Areas of Expertise
- Obligatory Intracellular Bacteria
- Anaplasma, Ehrlichia, and Neorickettsia
- M.S. University of Tokyo
- Ph.D. University of Tokyo
- Postdoc. Harvard Medical School
Ehrlichia, anaplasma, and neorickettsia are unique bacteria (obligatory intracellular bacteria) that infect leukocytes like HIV virus, and cause a severe flu-like disease collectively called “ehrlichiosis”. We study how ehrlichia subvert the host immune system; how they manipulate host cells to create an effective replicative niche; how they regulate the dichotomous tasks of intracellular replication and intercellular spreading; and how they cause human disease. The deletion of a large number of genes that are present in the genomes of free-living bacteria, including genes required for the biosynthesis of lipopolysaccharide and peptidoglycan, and the acquisition of a cholesterol uptake mechanism, has set these bacteria on the path towards a life within eukaryotic cells. In contrast, the repertoire of genes encoding outer membrane porins and the type IV secretion system has been expanded to ensure nutrient acquisition and subversion of host antimicrobial defenses. Our research program embraces “from genomes to animal models” and “from field to molecular works”: to analyze these bacterial genomes; to investigate suspected bacterial virulence factors and signaling mechanisms in vitro; to analyze molecular mechanisms of ehrlichial transmission from vectors to mammals; and test putative disease mechanisms in cultured cells and in relevant animal models, and improve diagnostic methods.
Examples of current research projects include:
1. Elucidation of Signaling Pathways for Entry and Survival of Ehrlichiae in Leukocytes: The objective of this project is to study bacterial molecules that drive safe entry and survival of ehrlichiae in the host cells by mobilizing actin cytoskeleton, inhibiting reactive oxygen species generation, lysosomal fusion, and leukocyte’s activation and apoptosis, and by competitively acquiring cholesterol, and nutrients by inducing autophagy.
2. Characterization of Type IV Secretion and Two-Component Regulatory Systems in Human Ehrlichiosis Agent: The objectives of this project are 1) to examine the functions and effectors of type IV secretion system in ehrlichial infection, 2) to elucidate molecular mechanisms by which three pairs of functional two-component systems (CckA-CtrA, NtrY-NtrX, and PleC-PleD) regulate ehrlichial intracellular growth and developmental cycle.
3. Roles of Ehrlichial Outer Membrane Proteins in Parasitism: The objective of this project is to examine biological activities of unique outer membrane proteins for invasion and bacterial physiology (porin, iron transport), and host signal transduction and immune modulation in a cell culture and an animal model of human ehrlichiosis.
4. Study Virulence Factors by Using Transposon Mutagenesis: The objective of this project has been to create Ehrlichia, Anaplasma, and Neorickettsia transposon insertion mutants to study their virulence and pathogenesis in animal models of disease.
Member, National Academy of Sciences
Yan, Qi, M. Lin, W. Huang, O. Teymournejad, J. M. Johnson, F. A. Hays, Z. Liang, G. Li, and Y. Rikihisa (2018) An Ehrlichia type IV secretion system effector Etf-2 binds to active RAB5 and delays endosome maturation. Proc. Natl. Acad. Sci. In press.
Teymournejad, O., M. Lin, and Y. Rikihisa (2017) Ehrlichia chaffeensis and Its Invasin EtpE Block Reactive oxygen Species Generation by Macrophages in a DNase X–Dependent Manner. mBio. 8: e01551-17. DOI: 10.1128/mBio.01551-17. PMID: 29162709
Rikihisa, Y. (2017) Role and Function of Type IV Secretion Systems in Anaplasma and Ehrlichia species. In: Type IV secretion in Gram-negative and Gram-positive bacteria. Ed. Steffen Backert & Elisabeth Grohmann. “Current Topics in Microbiology and Immunology” (CTMI) by Springer International Publishing AG Switzerland. In press.
