Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cells within cells: Rickettsiales and the obligate intracellular bacterial lifestyle

Nature Reviews Microbiology volume 19, pages 375–390 (2021)Cite this article

Subjects

Abstract

The Rickettsiales are a group of obligate intracellular vector-borne Gram-negative bacteria that include many organisms of clinical and agricultural importance, including Anaplasma spp., Ehrlichia chaffeensis, Wolbachia, Rickettsia spp. and Orientia tsutsugamushi. This Review provides an overview of the current state of knowledge of the biology of these bacteria and their interactions with host cells, with a focus on pathogenic species or those that are otherwise important for human health. This includes a description of rickettsial genomics, bacterial cell biology, the intracellular lifestyles of Rickettsiales and the mechanisms by which they induce and evade the innate immune response.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Phylogenetic tree showing relationship between selected Rickettsiales species as determined by 16S sequences.
Fig. 2: Overview of the intracellular life cycles of Rickettsiales.
Fig. 3: Attachment and invasion of Rickettsiales species into mammalian cells.
Fig. 4: Evasion of cellular innate immunity by Rickettsiales.

Similar content being viewed by others

References

  1. Casiraghi, M. et al. Phylogeny of Wolbachia pipientis based on gltA, groEL and ftsZ gene sequences: clustering of arthropod and nematode symbionts in the F supergroup, and evidence for further diversity in the Wolbachia tree. Microbiology 151, 4015–4022 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Gillespie, J. et al. Plasmids and rickettsial evolution: insight from Rickettsia felis. PLoS ONE 2, e266 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gillespie, J. et al. Rickettsia phylogenomics: unwinding the intricacies of obligate intracellular life. PLoS ONE 3, e2018 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Renvoisé, A., Merhej, V., Georgiades, K. & Raoult, D. Intracellular Rickettsiales: insights into manipulators of eukaryotic cells. Trends Mol. Med. 17, 573–583 (2011).

    Article  PubMed  Google Scholar 

  5. Werren, J., Baldo, L. & Clark, M. Wolbachia: master manipulators of invertebrate biology. Nat. Rev. Microbiol. 6, 741–751 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Luce-Fedrow, A. et al. A review of scrub typhus (Orientia tsutsugamushi and related organisms): then, now, and tomorrow. Tropical Med. Infect. Dis. 3, 8 (2018).

    Article  Google Scholar 

  7. Frances, S., Watcharapichat, P., Phulsuksombati, D. & Tanskul, P. Transmission of Orientia tsutsugamushi, the aetiological agent for scrub typhus, to co-feeding mites. Parasitology 120, 601–607 (2000).

    Article  PubMed  Google Scholar 

  8. Gillespie, J. et al. A tangled web: origins of reproductive parasitism. Genome Biol. Evol. 10, 2292–2309 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Inokuma, H. in Rickettsial Diseases (eds Parola, P. & Raoult, D.) 199–207 (CRC Press, 2007).

  10. Walker, D. & Ismail, N. Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events. Nat. Rev. Microbiol. 6, 375–386 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Sahni, A., Fang, R., Sahni, S. & Walker, D. Pathogenesis of rickettsial diseases: pathogenic and immune mechanisms of an endotheliotropic infection. Annu. Rev. Pathol. 14, 127–152 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Paris, D. et al. Orientia tsutsugamushi in human scrub typhus eschars shows tropism for dendritic cells and monocytes rather than endothelium. PLoS Negl. Trop. Dis. 6, e1466 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McBride, J. & Walker, D. Molecular and cellular pathobiology of Ehrlichia infection: targets for new therapeutics and immunomodulation strategies. Expert. Rev. Mol. Med. 13, e3 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Carlyon, J. & Fikrig, E. Invasion and survival strategies of Anaplasma phagocytophilum. Cell Microbiol. 5, 743–754 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Valbuena, G. & Walker, D. Infection of the endothelium by members of the order Rickettsiales. Thromb. Haemost. 102, 1071–1079 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Walker, D. The realities of biodefense vaccines against Rickettsia. Vaccine 27, D52–D55 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ismail, N., Bloch, K. & McBride, J. Human ehrlichiosis and anaplasmosis. Clin. Lab. Med. 30, 261–292 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Valbuena, G. & Walker, D. Approaches to vaccines against Orientia tsutsugamushi. Front. Cell Infect. Microbiol. 2, 170 (2012).

    PubMed  Google Scholar 

  19. Lina, T. et al. Hacker within! Ehrlichia chaffeensis effector driven phagocyte reprogramming strategy. Front. Cell Infect. Microbiol. 6, 58 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Paris, D., Shelite, T., Day, N. & Walker, D. Unresolved problems related to scrub typhus: a seriously neglected life-threatening disease. Am. J. Trop. Med. Hyg. 89, 301–307 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bhattacharya, T. & Newton, I. Mi Casa es Su Casa: how an intracellular symbiont manipulates host biology. Environ. Microbiol. 21, 3188–3196 (2017).

    Article  Google Scholar 

  22. Diaz, F., Abarca, K. & Kalergis, A. An update on host–pathogen interplay and modulation of immune responses during Orientia tsutsugamushi infection. Clin. Microbiol. Rev. 31, e00076-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ge, Y. & Rikihisa, Y. Subversion of host cell signaling by Orientia tsutsugamushi. Microbes Infect. 13, 638–648 (2011).

    Article  PubMed  Google Scholar 

  24. Moumène, A. & Meyer, D. Ehrlichia’s molecular tricks to manipulate their host cells. Microbes Infect. 18, 172–179 (2016).

