Journal of Medical and Biological Research
e-ISSN 2687-1491 DOI:10.37482/2687-1491

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Pathogenicity Factors of Anaplasma phagocytophilum (Review). P. 77–90

Section: Review articles

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[579.881.31:616.98](045)

DOI

https://doi.org/10.37482/2687-1491-Z286

Authors

Darya A. Gavrish* ORCID: https://orcid.org/0009-0003-9158-8099
Nushik S. Sarkisyan* ORCID: https://orcid.org/0000-0003-3512-5738
Marina V. Kolodina* ORCID: https://orcid.org/0009-0009-2581-2500
Alexandr N. Kulichenko* ORCID: https://orcid.org/0000-0002-9362-3949
*Stavropol Plague Control Research Institute (Stavropol, Russia)
Corresponding author: Marina Kolodina, address: ul. Sovetskaya 13–15, Stavropol, 355035, Russia; e-mail: kolodina_mv@snipchi.ru

Abstract

Human granulocytic anaplasmosis is a natural-focal vector-borne infection caused by the obligate intracellular pathogen Anaplasma phagocytophilum. The relevance of this study is due to the growing interest in the pathogenesis of anaplasmosis and the virulence factors of its causative agent amid increasing attention to natural- focal infections worldwide. The pathogen forms morulae in neutrophils and maintains intracellular persistence by reprogramming host cell signaling and regulatory pathways, thereby bypassing innate antibacterial defense mechanisms. The aim of this review is to systematize current concepts of the molecular mechanisms of A. phagocytophilum pathogenicity and its effector proteins. Original articles and reviews, selected from the PubMed, Elsevier, and CyberLeninka databases, are analyzed. Priority is given to publications over the last 10 years, while fundamental studies that first described the pathogen, the clinical characteristics of Anaplasma infection, and key effector mechanisms are included regardless of the date of publication. A total of 50 sources are included in the review. Particular attention is paid to experimental data on the AnkA, Ats-1, and AptA proteins, their interactions with cellular targets, and their effects on apoptosis, transcription, mitochondrial pathways, and signaling pathways. The mechanism of A. phagocytophilum survival in the host is considered, which involves the invasion of immune system cells and alteration of their functioning. Using the AnkA, Ats-1, and AptA proteins, the bacterium suppresses natural cell death (apoptosis), blocks the production of reactive oxygen species, and disrupts intracellular protein signaling. This enables the pathogen to persist in the host for a long time while avoiding elimination by the immune system. Pathogenic proteins are delivered into the host cell via the type IV secretion system, which is characteristic of a number of intracellular pathogens. Understanding the role of A. phagocytophilum effector proteins in the pathogenesis of anaplasmosis may provide a basis for the development of new diagnostic methods for this disease, targeted therapy, and epidemiological surveillance, especially in regions with natural nidality.

For citation: Gavrish D.A., Sarkisyan N.S., Kolodina M.V., Kulichenko A.N. Pathogenicity Factors of Anaplasma phagocytophilum (Review). Journal of Medical and Biological Research, 2026, vol. 14, no. 2, pp. 77–90. DOI: 10.37482/2687-1491-Z286

Keywords

Anaplasma phagocytophilum, electroneuromyography, neutrophil, type IV secretion system, effector proteins, intracellular persistence, apoptosis, autophagy

References

1. Barkhash A.V. Genetic Predisposition of Human and Laboratory Animals to Different Infections Transmitted by Ixodid Ticks. Mol. Genet. Microbiol. Virol., 2022, vol. 40, no. 2, pp. 3–13 (in Russ.). https://doi.org/10.17116/molgen2022400213

2. Matei I.A., Estrada-Peña A., Cutler S.J., Vayssier-Taussat M., Varela-Castro L., Potkonjak A., Zeller H., Mihalca A.D. A Review on the Eco-Epidemiology and Clinical Management of Human Granulocytic Anaplasmosis and Its Agent in Europe. Parasit. Vectors, 2019, vol. 12. Art. no. 599. https://doi.org/10.1186/s13071-019-3852-6

3. Chen S.M., Dumler J.S., Bakken J.S., Walker D.H. Identification of a Granulocytotropic Ehrlichia Species as the Etiologic Agent of Human Disease. J. Clin. Microbiol., 1994, vol. 32, no. 3, pp. 589–595. https://doi.org/10.1128/jcm.32.3.589-595.1994