Rikihisa, Y. (2017) Subversion of RAB5-Regulated Autophagy by the Intracellular Pathogen Ehrlichia chaffeensis. Small GTPase. PMID: 28650718 DOI. 10.1080/21541248.2017.1332506
Sharma, P., O. Teymournejad, and Y. Rikihisa (2017) Peptide Nucleic Acid Knockdown and Intra-Host Cell Complementation of Ehrlichia Type IV Secretion System Effector. Front. Cell. Infect. Microbiol. 7: 228 PMCID: PMC5461285 DOI: 10.3389/fcimb.2017.00228
Lin, M., K. Bachman, Z. Cheng, S.C. Daugherty, S. Nagaraj, N. Sengamalay, S. Ott, Al Godinez, L. J. Tallon, L. Sadzewicz, C. Fraser, J. C. Dunning Hotopp, and Y. Rikihisa. (2017) Analysis of Complete Genome Sequence and Major Surface Antigens of Neorickettsia helminthoeca, Causative Agent of Salmon Poisoning Disease. Microb. Biotechnol. 10:933-957. DOI: 10.1111/1751-7915.12731
Pritt, B.S., Allerdice M. E. J., L. M. Sloan, C. D. Paddock, U. G. Munderloh, Y. Rikihisa, T. Tajima, S. M. Paskewitz, D. F. Neitzel, D. K. H. Johnson, E. Schiffman, J. P. Davis, C. S. Goldsmith, C. M. Nelson, S. E. Karpathy. (2017) Proposal to reclassify Ehrlichia muris as Ehrlichia muris subsp. muris subsp. nov. and description of Ehrlichia muris subsp. eauclairensis subsp. nov., a newly recognized tick-borne pathogen of humans Int. J. Syst. Evol. Microbiol. 67:2121-2126. doi: 10.1099/ijsem.0.001896
Rikihisa, Y. (2017) The family Anaplasmataceae. In: Pathogenic bacteria, Virus. Ed. Hiroshi Oda, Hokkaido University Press. (In Japanese). PP 120-124.
Thomas, S., W. Alexander, J. Gilligan, and Y. Rikihisa. (2016) Importance of Rickettsiales infections. In: Rickettsiales. Biology, Molecular Biology, Epidemiology, and Vaccine Development. Ed. Sunil Thomas. Springer International Publishing AG Switzerland. PP.3-22.
Xiong, Q., H. Bekebrede, P. Sharma, L. G. Arroyo, J. D. Baird, and Y. Rikihisa. (2016) An ecotype of Neorickettsia risticii causing Potomac Horse Fever in Canada. Appl. Environ. Microbiol. 82: 6030-6036.
Lai, T-H, M.E. Parraga, E. Alvarez, and Y. Rikihisa. (2016) Anaplasma platys Immunoblot Test Using Major Surface Antigens. Vector-Borne and Zoonotic Diseases.16: 581-587.
- Lin, M., H. Liu, Q. Xiong, H. Niu, Z. Cheng, A. Yamamoto, and Y. Rikihisa (2016) Ehrlichia secretes Etf-1 to induce autophagy and capture nutrients for its growth through RAB5 and class III phosphatidylinositol 3-kinase. Autophagy. 12: 1-22.
- Greiman S, Rikihisa Y, Cain J, Vaughan J & Tkach V. (2016) Germs within worms: Localization of Neorickettsia sp. within life cycle stages of digenean Plagiorchis elegans. Appl Environ. Microbiol. 82: 2356-2362.
- Ge Y, Yin H, Rikihisa Y, Pan W & Yin H. (2016) Molecular detection of tick-borne pathogens in Rickettsiales in goats and sheep from southeastern China. Vector-Borne and Zoonotic Dis. 16: 309-316.
- Niu, H. and Y. Rikihisa (2016) Chapter 8. Intracellular Bacterium Anaplasma phagocytophilum Induces Autophagy by Secreting Substrate Ats-1 that neutralizes the Beclin 1-ATG14L Autophagy Initiation Pathway. In: AUTOPHAGY: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging. Ed. M. A. Hayat. Elsevier Publishing Company Amsterdam, Netherlands. volume 9 Human Diseases and Autophagosome: PP 308-314.
- Kumar DM, Lin M, Xiong Q, Webber MJ, Kural C & Rikihisa Y. (2015) 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.
- Harasawa R, Fujita H, Kadosaka T, Ando S & Rikihisa Y. (2015) Proposal for 'Candidatus Mycoplasma haemomuris subsp. musculi' in mice, and 'Candidatus Mycoplasma haemomuris subsp. ratti' in rats. Int. J. Syst. Evol. Microbiol. 65: 734-737. 2.
- Rikihisa Y. (2015) Salmon poisoning disease and Elokomin fluke fever. Merck Veterinary Manual. Veterinary professionals, Generalized Conditions, Rickettsial Diseases.
- Rikihisa Y. (2015) Molecular Pathogenesis of Ehrlichia chaffeensis Infection. Ann. Rev. Microbiol. In press.