    Article  PubMed  Google Scholar 

  25. Rikihisa, Y. Anaplasma phagocytophilum and Ehrlichia chaffeensis: subversive manipulators of host cells. Nat. Rev. Microbiol. 8, 328–339 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Socolovschi, C., Mediannikov, O., Raoult, D. & Parola, P. The relationship between spotted fever group Rickettsiae and ixodid ticks. Vet. Res. 40, 34 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sonenshine, D. & Macaluso, K. Microbial invasion vs. tick immune regulation. Front. Cell Infect. Microbiol. 7, 390 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  28. de la Fuente, J. et al. Tick–pathogen interactions and vector competence: identification of molecular drivers for tick-borne diseases. Front. Cell Infect. Microbiol. 7, 114 (2017).

    PubMed  PubMed Central  Google Scholar 

  29. Sällström, B. & Andersson, S. Genome reduction in the alpha-proteobacteria. Curr. Opin. Microbiol. 8, 579–585 (2005).

    Article  PubMed  Google Scholar 

  30. Dunning Hotopp, J. C. et al. Comparative genomics of emerging human ehrlichiosis agents. PLoS Genet. 2, e21 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bliven, K. & Maurelli, A. Antivirulence genes: insights into pathogen evolution through gene loss. Infect. Immun. 80, 4061–4070 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Merhej, V., Georgiades, K. & Raoult, D. Postgenomic analysis of bacterial pathogens repertoire reveals genome reduction rather than virulence factors. Brief. Funct. Genomics 12, 291–304 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Felsheim, R., Kurtti, T. & Munderloh, U. Genome sequence of the endosymbiont Rickettsia peacockii and comparison with virulent Rickettsia rickettsii: identification of virulence factors. PLoS ONE 4, e8361 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Clark, T. et al. Comparative genome sequencing of Rickettsia rickettsii strains that differ in virulence. Infect. Immun. 83, 1568–1576 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ogata, H. et al. Mechanisms of evolution in Rickettsia conorii and R. prowazekii. Science 293, 2093–2098 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Fournier, P. et al. Analysis of the Rickettsia africae genome reveals that virulence acquisition in Rickettsia species may be explained by genome reduction. BMC Genomics 10, 166 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Merhej, V. & Raoult, D. Rickettsial evolution in the light of comparative genomics. Biol. Rev. Camb. Philos. Soc. 86, 379–405 (2011).

    Article  PubMed  Google Scholar 

  38. Ammerman, N., Gillespie, J., Neuwald, A., Sobral, B. & Azad, A. A typhus group-specific protease defies reductive evolution in rickettsiae. J. Bacteriol. 191, 7609–7613 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu, M. et al. Phylogenomics of the reproductive parasite Wolbachia pipientis wMel: a streamlined genome overrun by mobile genetic elements. PLoS Biol. 2, E69 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hagen, R., Verhoeve, V., Gillespie, J. & Driscoll, T. Conjugative transposons and their cargo genes vary across natural populations of Rickettsia buchneri infecting the tick Ixodes scapularis. Genome Biol. Evol. 10, 3218–3229 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Batty, E. M. et al. Long-read whole genome sequencing and comparative analysis of six strains of the human pathogen Orientia tsutsugamushi. PLoS Negl. Trop. Dis. 12, e0006566 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Baldridge, G., Burkhardt, N., Felsheim, R., Kurtti, T. & Munderloh, U. Transposon insertion reveals pRM, a plasmid of Rickettsia monacensis. Appl. Environ. Microbiol. 73, 4984–4995 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Burkhardt, N. et al. Development of shuttle vectors for transformation of diverse Rickettsia species. PLoS ONE 6, e29511 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Otten, C., Brilli, M., Vollmer, W., Viollier, P. & Salje, J. Peptidoglycan in obligate intracellular bacteria. Mol. Microbiol. 107, 142–163 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Lin, M. & Rikihisa, Y. Ehrlichia chaffeensis and Anaplasma phagocytophilum lack genes for lipid A biosynthesis and incorporate cholesterol for their survival. Infect. Immun. 71, 5324–5331 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pang, H. & Winkler, H. Analysis of the peptidoglycan of Rickettsia prowazekii. J Bacteriol. 176, 923–926 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Atwal, S. et al. Evidence for a peptidoglycan-like structure in Orientia tsutsugamushi. Mol. Microbiol. 105, 440–452 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Henrichfreise, B. et al. Functional conservation of the lipid II biosynthesis pathway in the cell wall-less bacteria Chlamydia and Wolbachia: why is lipid II needed? Mol. Microbiol. 73, 913–923 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Xiong, Q., Lin, M. & Rikihisa, Y. Cholesterol-dependent Anaplasma phagocytophilum exploits the low-density lipoprotein uptake pathway. PLoS Pathog. 5, e1000329 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Lin, M. et al. Host membrane lipids are trafficked to membranes of intravacuolar bacterium Ehrlichia chaffeensis. Proc. Natl Acad. Sci. USA 117, 8032–8043 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Brayton, K. et al. Complete genome sequencing of Anaplasma marginale reveals that the surface is skewed to two superfamilies of outer membrane proteins. Proc. Natl Acad. Sci. USA 102, 844–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Long, S. et al. Antigenic variation of Ehrlichia chaffeensis resulting from differential expression of the 28-kilodalton protein gene family. Infect. Immun. 70, 1824–1831 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Baldo, L., Lo, N. & Werren, J. Mosaic nature of the Wolbachia surface protein. J. Bacteriol. 187, 5406–5418 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ha, N., Cho, N., Kim, Y., Choi, M. & Kim, I. An autotransporter protein from Orientia tsutsugamushi mediates adherence to nonphagocytic host cells. Infect. Immun. 79, 1718–1727 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Koralur, M., Ramaiah, A. & Dasch, G. Detection and distribution of Sca autotransporter protein antigens in diverse isolates of Orientia tsutsugamushi. PLoS Negl. Trop. Dis. 12, e0006784 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Haglund, C., Choe, J., Skau, C., Kovar, D. & Welch, M. Rickettsia Sca2 is a bacterial formin-like mediator of actin-based motility. Nat. Cell Biol. 12, 1057–1063 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ge, Y. & Rikihisa, Y. Surface-exposed proteins of Ehrlichia chaffeensis. Infect. Immun. 75, 3833–3841 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Noh, S. et al. Composition of the surface proteome of Anaplasma marginale and its role in protective immunity induced by outer membrane immunization. Infect. Immun. 76, 2219–2226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sears, K. et al. Surface proteome analysis and characterization of surface cell antigen (Sca) or autotransporter family of Rickettsia typhi. PLoS Pathog. 8, e1002856 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gong, W. et al. Identification of novel surface-exposed proteins of Rickettsia rickettsii by affinity purification and proteomics. PLoS ONE 9, e100253 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Contreras, M. et al. Anaplasma phagocytophilum MSP4 and HSP70 proteins are involved in interactions with host cells during pathogen infection. Front. Cell Infect. Microbiol. 7, 307 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Kim, G. et al. Diversification of Orientia tsutsugamushi genotypes by intragenic recombination and their potential expansion in endemic areas. PLoS Negl. Trop. Dis. 11, e0005408 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ohashi, N., Tamura, A. & Suto, T. Immunoblotting analysis of anti-rickettsial antibodies produced in patients of Tsutsugamushi disease. Microbiol. Immunol. 32, 1085–1092 (1988).

