encodes the dual functions of the chlamydial protein IncA. J Biol Chem 289:33469–33480 http://dx.doi.org/10.1074/jbc.M114.592063. [PubMed][CrossRef]
127. Ronzone E, Paumet F. 2013. Two coiled-coil domains of Chlamydia trachomatis IncA affect membrane fusion events during infection. PLoS One 8:e69769 http://dx.doi.org/10.1371/journal.pone.0069769. [PubMed][CrossRef]
128. Gauliard E, Ouellette SP, Rueden KJ, Ladant D. 2015. Characterization of interactions between inclusion membrane proteins from Chlamydia trachomatis. Front Cell Infect Microbiol 5:13 http://dx.doi.org/10.3389/fcimb.2015.00013. [PubMed][CrossRef]
129. Heuer D, Rejman Lipinski A, Machuy N, Karlas A, Wehrens A, Siedler F, Brinkmann V, Meyer TF. 2009. Chlamydia causes fragmentation of the Golgi compartment to ensure reproduction. Nature 457:731–735 http://dx.doi.org/10.1038/nature07578. [CrossRef]
130. Gurumurthy RK, Chumduri C, Karlas A, Kimmig S, Gonzalez E, Machuy N, Rudel T, Meyer TF. 2014. Dynamin-mediated lipid acquisition is essential for Chlamydia trachomatis development. Mol Microbiol 94:186–201 http://dx.doi.org/10.1111/mmi.12751. [PubMed][CrossRef]
131. Burd C, Cullen PJ. 2014. Retromer: a master conductor of endosome sorting. Cold Spring Harb Perspect Biol 6:a016774 http://dx.doi.org/10.1101/cshperspect.a016774. [PubMed][CrossRef]
132. Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A. 2016. Structural mechanism for cargo recognition by the retromer complex. Cell 167:1623–1635.e1614. [PubMed][CrossRef]
133. Rojas R, Kametaka S, Haft CR, Bonifacino JS. 2007. Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors. Mol Cell Biol 27:1112–1124 http://dx.doi.org/10.1128/MCB.00156-06. [CrossRef]
134. Finsel I, Ragaz C, Hoffmann C, Harrison CF, Weber S, van Rahden VA, Johannes L, Hilbi H. 2013. The Legionella effector RidL inhibits retrograde trafficking to promote intracellular replication. Cell Host Microbe 14:38–50 http://dx.doi.org/10.1016/j.chom.2013.06.001. [PubMed][CrossRef]
135. Mirrashidi KM, Elwell CA, Verschueren E, Johnson JR, Frando A, Von Dollen J, Rosenberg O, Gulbahce N, Jang G, Johnson T, Jäger S, Gopalakrishnan AM, Sherry J, Dunn JD, Olive A, Penn B, Shales M, Cox JS, Starnbach MN, Derre I, Valdivia R, Krogan NJ, Engel J. 2015. Global mapping of the Inc-human interactome reveals that retromer restricts Chlamydia infection. Cell Host Microbe 18:109–121 http://dx.doi.org/10.1016/j.chom.2015.06.004. [CrossRef]
136. Aeberhard L, Banhart S, Fischer M, Jehmlich N, Rose L, Koch S, Laue M, Renard BY, Schmidt F, Heuer D. 2015. The proteome of the isolated Chlamydia trachomatis containing vacuole reveals a complex trafficking platform enriched for retromer components. PLoS Pathog 11:e1004883 http://dx.doi.org/10.1371/journal.ppat.1004883. [PubMed][CrossRef]
137. Smith RD, Lupashin VV. 2008. Role of the conserved oligomeric Golgi (COG) complex in protein glycosylation. Carbohydr Res 343:2024–2031 http://dx.doi.org/10.1016/j.carres.2008.01.034.
138. Ruiz-Albert J, Yu XJ, Beuzón CR, Blakey AN, Galyov EE, Holden DW. 2002. Complementary activities of SseJ and SifA regulate dynamics of the Salmonella typhimurium vacuolar membrane. Mol Microbiol 44:645–661 http://dx.doi.org/10.1046/j.1365-2958.2002.02912.x. [CrossRef]
139. Creasey EA, Isberg RR. 2012. The protein SdhA maintains the integrity of the Legionella-containing vacuole. Proc Natl Acad Sci USA 109:3481–3486 http://dx.doi.org/10.1073/pnas.1121286109. [PubMed][CrossRef]
140. Birmingham CL, Smith AC, Bakowski MA, Yoshimori T, Brumell JH. 2006. Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. J Biol Chem 281:11374–11383 http://dx.doi.org/10.1074/jbc.M509157200. [CrossRef]
141. Noad J, von der Malsburg A, Pathe C, Michel MA, Komander D, Randow F. 2017. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB. Nat Microbiol 2:17063 http://dx.doi.org/10.1038/nmicrobiol.2017.63. [PubMed][CrossRef]
142. Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M, Kim M, Mimuro H, Nakagawa I, Yanagawa T, Ishii T, Kakizuka A, Sztul E, Chakraborty T, Sasakawa C. 2009. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat Cell Biol 11:1233–1240 http://dx.doi.org/10.1038/ncb1967. [CrossRef]
143. Kraft C, Peter M, Hofmann K. 2010. Selective autophagy: ubiquitin-mediated recognition and beyond. Nat Cell Biol 12:836–841 http://dx.doi.org/10.1038/ncb0910-836. [PubMed][CrossRef]
144. Noda NN, Ohsumi Y, Inagaki F. 2010. Atg8-family interacting motif crucial for selective autophagy. FEBS Lett 584:1379–1385 http://dx.doi.org/10.1016/j.febslet.2010.01.018. [PubMed][CrossRef]
145. Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T. 2005. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171:603–614 http://dx.doi.org/10.1083/jcb.200507002. [CrossRef]
146. Bjørkøy G, Lamark T, Johansen T. 2006. p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy 2:138–139 http://dx.doi.org/10.4161/auto.2.2.2405. [CrossRef]
147. Thurston TLM, Wandel MP, von Muhlinen N, Foeglein A, Randow F. 2012. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482:414–418 http://dx.doi.org/10.1038/nature10744. [CrossRef]
148. Feeley EM, Pilla-Moffett DM, Zwack EE, Piro AS, Finethy R, Kolb JP, Martinez J, Brodsky IE, Coers J. 2017. Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems. Proc Natl Acad Sci USA 114:E1698–E1706 http://dx.doi.org/10.1073/pnas.1615771114. [PubMed][CrossRef]
149. Choy A, Dancourt J, Mugo B, O’Connor TJ, Isberg RR, Melia TJ, Roy CR. 2012. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338:1072–1076 http://dx.doi.org/10.1126/science.1227026. [CrossRef]
150. Horenkamp FA, Kauffman KJ, Kohler LJ, Sherwood RK, Krueger KP, Shteyn V, Roy CR, Melia TJ, Reinisch KM. 2015. The Legionella anti-autophagy effector RavZ targets the autophagosome via PI3P- and curvature-sensing motifs. Dev Cell 34:569–576 http://dx.doi.org/10.1016/j.devcel.2015.08.010. [PubMed][CrossRef]
151. Rolando M, Escoll P, Buchrieser C. 2016. Legionella pneumophila restrains autophagy by modulating the host’s sphingolipid metabolism. Autophagy 12:1053–1054 http://dx.doi.org/10.1080/15548627.2016.1166325. [CrossRef]