4. Alberdi P., Espinosa P.J., Cabezas-Cruz A., de la Fuente J. Anaplasma phagocytophilum Manipulates Host Cell Apoptosis by Different Mechanisms to Establish Infection. Vet. Sci., 2016, vol. 3, no. 3. Art. no. 15. https://doi.org/10.3390/vetsci3030015

5. Bakken J.S., Dumler J.S. Human Granulocytic Anaplasmosis. Infect. Dis. Clin. North Am., 2015, vol. 29, no. 2, pp. 341–355. https://doi.org/10.1016/j.idc.2015.02.007

6. Dumic I., Jevtic D., Veselinovic M., Nordstrom C.W., Jovanovic M., Mogulla V., Veselinovic E.M., Hudson A., Simeunovic G., Petcu E., Ramanan P. Human Granulocytic Anaplasmosis – a Systematic Review of Published Cases. Microorganisms, 2022, vol. 10, no. 7. Art. no. 1433. https://doi.org/10.3390/microorganisms10071433

7. MacQueen D., Centellas F. Human Granulocytic Anaplasmosis. Infect. Dis. Clin. North Am., 2022, vol. 36, no. 3, pp. 639–654. https://doi.org/10.1016/j.idc.2022.02.008

8. Londoño A.F., Scorpio D.G., Dumler J.S. Innate Immunity in Rickettsial Infections. Front. Cell. Infect. Microbiol., 2023, vol. 13. Art. no. 1187267. https://doi.org/10.3389/fcimb.2023.1187267

9. Park J.M., Genera B.M., Fahy D., Swallow K.T., Nelson C.M., Oliver J.D., Shaw D.K., Munderloh U.G., Brayton K.A. An Anaplasma phagocytophilum T4SS Effector, AteA, Is Essential for Tick Infection. mBio, 2023, vol. 14, no. 5. Art. no. e0171123. https://doi.org/10.1128/mbio.01711-23

10. Namjoshi P., Kolape J., Patel A., Sultana H., Neelakanta G. Rickettsial Pathogen Augments Tick Vesicular-Associated Membrane Proteins for Infection and Survival in the Vector Host. mBio, 2025, vol. 16, no. 3. Art. no. e0354924. https://doi.org/10.1128/mbio.03549-24

11. Ramasamy E., Taank V., Anderson J.F., Sultana H., Neelakanta G. Repression of Tick microRNA-133 Induces Organic Anion Transporting Polypeptide Expression Critical for Anaplasma phagocytophilum Survival in the Vector and Transmission to the Vertebrate Host. PLoS Genet., 2020, vol. 16, no. 7. Art. no. e1008856. https://doi.org/10.1371/journal.pgen.1008856

12. Turck J.W., Sultana H., Neelakanta G. Arthropod Autophagy Molecules Facilitate Anaplasma phagocytophilum Infection of Ixodes scapularis Tick Cells. Commun. Biol., 2025, vol. 8, no. 1. Art. no. 433. https://doi.org/10.1038/s42003-025-07859-6

13. Chiarelli T.J., Sanchez S.E., Lind M.C.H., O’Bier N.S., Read C.B., Marconi R.T., Carlyon J.A. Distinct Modes of Cell Division Drive Anaplasma phagocytophilum Morphotype Development and the Infection Cycle. mBio, 2025, vol. 16, no. 10. Art. no. e0197225. https://doi.org/10.1128/mbio.01972-25

14. Ma Z., Li R., Hu R., Zheng W., Yu S., Cheng K., Zhang H., Xiao Y., Yi J., Wang Y., Chen C. Anaplasma phagocytophilum AptA Enhances the UPS, Autophagy, and Anti-Apoptosis of Host Cells by PSMG3. Int. J. Biol. Macromol., 2021, vol. 184, pp. 497–508. https://doi.org/10.1016/j.ijbiomac.2021.06.039

15. Li R., Ma Z., Zheng W., Xiao Y., Wang Z., Yi J., Wang Y., Chen C. Anaplasma phagocytophilum Ats-1 Enhances Exosome Secretion Through Syntenin-1. BMC Microbiol., 2023, vol. 23, no. 1. Art. no. 271. https://doi.org/10.1186/s12866-023-03023-4

16. Yoshikawa Y., Sugimoto K., Ochiai Y., Ohashi N. Intracellular Proliferation of Anaplasma phagocytophilum Is Promoted via Modulation of Endoplasmic Reticulum Stress Signaling in Host Cells. Microbiol. Immunol., 2020, vol. 64, no. 4, pp. 270–279. https://doi.org/10.1111/1348-0421.12770