    Article  CAS  PubMed  Google Scholar 

  64. Kim, M., Kim, M. & Kang, J. Involvement of lipid rafts in the budding-like exit of Orientia tsutsugamushi. Microb. Pathog. 63C, 37–43 (2013).

    Article  Google Scholar 

  65. Cheng, Z., Kumagai, Y., Lin, M., Zhang, C. & Rikihisa, Y. Intra-leukocyte expression of two-component systems in Ehrlichia chaffeensis and Anaplasma phagocytophilum and effects of the histidine kinase inhibitor closantel. Cell Microbiol. 8, 1241–1252 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Rikihisa, Y. Mechanisms of obligatory intracellular infection with Anaplasma phagocytophilum. Clin. Microbiol. Rev. 24, 469–489 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu, H., Von Ohlen, T., Cheng, C., Faburay, B. & Ganta, R. Transcription of Ehrlichia chaffeensis genes is accomplished by RNA polymerase holoenzyme containing either sigma 32 or sigma 70. PLoS ONE 8, e81780 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Cheng, Z., Lin, M. & Rikihisa, Y. Ehrlichia chaffeensis proliferation begins with NtrY/NtrX and PutA/GlnA upregulation and CtrA degradation induced by proline and glutamine uptake. mBio 5, e02141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gillespie, J. et al. Secretome of obligate intracellular Rickettsia. FEMS Microbiol. Rev. 39, 47–80 (2015).