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In this article, we explore the unique adaptations of intracellular bacterial pathogens that manipulate conserved cellular pathways, organelles, and cargo to convert the phagosome into a pathogen-containing vacuole (PCV). The phagosome is a degradative organelle that rapidly acidifies as it delivers cargo to the lysosome to destroy microbes and cellular debris. However, to avoid this fate, intracellular bacterial pathogens hijack the key molecular modulators of intracellular traffic: small GTPases, phospholipids, SNAREs, and their associated effectors. Following uptake, pathogens that reside in the phagosome either remain associated with the endocytic pathway or rapidly diverge from the preprogrammed route to the lysosome. Both groups rely on effector-mediated mechanisms to meet the common challenges of intracellular life, such as nutrient acquisition, vacuole expansion, and evasion of the host immune response. , , and serve as a lens through which we explore regulators of the canonical endocytic route and pathogens that seek to subvert it. On the other hand, pathogens such as , , and disconnect from the canonical endocytic route. This bifurcation is linked to extensive hijacking of the secretory pathway and repurposing of the PCV into specialized compartments that resemble organelles in the secretory network. Finally, each pathogen devises specific strategies to counteract host immune responses, such as autophagy, which aim to destroy these aberrant organelles. Collectively, each unique intracellular niche and the pathogens that construct them reflect the outcome of an aggressive and ongoing molecular arms race at the host-pathogen interface. Improving our understanding of these well-adapted pathogens can help us refine our knowledge of conserved cell biological processes.