17. Sorokina Yu.V., Korenberg E.I., Nefedova V.V., Kovalevskiy Yu.V. Kleshch Ixodes trianguliceps Bir. kak vozmozhnoe zveno tsirkulyatsii vozbuditeley obligatno-transmissivnykh infektsiy v lesnykh sochetannykh prirodnykh ochagakh Vostochnoy Evropy [Ixodes trianguliceps as a Possible Part of Circulation of Tick-Borne Obligate Infection in Eastern European Mixed Forest Foci]. Natsional’nye prioritety Rossii, 2021, no. 3, pp. 275–279.

18. Lagunova E.K., Khasnatinov M.A., Danchinova G.A. Characteristics of Tick-Borne Infections in the Underexplored Areas of the Trans-Baikal Territory. Acta biomed. sci., 2023, vol. 8, no. 6, pp. 130–140. https://doi.org/10.29413/ABS.2023-8.6.12

19. Samaddar S., Rolandelli A., O’Neal A.J., Laukaitis-Yousey H.J., Marnin L., Singh N., Wang X., Butler L.R., Rangghran P., Kitsou C., Cabrera Paz F.E., Valencia L., Ferraz C.R., Munderloh U.G., Khoo B., Cull B., Rosche K.L., Shaw D.K., Oliver J., Narasimhan S., Fikrig E., Pal U., Fiskum G.M., Polster B.M., Pedra J.H.F. Bacterial Reprogramming of Tick Metabolism Impacts Vector Fitness and Susceptibility to Infection. Nat. Microbiol., 2024, vol. 9, no. 9, pp. 2278–2291. https://doi.org/10.1038/s41564-024-01756-0

20. Dahmani M., Anderson J.F., Sultana H., Neelakanta G. Rickettsial Pathogen Uses Arthropod Tryptophan Pathway Metabolites to Evade Reactive Oxygen Species in Tick Cells. Cell. Microbiol., 2020, vol. 22, no. 10. Art. no. e13237. https://doi.org/10.1111/cmi.13237

21. Tinoco R., Otero D.C., Takahashi A.A., Bradley L.M. PSGL-1: A New Player in the Immune Checkpoint Landscape. Trends Immunol., 2017, vol. 38, no. 5, pp. 323–335. https://doi.org/10.1016/j.it.2017.02.002

22. Sukumaran B., Mastronunzio J.E., Narasimhan S., Fankhauser S., Uchil P.D., Levy R., Graham M., Colpitts T.M., Lesser C.F., Fikrig E. Anaplasma phagocytophilum AptA Modulates Erk1/2 Signalling. Cell. Microbiol., 2011, vol. 13, no. 1, pp. 47–61. https://doi.org/10.1111/j.1462-5822.2010.01516.x

23. Al-Khedery B., Lundgren A.M., Stuen S., Granquist E.G., Munderloh U.G., Nelson C.M., Alleman A.R., Mahan S.M., Barbet A.F. Structure of the Type IV Secretion System in Different Strains of Anaplasma phagocytophilum. BMC Genomics, 2012, vol. 13. Art. no. 678. https://doi.org/10.1186/1471-2164-13-678

24. Sheedlo M.J., Ohi M.D., Lacy D.B., Cover T.L. Molecular Architecture of Bacterial Type IV Secretion Systems. PLoS Pathog., 2022, vol. 18, no. 8. Art. no. e1010720. https://doi.org/10.1371/journal.ppat.1010720

25. Niu H., Kozjak-Pavlovic V., Rudel T., Rikihisa Y. Anaplasma phagocytophilum Ats-1 Is Imported into Host Cell Mitochondria and Interferes with Apoptosis Induction. PLoS Pathog., 2010, vol. 6, no. 2. Art. no. e1000774. https://doi.org/10.1371/journal.ppat.1000774

26. Niu H., Rikihisa Y., Yamaguchi M., Ohashi N. Differential Expression of VirB9 and VirB6 During the Life Cycle of Anaplasma phagocytophilum in Human Leukocytes Is Associated with Differential Binding and Avoidance of Lysosome Pathway. Cell. Microbiol., 2006, vol. 8, no. 3, pp. 523–534. https://doi.org/10.1111/j.1462-5822.2005.00643.x