    CAS  PubMed  Google Scholar 

  70. Schroeder, C. et al. Bacterial small RNAs in the genus Rickettsia. BMC Genomics 16, 1075 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Mika-Gospodorz, B. et al. Dual RNA-seq of Orientia tsutsugamushi informs on host–pathogen interactions for this neglected intracellular human pathogen. Nat. Commun. 11, 3363 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Mayoral, J. et al. Wolbachia small noncoding RNAs and their role in cross-kingdom communications. Proc. Natl Acad. Sci. USA 111, 18721–18726 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Chan, Y., Cardwell, M., Hermanas, T., Uchiyama, T. & Martinez, J. Rickettsial outer-membrane protein B (rOmpB) mediates bacterial invasion through Ku70 in an actin, c-Cbl, clathrin and caveolin 2-dependent manner. Cell Microbiol. 11, 629–644 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Martinez, J. & Cossart, P. Early signaling events involved in the entry of Rickettsia conorii into mammalian cells. J. Cell Sci. 117, 5097–5106 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Martinez, J., Seveau, S., Veiga, E., Matsuyama, S. & Cossart, P. Ku70, a component of DNA-dependent protein kinase, is a mammalian receptor for Rickettsia conorii. Cell 123, 1013–1023 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Uchiyama, T., Kawano, H. & Kusuhara, Y. The major outer membrane protein rOmpB of spotted fever group rickettsiae functions in the rickettsial adherence to and invasion of Vero cells. Microbes Infect. 8, 801–809 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Hillman, R. J., Baktash, Y. & Martinez, J. OmpA-mediated rickettsial adherence to and invasion of human endothelial cells is dependent upon interaction with α2β1 integrin. Cell Microbiol. 15, 727–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Riley, S. et al. The Rickettsia conorii autotransporter protein Sca1 promotes adherence to nonphagocytic mammalian cells. Infect. Immun. 78, 1895–1904 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cardwell, M. & Martinez, J. The Sca2 autotransporter protein from Rickettsia conorii is sufficient to mediate adherence to and invasion of cultured mammalian cells. Infect. Immun. 77, 5272–5280 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gong, B. et al. Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses. Proc. Natl Acad. Sci. USA 110, 19615–19620 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Reed, S., Serio, A. & Welch, M. Rickettsia parkeri invasion of diverse host cells involves an Arp2/3 complex, WAVE complex and Rho-family GTPase-dependent pathway. Cell Microbiol. 14, 529–545 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Reed, S., Lamason, R., Risca, V., Abernathy, E. & Welch, M. Rickettsia actin-based motility occurs in distinct phases mediated by different actin nucleators. Curr. Biol. 24, 98–103 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Rennoll-Bankert, K. et al. RalF-mediated activation of Arf6 controls Rickettsia typhi invasion by co-opting phosphoinositol metabolism. Infect. Immun. 84, 3496–3506 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Lee, J. et al. Fibronectin facilitates the invasion of Orientia tsutsugamushi into host cells through interaction with a 56-kDa type-specific antigen. J. Infect. Dis. 198, 250–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Chu, H. et al. Exploitation of the endocytic pathway by Orientia tsutsugamushi in nonprofessional phagocytes. Infect. Immun. 74, 4246–4253 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cho, B., Cho, N., Seong, S., Choi, M. & Kim, I. Intracellular invasion by Orientia tsutsugamushi is mediated by integrin signaling and actin cytoskeleton rearrangements. Infect. Immun. 78, 1915–1923 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Green, R. et al. Binding of host cell surface protein disulfide isomerase by Anaplasma phagocytophilum Asp14 enables pathogen infection. mBio 11, e03141-19 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Truchan, H., Seidman, D. & Carlyon, J. Breaking in and grabbing a meal: Anaplasma phagocytophilum cellular invasion, nutrient acquisition, and promising tools for their study. Microbes Infect. 15, 1017–1025 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lin, M. & Rikihisa, Y. Obligatory intracellular parasitism by Ehrlichia chaffeensis and Anaplasma phagocytophilum involves caveolae and glycosylphosphatidylinositol-anchored proteins. Cell Microbiol. 5, 809–820 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Hebert, K. et al. Anaplasma marginale outer membrane protein A is an adhesin that recognizes sialylated and fucosylated glycans and functionally depends on an essential binding domain. Infect. Immun. 85, e00968-16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mohan Kumar, D. et al. EtpE binding to DNase X induces ehrlichial entry via CD147 and hnRNP-K recruitment, followed by mobilization of N-WASP and actin. mBio 6, e01541-15 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Luo, T., Dunphy, P., Lina, T. & McBride, J. Ehrlichia chaffeensis exploits canonical and noncanonical host Wnt signaling pathways to stimulate phagocytosis and promote intracellular survival. Infect. Immun. 84, 686–700 (2015).

    Article  PubMed  Google Scholar 

  93. Cheng, Z., Miura, K., Popov, V., Kumagai, Y. & Rikihisa, Y. Insights into the CtrA regulon in development of stress resistance in obligatory intracellular pathogen Ehrlichia chaffeensis. Mol. Microbiol. 82, 1217–1234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Dobson, S. L., Marsland, E. J., Veneti, Z., Bourtzis, K. & O’Neill, S. L. Characterization of Wolbachia host cell range via the in vitro establishment of infections. Appl. Environ. Microbiol. 68, 656–660 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Rasgon, J., Gamston, C. & Ren, X. Survival of Wolbachia pipientis in cell-free medium. Appl. Environ. Microbiol. 72, 6934–6937 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. White, P. et al. Mechanisms of horizontal cell-to-cell transfer of Wolbachia spp. in Drosophila melanogaster. Appl. Environ. Microbiol. 83, e03425-16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Renesto, P. et al. Identification and characterization of a phospholipase D–superfamily gene in Rickettsiae. J. Infect. Dis. 188, 1276–1283 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Rahman, M. et al. Rickettsia typhi possesses phospholipase A2 enzymes that are involved in infection of host cells. PLoS Pathog. 9, e1003399 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Boscaro, V., Petroni, G., Ristori, A., Verni, F. & Vannini, C. "Candidatus Defluviella procrastinata" and "Candidatus Cyrtobacter zanobii", two novel ciliate endosymbionts belonging to the "Midichloria clade". Microb. Ecol. 65, 302–310 (2013).

    Article  PubMed  Google Scholar 

  100. Mariconti, M. et al. A study on the presence of flagella in the order Rickettsiales: the case of ‘Candidatus Midichloria mitochondrii’. Microbiology 158, 1677–1683 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Heinzen, R. Rickettsial actin-based motility: behavior and involvement of cytoskeletal regulators. Ann. N. Y. Acad. Sci. 990, 535–547 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Kim, S. et al. Microtubule- and dynein-mediated movement of Orientia tsutsugamushi to the microtubule organizing center. Infect. Immun. 69, 494–500 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Levin, M. et al. Minimal duration of tick attachment sufficient for transmission of infectious Rickettsia rickettsii (Rickettsiales: Rickettsiaceae) by its primary vector Dermacentor variabilis (Acari: Ixodidae): duration of Rickettsial reactivation in the vector revisited. J. Med. Entomol. 57, 585–594 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Galletti, M. et al. Virulence genes of Rickettsia rickettsii are differentially modulated by either temperature upshift or blood-feeding in tick midgut and salivary glands. Parasit. Vectors 9, 331 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Sunyakumthorn, P. et al. Characterization and growth of polymorphic Rickettsia felis in a tick cell line. Appl. Env. Microbiol. 74, 3151–3158 (2008).