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Image of FIGURE 1

Rab GTPase signature of PCVs that interact with the endocytic pathway. The figure depicts canonical phagocytosis, with a subset of intracellular pathogens that manipulate endosomal traffic to avoid lysosomal degradation. When professional phagocytes recognize bacteria, local rearrangement of the actin cytoskeleton allows the plasma membrane to form protrusions that engulf bacterial cells into a host-derived membrane called the phagosome. Nascent phagosomes transiently interact with early and late endosomes to convert this compartment into an acidic and microbicidal organelle. The early-endosomal marker Rab5 associates with newly formed phagosomes, and as maturation progresses, Rab5 is displaced by the late-endosomal marker Rab7. This process culminates with lysosomal fusion, which generates a hybrid organelle called the phagolysosome that promotes complete degradation of phagocytosed bacteria. Following uptake, interacts with early endosomes but immediately stalls maturation to avoid acidification of the MCV. suspends normal transit along the endocytic route by interfering with the conversion of Rab5 to Rab7 on the MCV membrane. Consequently, by arresting the development of phagosomes during early stages of uptake, the MCV retains features of an early-endosome-like compartment and avoids delivery to the lysosome. Additionally, Rab22a and Rab14 have been detected on vacuoles. In contrast, the SCV transits further down the endocytic route and interacts with both early and late endosomes. The conventional (early- and late-endosome) Rab GTPases Rab5 and Rab7 localize to mature SCVs along with the late-endosome marker LAMP-1/2. Mature SCVs are dynamic compartments that closely resemble late endosomes. Unlike and , does not resist delivery to the lysosome. vacuoles progress along the standard endocytic route in a process that closely resembles canonical phagocytosis, and these compartments display many markers that associate with mature phagosomes, such as Rab5, Rab7, and LAMP-1. Delivery to the lysosome activates the T4SS machinery and triggers effector-mediated mechanisms that drastically alter properties of the lysosome and support biogenesis of the CCV. repurposes the lysosome into a phenotypically distinct lysosome-derived organelle that participates in unregulated fusion events in an autophagy-dependent manner. Interestingly, additional Rab GTPases that have been linked to the autophagy pathway, Rab1 and Rab24, have been shown to contribute to replication.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0022-2019
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Image of FIGURE 2

Rab GTPase signature of PCVs that diverge from the endocytic pathway and manipulate the pathway. The figure depicts a class of intracellular pathogens that not only avoid lysosomal degradation but also disconnect from the standard endocytic route and extensively manipulate secretory traffic. Once internalized, these pathogens manipulate Rab GTPases to create a unique molecular signature on the phagosomal membrane. Consequently, this signature rewrites the function of the original phagosome and allows each pathogen to exploit host membrane transport of secretory organelles (ER and Golgi apparatus) and their associated vesicles. As such, the atypical recruitment and association of Rab GTPases on each PCV membrane provides insight into the organelles that are hijacked and exploited for PCV biogenesis and maintenance. The -containing phagosome disassociates from the endocytic pathway very early after uptake, as the early-endosome marker Rab5 is not detected on this compartment. However, Rab1, an ER-associated Rab GTPase, is recruited to the -containing vacuole (LCV) following internalization. The localization of activated Rab1 on the LCV membrane allows this pathogen to hijack ER-derived vesicles and redirect them to the LCV surface. As the infection proceeds, the LCV matures into a ribosome-studded organelle that communicates extensively with the ER. Similar to , remodels the phagosome into an ER-like organelle. In contrast, the BCV does not acquire Rab1 to hijack vesicles from ERES. Instead, the recruitment of Rab2 to the BCV is required to subvert ER-Golgi traffic and support BCV biogenesis. is initially phagocytosed as an elementary body (EB), which represents the metabolically inactive and infectious form of the biphasic cycle. As the infection progresses, the EB differentiates into the metabolically active and replicative form termed the reticulate body (RB). The specialized organelle that supports replication, named the inclusion, is largely devoid of endocytic Rabs, including Rab5, Rab7, and Rab9. This indicates that divergence from the endocytic route is an early and rapid event. A wide assortment of Rab GTPases are recruited to the inclusion membrane, such as Rab1, Rab4, Rab6, Rab11, and Rab14. A hallmark of intracellular infection is the presence of fragmented Golgi stacks that surround the inclusion.

Source: microbiolspec April 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.BAI-0022-2019
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