- Cheng Z, Lin M, & Rikihisa Y (2014) Ehrlichia chaffeensis proliferation begins with NtrY/NtrX and PutA/GlnA upregulation and CtrA degradation induced by proline and glutamine. mBio. 5: e02141-14.
- Niu H & Rikihisa Y (2014) Investigating interference with apoptosis induction by bacterial proteins. Methods in Molecular Biology. Ed. David O’ Callaghan and Annette Vergunst. 1197: 169-184.
- Kumar DM, Yamaguchi M, Miura K, Lin M, Los M, Coy JF, & Rikihisa Y (2013) Ehrlichia chaffeensis uses its surface protein EtpE to bind GPI-anchored protein DNase X and trigger entry into mammalian cells. PLoS Pathog. 9: e1003666
- Niu H & Rikihisa Y (2013) Ats-1, a novel bacterial molecule that links autophagy to bacterial nutrition. Autophagy, 9: 1-2.
- Niu H, Xiong Q, Yamamoto A, Hayashi-Nishino M, & Rikihisa Y (2012) Autophagosomes Induced by a Bacterial Beclin 1-binding Protein Facilitate Obligatory Intracellular Infection. Proc. Natl. Acad. Sci. 109:20800-20807.
- Liu H, Bao W, Lin M, Niu H, & Rikihisa Y (2012) Ehrlichia chaffeensis Type IV Secretion Effector ECH0825 is Translocated to Mitochondria, and Inhibits Apoptosis by upregulating Host MnSOD. Cell. Microbiol. 14: 1037-1050.
- Xiong Q & Rikihisa Y (2012) Subversion of NPC1 pathway of cholesterol transport by Anaplasma phagocytophilum. Cell. Microbiol. 14: 560-576.
- Cheng Z, Miura K, Popov VL, Kumagai Y & Rikihisa Y (2011) Insights into the CtrA Regulon in Development of Stress-resistance in Obligatory Intracellular Pathogen Ehrlichia chaffeensis. Mol. Microbiol. 82: 1217-1234.
Other Relevant Publications
- Rikihisa Y. (2011) Mechanisms of obligatory intracellular infection with Anaplasma phagocytophilum. Clin. Microbiol. Rev. 24: 469-489.
- Miura K, Matsuo J, Rahman MA, Kumagai Y, Li X & Rikihisa Y (2011) Ehrlichia chaffeensis Induces Monocyte Inflammatory Responses Through MyD88, ERK and NF-κB, but not through TRIF, IL-1R1/IL-18R1, or TLRs. Infect. Immun. 79: 4947-4956.
- Kumagai Y, Matsuo J, Cheng Z, Hayakawa Y & Rikihisa Y (2011) c-di-GMP Signaling Regulates Intracellular Aggregation, Sessility, and Growth of Ehrlichia chaffeensis Infect. Immun. 79: 3905-3912.
- Lai T, Orellana NG, Yuasa Y & Rikihisa Y (2011) Cloning of the Major OMP Expression Locus in Anaplasma platys and Seroreactivity of a Species-Specific Antigen. J. Bacteriol. 193: 2924–2930.
- Gibson K, Kumagai Y & Rikihisa Y (2010) Proteomic Analysis of Neorickettsia sennetsu Surface-exposed Proteins and Porin Activity of the Major Surface Protein P51. J. Bacteriol. 192: 5898-5905.
- Niu H, Kozjak-Pavlovic V, Rudel T & Rikihisa Y (2009) Anaplasma phagocytophilum Ats-1 is Imported into Host Cell Mitochondria and Interferes with Apoptosis Induction. PLoS Pathogens 6: e1000774.
- Lin M, Zhang C, Gibson K & Rikihisa Y (2009) Analysis of Complete Genome Sequence of Neorickettsia risticii: the Causative Agent of Potomac Horse Fever. Nuc. Acid Res. 37: 6076-6091.
- Xiong Q, Lin M, & Rikihisa Y (2009) Anaplasma phagocytophilum acquires cholesterol through low-density lipoprotein uptake pathway. PLoS Pathogens. 5:e1000329
- Lai T-H, Kumagai Y, Hyodo M, Hayakawa Y, & Rikihisa Y. (2009) Anaplasma phagocytophilum PleC histidine kinase and PleD diguanylate cyclase two-component system and role of cyclic di-GMP in host-cell infection. J. Bacteriol. 191: 693-700.