    Article  CAS  Google Scholar 

  106. Niu, H., Yamaguchi, M. & Rikihisa, Y. Subversion of cellular autophagy by Anaplasma phagocytophilum. Cell Microbiol. 10, 593–605 (2008).

    Article  CAS  PubMed  Google Scholar 

  107. Huang, B. et al. The Anaplasma phagocytophilum-occupied vacuole selectively recruits Rab-GTPases that are predominantly associated with recycling endosomes. Cell Microbiol. 12, 1292–1307 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Truchan, H. et al. The pathogen-occupied vacuoles of Anaplasma phagocytophilum and Anaplasma marginale interact with the endoplasmic reticulum. Front. Cell Infect. Microbiol. 6, 22 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Truchan, H. et al. Anaplasma phagocytophilum Rab10-dependent parasitism of the trans-Golgi network is critical for completion of the infection cycle. Cell Microbiol. 18, 260–281 (2016).

    Article  CAS  PubMed  Google Scholar 

  110. Munderloh, U. et al. Infection of endothelial cells with Anaplasma marginale and A. phagocytophilum. Vet. Microbiol. 101, 53–64 (2004).

    Article  PubMed  Google Scholar 

  111. Pruneau, L. et al. Understanding Anaplasmataceae pathogenesis using "Omics" approaches. Front. Cell Infect. Microbiol. 4, 86 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Magunda, F., Thompson, C., Schneider, D. & Noh, S. Anaplasma marginale actively modulates vacuolar maturation during intracellular infection of its tick vector, Dermacentor andersoni. Appl. Environ. Microbiol. 82, 4715–4731 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mott, J., Barnewall, R. & Rikihisa, Y. Human granulocytic ehrlichiosis agent and Ehrlichia chaffeensis reside in different cytoplasmic compartments in HL-60 cells. Infect. Immun. 67, 1368–1378 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Felsheim, R. et al. Transformation of Anaplasma marginale. Vet. Parasitol. 167, 167–174 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cheng, Y. et al. Proteomic analysis of the Ehrlichia chaffeensis phagosome in cultured DH82 cells. PLoS ONE 9, e88461 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Fattouh, N., Cazevieille, C. & Landmann, F. Wolbachia endosymbionts subvert the endoplasmic reticulum to acquire host membranes without triggering ER stress. PLoS Negl. Trop. Dis. 13, e0007218 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cho, K., Kim, G. & Lee, O. Wolbachia bacteria reside in host Golgi-related vesicles whose position is regulated by polarity proteins. PLoS ONE 6, e22703 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Driscoll, T. et al. Wholly Rickettsia! Reconstructed metabolic profile of the quintessential bacterial parasite of eukaryotic cells. mBio 8, e00859-17 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Min, C. et al. Genome-based construction of the metabolic pathways of Orientia tsutsugamushi and comparative analysis within the Rickettsiales order. Comp. Funct. Genomics 2008, 623145 (2008).

    Article  PubMed Central  Google Scholar 

  120. White, P. et al. Reliance of Wolbachia on high rates of host proteolysis revealed by a genome-wide RNAi screen of Drosophila cells. Genetics 205, 1473–1488 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rodino, K. et al. Orientia tsutsugamushi modulates endoplasmic reticulum-associated degradation to benefit its growth. Infect. Immun. 86, e00596-17 (2018).

    Article  CAS  PubMed  Google Scholar 

  122. Lehman, S. et al. The rickettsial ankyrin repeat protein 2 is a type IV secreted effector that associates with the endoplasmic reticulum. mBio 9, e00975-18 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Silverman, D. & Wisseman, C. In vitro studies of Rickettsia–host cell interactions: ultrastructural changes induced by Rickettsia rickettsii infection of chicken embryo fibroblasts. Infect. Immun. 26, 714–727 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lamason, R. et al. Rickettsia Sca4 reduces vinculin-mediated intercellular tension to promote spread. Cell 167, 670–683.e10 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Silverman, D., Wisseman, C. & Waddell, A. In vitro studies of Rickettsia–host cell interactions: ultrastructural study of Rickettsia prowazekii-infected chicken embryo fibroblasts. Infect. Immun. 29, 778–790 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Thomas, S., Popov, V. & Walker, D. Exit mechanisms of the intracellular bacterium Ehrlichia. PLoS ONE 5, e15775 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Popov, V. et al. Ultrastructural differentiation of the genogroups in the genus Ehrlichia. J. Med. Microbiol. 47, 235–251 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Evans, S., Rodino, K., Adcox, H. & Carlyon, J. Orientia tsutsugamushi uses two Ank effectors to modulate NF-κB p65 nuclear transport and inhibit NF-κB transcriptional activation. PLoS Pathog. 14, e1007023 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Farris, T., Dunphy, P., Zhu, B., Kibler, C. & McBride, J. Ehrlichia chaffeensis TRP32 is a nucleomodulin that directly regulates expression of host genes governing differentiation and proliferation. Infect. Immun. 84, 3182–3194 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Klema, V. et al. Ehrlichia chaffeensis TRP120 nucleomodulin binds DNA with disordered tandem repeat domain. PLoS ONE 13, e0194891 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Rikihisa, Y. Role and function of the type IV secretion system in Anaplasma and Ehrlichia species. Curr. Top. Microbiol. Immunol. 413, 297–321 (2017).