27. Crosby F.L., Munderloh U.G., Nelson C.M., Herron M.J., Lundgren A.M., Xiao Y.-P., Allred D.R., Barbet A.F. Disruption of VirB6 Paralogs in Anaplasma phagocytophilum Attenuates Its Growth. J. Bacteriol., 2020, vol. 202, no. 23. Art. no. e00301-20. https://doi.org/10.1128/JB.00301-20

28. Rikihisa Y., Lin M., Niu H. Type IV Secretion in the Obligatory Intracellular Bacterium Anaplasma phagocytophilum. Cell. Microbiol., 2010, vol. 12, no. 9, pp. 1213–1221. https://doi.org/10.1111/j.1462-5822.2010.01500.x

29. Kim Y., Wang J., Clemens E.G., Grab D.J., Dumler J.S. Anaplasma phagocytophilum Ankyrin A Protein (AnkA) Enters the Nucleus Using an Importin-β-, RanGTP-Dependent Mechanism. Front. Cell. Infect. Microbiol., 2022, vol. 12. Art. no. 828605. https://doi.org/10.3389/fcimb.2022.828605

30. Lin M., Den Dulk-Ras A., Hooykaas P.J.J., Rikihisa Y. Anaplasma phagocytophilum AnkA Secreted by Type IV Secretion System Is Tyrosine-Phosphorylated by Abl-1 to Facilitate Infection. Cell. Microbiol., 2007, vol. 9, no. 11, pp. 2644–2657. https://doi.org/10.1111/j.1462-5822.2007.00985.x

31. IJdo J.W., Carlson A.C., Kennedy E.L. Anaplasma phagocytophilum AnkA Is Tyrosine-Phosphorylated at EPIYA Motifs and Recruits SHP-1 During Early Infection. Cell. Microbiol., 2007, vol. 9, no. 5, pp. 1284–1296. https://doi.org/10.1111/j.1462-5822.2006.00871.x

32. Mott J., Rikihisa Y. Human Granulocytic Ehrlichiosis Agent Inhibits Superoxide Anion Generation by Human Neutrophils. Infect. Immun., 2000, vol. 68, no. 12, pp. 6697–6703. https://doi.org/10.1128/iai.68.12.6697-6703.2000

33. Mott J., Rikihisa Y., Tsunawaki S. Effects of Anaplasma phagocytophila on NADPH Oxidase Components in Human Neutrophils and HL-60 Cells. Infect. Immun., 2002, vol. 70, no. 3, pp. 1359–1366. https://doi.org/10.1128/IAI.70.3.1359-1366.2002

34. Carlyon J.A., Fikrig E. Mechanisms of Evasion of Neutrophil Killing by Anaplasma phagocytophilum. Curr. Opin. Hematol., 2006, vol. 13, no. 1, pp. 28–33. https://doi.org/10.1097/01.moh.0000190109.00532.56

35. Gene ID: 1536 CYBB Cytochrome b-245 Beta Chain [Homo sapiens (Human)], Updated on 25 November 2025. Available at: https://www.ncbi.nlm.nih.gov/gene/1536 (accessed: 15 December 2025).

36. Rennoll-Bankert K.E., Dumler J.S. Lessons from Anaplasma phagocytophilum: Chromatin Remodeling by Bacterial Effectors. Infect. Disord. Drug Targets, 2012, vol. 12, no. 5, pp. 380–387. https://doi.org/10.2174/187152612804142242

37. Rennoll-Bankert K.E., Garcia-Garcia J.C., Sinclair S.H., Dumler J.S. Chromatin-Bound Bacterial Effector Ankyrin A Recruits Histone Deacetylase 1 and Modifies Host Gene Expression. Cell. Microbiol., 2015, vol. 17, no. 11, pp. 1640–1652. https://doi.org/10.1111/cmi.12461

38. Akgul C., Moulding D.A., Edwards S.W. Molecular Control of Neutrophil Apoptosis. FEBS Lett., 2001, vol. 487, no. 3, pp. 318–322. https://doi.org/10.1016/s0014-5793(00)02324-3

39. Choi K.-S., Park J.T., Dumler J.S. Anaplasma phagocytophilum Delay of Neutrophil Apoptosis Through the p38 Mitogen-Activated Protein Kinase Signal Pathway. Infect. Immun., 2005, vol. 73, no. 12, pp. 8209–8218. https://doi.org/10.1128/IAI.73.12.8209-8218.2005