    CAS  PubMed  Google Scholar 

  132. Kaur, S. et al. TolC-dependent secretion of an ankyrin repeat-containing protein of Rickettsia typhi. J. Bacteriol. 194, 4920–4932 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Pichon, S. et al. The expression of one ankyrin pk2 allele of the WO prophage is correlated with the Wolbachia feminizing effect in isopods. BMC Microbiol. 12, 55 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Cerveny, L. et al. Tetratricopeptide repeat motifs in the world of bacterial pathogens: role in virulence mechanisms. Infect. Immun. 81, 629–635 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bang, S. et al. Inhibition of eukaryotic translation by tetratricopeptide-repeat proteins of Orientia tsutsugamushi. J. Microbiol. 54, 136–144 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Dunphy, P., Luo, T. & McBride, J. Ehrlichia chaffeensis exploits host SUMOylation pathways to mediate effector–host interactions and promote intracellular survival. Infect. Immun. 82, 4154–4168 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Zhu, B., Das, S., Mitra, S., Farris, T. & McBride, J. Ehrlichia chaffeensis TRP120 moonlights as a HECT E3 ligase involved in self- and host ubiquitination to influence protein interactions and stability for intracellular survival. Infect. Immun. 85, e00290-17 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mitra, S. et al. Ehrlichia chaffeensis TRP120 effector targets and recruits host polycomb group proteins for degradation to promote intracellular infection. Infect. Immun. 86, e00845-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Wang, J. et al. Ehrlichia chaffeensis TRP120-mediated ubiquitination and proteasomal degradation of tumor suppressor FBW7 increases oncoprotein stability and promotes infection. PLoS Pathog. 16, e1008541 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Berk, J. et al. A deubiquitylase with an unusually high-affinity ubiquitin-binding domain from the scrub typhus pathogen Orientia tsutsugamushi. Nat. Commun. 11, 2343 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ote, M., Ueyama, M. & Yamamoto, D. Wolbachia protein TomO targets nanos mRNA and restores germ stem cells in Drosophila sex-lethal mutants. Curr. Biol. 26, 2223–2232 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Sheehan, K., Martin, M., Lesser, C., Isberg, R. & Newton, I. Identification and characterization of a candidate Wolbachia pipientis type IV effector that interacts with the actin cytoskeleton. mBio 7, e00622-16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Carpinone, E. et al. Identification of putative effectors of the type IV secretion system from the Wolbachia endosymbiont of Brugia malayi. PLoS ONE 13, e0204736 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Esna Ashari, Z., Brayton, K. & Broschat, S. Prediction of T4SS effector proteins for Anaplasma phagocytophilum using OPT4e, a new software tool. Front. Microbiol. 10, 1391 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Voss, O. et al. Risk1, a phosphatidylinositol 3-kinase effector, promotes Rickettsia typhi intracellular survival. mBio 11, e00820-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Lockwood, S. et al. Identification of Anaplasma marginale type IV secretion system effector proteins. PLoS ONE 6, e27724 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. VieBrock, L. et al. Orientia tsutsugamushi ankyrin repeat-containing protein family members are type 1 secretion system substrates that traffic to the host cell endoplasmic reticulum. Front. Cell Infect. Microbiol. 4, 186 (2014).

    PubMed  Google Scholar 

  148. Luo, T., Dunphy, P. & McBride, J. Ehrlichia chaffeensis tandem repeat effector targets differentially influence infection. Front. Cell Infect. Microbiol. 7, 178 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Brattig, N. et al. The major surface protein of Wolbachia endosymbionts in filarial nematodes elicits immune responses through TLR2 and TLR4. J. Immunol. 173, 437–445 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Chattoraj, P., Yang, Q., Khandai, A., Al-Hendy, O. & Ismail, N. TLR2 and Nod2 mediate resistance or susceptibility to fatal intracellular Ehrlichia infection in murine models of ehrlichiosis. PLoS ONE 8, e58514 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Choi, K., Scorpio, D. & Dumler, J. Anaplasma phagocytophilum ligation to Toll-like receptor (TLR) 2, but not to TLR4, activates macrophages for nuclear factor-κB nuclear translocation. J. Infect. Dis. 189, 1921–1925 (2004).

    Article  CAS  PubMed  Google Scholar 

  152. Gharaibeh, M. et al. Toll-like receptor 2 recognizes Orientia tsutsugamushi and increases susceptibility to murine experimental scrub typhus. Infect. Immun. 84, 3379–3387 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cho, K. et al. Orientia tsutsugamushi induced endothelial cell activation via the NOD1–IL-32 pathway. Microb. Pathog. 49, 95–104 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Ajendra, J. et al. NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae. Sci. Rep. 6, 39648 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Netea, M. et al. NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn’s disease. Eur. J. Immunol. 34, 2052–2059 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Pan, X. et al. The bacterium Wolbachia exploits host innate immunity to establish a symbiotic relationship with the dengue vector mosquito Aedes aegypti. ISME J. 12, 277–288 (2018).

    Article  CAS  PubMed  Google Scholar 

  157. Zug, R. & Hammerstein, P. Wolbachia and the insect immune system: what reactive oxygen species can tell us about the mechanisms of Wolbachia–host interactions. Front. Microbiol. 6, 1201 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Burke, T. et al. Inflammasome-mediated antagonism of type I interferon enhances Rickettsia pathogenesis. Nat. Microbiol. 5, 688–696 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Velayutham, T. et al. Ehrlichia chaffeensis outer membrane protein 1-specific human antibody-mediated immunity is defined by intracellular TRIM21-dependent innate immune activation and extracellular neutralization. Infect. Immun. 87, e00383-19 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lina, T., Dunphy, P., Luo, T. & McBride, J. Ehrlichia chaffeensis TRP120 activates canonical notch signaling to downregulate TLR2/4 expression and promote intracellular survival. mBio 7, e00672-16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Garcia-Garcia, J., Barat, N., Trembley, S. & Dumler, J. Epigenetic silencing of host cell defense genes enhances intracellular survival of the rickettsial pathogen Anaplasma phagocytophilum. PLoS Pathog. 5, e1000488 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Ojogun, N. et al. Anaplasma phagocytophilum infects mast cells via α1,3-fucosylated but not sialylated glycans and inhibits IgE-mediated cytokine production and histamine release. Infect. Immun. 79, 2717–2726 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rumfield, C., Hyseni, I., McBride, J., Walker, D. & Fang, R. Activation of ASC inflammasome driven by Toll-like receptor 4 contributes to host immunity against rickettsial infection. Infect. Immun. 88, e00886-19 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Smalley, C. et al. Rickettsia australis activates inflammasome in human and murine macrophages. PLoS ONE 11, e0157231 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Wang, T. et al. Superoxide anion production during Anaplasma phagocytophila infection. J. Infect. Dis. 186, 274–280 (2002).

    Article  CAS  PubMed  Google Scholar 

  166. Teymournejad, O. & Rikihisa, Y. Ehrlichia chaffeensis uses an invasin to suppress reactive oxygen species generation by macrophages via CD147-dependent inhibition of Vav1 to block Rac1 activation. mBio 11, e00267-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Sahni, S. & Rydkina, E. Host–cell interactions with pathogenic Rickettsia species. Future Microbiol. 4, 323–339 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Morchón, R. et al. iNOs expression is stimulated by the major surface protein (rWSP) from Wolbachia bacterial endosymbiont of Dirofilaria immitis following subcutaneous injection in mice. Parasitol. Int. 56, 71–75 (2007).

    Article  PubMed  Google Scholar 

  169. Bechelli, J. et al. Atg5 supports Rickettsia australis infection in macrophages in vitro and in vivo. Infect. Immun. 87, e00651-18 (2019).

    Article  CAS  PubMed  Google Scholar 

  170. Engström, P. et al. Evasion of autophagy mediated by Rickettsia surface protein OmpB is critical for virulence. Nat. Microbiol. 4, 2538–2551 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Choi, J. et al. Orientia tsutsugamushi subverts dendritic cell functions by escaping from autophagy and impairing their migration. PLoS Negl. Trop. Dis. 7, e1981 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ko, Y. et al. Active escape of Orientia tsutsugamushi from cellular autophagy. Infect. Immun. 81, 552–559 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Gill, A., Darby, A. & Makepeace, B. Iron necessity: the secret of Wolbachia’s success. PLoS Negl. Trop. Dis. 8, e3224 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Joshi, S., Francis, C., Silverman, D. & Sahni, S. NF-κB activation suppresses host cell apoptosis during Rickettsia rickettsii infection via regulatory effects on intracellular localization or levels of apoptogenic and anti-apoptotic proteins. FEMS Microbiol. Lett. 234, 333–341 (2004).

    CAS  PubMed  Google Scholar 

  175. Xiong, Q., Bao, W., Ge, Y. & Rikihisa, Y. Ehrlichia ewingii infection delays spontaneous neutrophil apoptosis through stabilization of mitochondria. J. Infect. Dis. 197, 1110–1118 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Yoshiie, K., Kim, H., Mott, J. & Rikihisa, Y. Intracellular infection by the human granulocytic ehrlichiosis agent inhibits human neutrophil apoptosis. Infect. Immun. 68, 1125–1133 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Andersson, S. et al. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396, 133–140 (1998).

    Article  CAS  PubMed  Google Scholar 

  178. Uchiyama, T. Tropism and pathogenicity of rickettsiae. Front. Microbiol. 3, 230 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Nicholson, W. & Paddock, C. in Yellow Book (eds Centers for Disease Control and Prevention, Brunette, G. W. & Nemhauser, J. B.) (Oxford Univ. Press, 2020).

  180. Foster, J. et al. The Wolbachia genome of Brugia malayi: endosymbiont evolution within a human pathogenic nematode. PLoS Biol. 3, e121 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Parola, P. et al. Update on tick-borne rickettsioses around the world: a geographic approach. Clin. Microbiol. Rev. 26, 657–702 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  182. McClure, E. et al. Engineering of obligate intracellular bacteria: progress, challenges and paradigms. Nat. Rev. Microbiol. 15, 544–558 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Felsheim, R. et al. Transformation of Anaplasma phagocytophilum. BMC Biotechnol. 6, 42 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Cheng, C. et al. Targeted and random mutagenesis of Ehrlichia chaffeensis for the identification of genes required for in vivo infection. PLoS Pathog. 9, e1003171 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Riley, S., Macaluso, K. & Martinez, J. Electrotransformation and clonal isolation of Rickettsia species. Curr. Protoc. Microbiol. 39, 3A.6.1–3A.6.20 (2015).

    Article  Google Scholar 

  186. Oki, A. et al. Dendrimer-enabled transformation of Anaplasma phagocytophilum. Microbes Infect. 17, 817–822 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Liu, Z., Tucker, A., Driskell, L. & Wood, D. Mariner-based transposon mutagenesis of Rickettsia prowazekii. Appl. Env. Microbiol. 73, 6644–6649 (2007).

    Article  CAS  Google Scholar 

  188. Kim, H., Premaratna, R., Missiakas, D. & Schneewind, O. Rickettsia conorii O antigen is the target of bactericidal Weil–Felix antibodies. Proc. Natl Acad. Sci. USA 116, 19659–19664 (2019).