40. Ge Y., Rikihisa Y. Anaplasma phagocytophilum Delays Spontaneous Human Neutrophil Apoptosis by Modulation of Multiple Apoptotic Pathways. Cell. Microbiol., 2006, vol. 8, no. 9, pp. 1406–1416. https://doi.org/10.1111/j.1462-5822.2006.00720.x

41. Ge Y., Yoshiie K., Kuribayashi F., Lin M., Rikihisa Y. Anaplasma phagocytophilum Inhibits Human Neutrophil Apoptosis via Upregulation of bfl-1, Maintenance of Mitochondrial Membrane Potential and Prevention of Caspase 3 Activation. Cell. Microbiol., 2005, vol. 7, no. 1, pp. 29–38. https://doi.org/10.1111/j.1462-5822.2004.00427.x

42. Li R., Ma Z., Zheng W., Wang Z., Yi J., Xiao Y., Wang Y., Chen C. Multiomics Analyses Reveals Anaplasma phagocytophilum Ats-1 Induces Anti-Apoptosis and Energy Metabolism by Upregulating the Respiratory Chain-mPTP Axis in Eukaryotic Mitochondria. BMC Microbiol., 2022, vol. 22, no. 1. Art. no. 271. https://doi.org/10.1186/s12866-022-02668-x

43. Kumar N., Robidoux J., Daniel K.W., Guzman G., Floering L.M., Collins S. Requirement of Vimentin Filament Assembly for Beta3-Adrenergic Receptor Activation of ERK MAP Kinase and Lipolysis. J. Biol. Chem., 2007, vol. 282, no. 12, pp. 9244–9250. https://doi.org/10.1074/jbc.M605571200

44. Perlson E., Michaelevski I., Kowalsman N., Ben-Yaakov K., Shaked M., Seger R., Eisenstein M., Fainzilber M. Vimentin Binding to Phosphorylated Erk Sterically Hinders Enzymatic Dephosphorylation of the Kinase. J. Mol. Biol., 2006, vol. 364, no. 5, pp. 938–944. https://doi.org/10.1016/j.jmb.2006.09.056

45. Murata S., Yashiroda H., Tanaka K. Molecular Mechanisms of Proteasome Assembly. Nat. Rev. Mol. Cell Biol., 2009, vol. 10, no. 2, pp. 104–115. https://doi.org/10.1038/nrm2630

46. Khoo B.S., Fountain-Jones N.M., Burton E.N., Oliver J.D. Targeted Surveillance of Tick-Borne Pathogens in Adult Ixodes scapularis (Acari: Ixodidae) Populations Across the Upper Midwest. J. Med. Entomol., 2025, vol. 63, no. 2. Art. no. tjaf170. https://doi.org/10.1093/jme/tjaf170

47. Garshong R.A., Adams D.R., Seagle S.W., Wasserberg G., Reiskind M.H., Teague J.L., Williams C.J., Barbarin A.M. Expanding Range of Ixodes scapularis Say (Acari: Ixodidae) and Borrelia burgdorferi Infection in North Carolina Counties, 2018–2023. PLoS One, 2025, vol. 20, no. 8. Art. no. e0329511. https://doi.org/10.1371/journal.pone.0329511

48. Stachera W., Szuba M., Kim A.T., Yu S., Choi J., Nzekea D., Wu Y.C., Brzozowska A., Sota M., Misiak M., Dybicz M. What Stage Are We at in the Development of Vaccines Against Tick-Borne Diseases? Vaccines (Basel), 2025, vol. 13, no. 9. Art. no. 990. https://doi.org/10.3390/vaccines13090990

49. Mahesh P.P., Namjoshi P., Sultana H., Neelakanta G. Immunization Against Arthropod Protein Impairs Transmission of Rickettsial Pathogen from Ticks to the Vertebrate Host. NPJ Vaccines, 2023, vol. 8, no. 1. Art. no. 79. https://doi.org/10.1038/s41541-023-00678-y

50. Lesiczka P.M., von Loewenich F.D., Kohl R., Krawczyk A.I., Dirks R.P., Boyer P.H., Jaulhac B., Moniuszko-Malinowska A., Uršič T., Strle F., Lotrič-Furlan S., Avšič-Županc T., Petrovec M., Sprong H. European Human Granulocytic Anaplasmosis Is Caused by a Subcluster of Anaplasma phagocytophilum Ecotype I. Curr. Res. Parasitol. Vector Borne Dis., 2025, vol. 8. Art. no. 100324. https://doi.org/10.1016/j.crpvbd.2025.100324

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