    Article  CAS  PubMed  Google Scholar 

  189. Driskell, L. et al. Directed mutagenesis of the Rickettsia prowazekii pld gene encoding phospholipase D. Infect. Immun. 77, 3244–3248 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Noriea, N., Clark, T. & Hackstadt, T. Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence in a mammalian model system. mBio 6, e00323-15 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Baldridge, G., Burkhardt, N., Herron, M., Kurtti, T. & Munderloh, U. Analysis of fluorescent protein expression in transformants of Rickettsia monacensis, an obligate intracellular tick symbiont. Appl. Environ. Microbiol. 71, 2095–2105 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Hauptmann, M. et al. GFPuv-expressing recombinant Rickettsia typhi: a useful tool for the study of pathogenesis and CD8. Infect. Immun. 85, e00156-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Ammerman, N., Beier-Sexton, M. & Azad, A. Laboratory maintenance of Rickettsia rickettsii. Curr. Protoc. Microbiol. 11, 3A.5.1–3A.5.21 (2008).

    Article  Google Scholar 

  194. Atwal, S. et al. Clickable methionine as a universal probe for labelling intracellular bacteria. J. Microbiol. Methods 169, 105812 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Atwal, S., Giengkam, S., VanNieuwenhze, M. & Salje, J. Live imaging of the genetically intractable obligate intracellular bacteria Orientia tsutsugamushi using a panel of fluorescent dyes. J. Microbiol. Methods 130, 169–176 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Casper-Lindley, C. et al. Rapid fluorescence-based screening for Wolbachia endosymbionts in Drosophila germ line and somatic tissues. Appl. Env. Microbiol. 77, 4788–4794 (2011).

    Article  CAS  Google Scholar 

  197. Luce-Fedrow, A., Von Ohlen, T. & Chapes, S. Ehrlichia chaffeensis infections in Drosophila melanogaster. Infect. Immun. 77, 4815–4826 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Venard, C., Crain, P. & Dobson, S. SYTO11 staining vs FISH staining: a comparison of two methods to stain Wolbachia pipientis in cell cultures. Lett. Appl. Microbiol. 52, 168–176 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Sakamoto, J. & Azad, A. Propagation of arthropod-borne Rickettsia spp. in two mosquito cell lines. Appl. Environ. Microbiol. 73, 6637–6643 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author apologizes to colleagues whose work could not be cited due to space limitations. J.S. is grateful to the reviewers for their time and effort in carefully reviewing the manuscript, and to past and current laboratory members for scientific contributions. J.S. was funded by a Dorothy Hodgkin Fellowship from the Royal Society and by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant 1R21AI144385-01A1.

Author information

Authors and Affiliations

  1. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    Jeanne Salje

  2. Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

    Jeanne Salje

  3. Public Health Research Institute, Rutgers University, Newark, NJ, USA

    Jeanne Salje

Authors
  1. Jeanne Salje
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeanne Salje.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Peer review information

Nature Reviews Microbiology thanks U. Munderloh, who co-reviewed with X.-R. Wang, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Chlamydiales

An order of obligate intracellular bacteria that live in animals, insects and protozoa and includes species that are pathogenic to humans.

Endosymbiont

An organism that lives within another organism, either intracellularly or extracellularly, usually but not always in a mutually beneficial symbiosis.

Eschar

A small mark on the skin that resembles a cigarette burn and that forms at the site of infection by Orientia tsutsugamushi and some spotted fever group rickettsiae.

Pseudogenization

An evolutionary process in which a gene loses its function through mutation or disruption of the coding sequence.

Peptidoglycan

A highly cross-linked polymer composed of a polysaccharide backbone and short peptide sidechains that encases bacterial cells and confers osmotic protection and rigidity.

Lipopolysaccharide

(LPS). A large, negatively charged, lipid-anchored polysaccharide that comprises the outer leaflet of the outer membrane of most Gram-negative bacteria.

RecF-mediated gene conversion

A pathway of homologous recombination that repairs double-stranded breaks in bacteria.

Autotransporter family proteins

A family of outer membrane proteins that are widespread in pathogenic bacteria and are composed of a transmembrane β-barrel domain and a soluble extracellular passenger domain, which is sometimes cleaved and secreted into the extracellular space.

PDZ domains

Common structural domains of 80–90 amino acids found in proteins in both prokaryotes and eukaryotes.

Two-component systems

Signalling systems common in bacteria, typically comprising a histidine kinase sensor protein and a corresponding response regulator.

Endocytosis

A process by which eukaryotic cells internalize extracellular material that includes phagocytosis, pinocytosis and receptor-mediated endocytosis.

Filopodia

Thin, actin-rich membrane protrusions that extend from the edge of eukaryotic cells and play a role in sensing the environment, cell migration and cell–cell interactions.

Ankyrin repeat-containing proteins

(Ank proteins). A large family of mostly eukaryotic proteins that contain 1–34 copies of an Ankyrin repeat of ~33 amino acids, present in pathogenic bacteria and viruses.

Tetratricopeptide repeat proteins

(TPR). A family of proteins containing a repeat of 34 amino acids arrayed in a tandem of 3–16 motifs, present in both prokaryotic and eukaryotic organisms.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Salje, J. Cells within cells: Rickettsiales and the obligate intracellular bacterial lifestyle. Nat Rev Microbiol 19, 375–390 (2021). https://doi.org/10.1038/s41579-020-00507-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41579-020-00507-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology