Department of Microbiology and Molecular Genetics, College of Biological Sciences
Host-pathogen interactions; trogocytosis; cell death and repair
We focus on interactions between the microbial eukaryote Entamoeba histolytica and the human host. E. histolytica causes amoebiasis, a potentially lethal diarrheal disease in the developing world. The species was named “histolytica” (histo-: tissue; lytic-: dissolving) for its ability to injure host tissue. E. histolytica trophozoites (“amoebae”) possess potent cell-killing activity that is likely to drive tissue damage, but the mechanism by which amoebae kill cells was previously unclear. We discovered that amoebae kill human cells via an unusual mechanism, in which they bite off and ingest human cell fragments that contain human cell membrane, cytoplasm, and organelles. We named this “amoebic trogocytosis” (trogo-: nibble). Trogocytosis provides a new paradigm for the pathogenesis of amoebiasis. As an unusual cell killing insult, it further provides a vehicle to uncover new host cell death and survival signaling.
Unlike phagocytosis (phago-: devour), in which one cell “swallows” another, trogocytosis is poorly understood. However, there is an emerging appreciation that many eukaryotes take bites of membrane from other cells, sometimes together with intracellular contents, suggesting that this process is likely to be fundamental. Trogocytosis plays a role in signaling between immune cells, and intracellular bacteria stimulate host cell trogocytosis to promote their transfer from one cell to another. Other eukaryotic microbes use trogocytosis for cell killing, including the “brain-eating” amoeba, Naegleria fowleri. Therefore, trogocytosis might represent a conserved strategy for eukaryotic intercellular exchange that is exaggerated and exploited for cell killing by microbial pathogens. Our work is therefore broadly relevant to conserved mechanisms for eukaryotic cell-cell interaction.
Grad Group Affiliations
- Biochemistry, Molecular, Cellular and Developmental Biology
- Integrative Genetics and Genomics
Specialties / Focus
- Cell Biology
- Genomics, Proteomics and Metabolomics
- Molecular Genetics
- Molecular Microbiology
- Organelle and Membrane Biology
- Signal Transduction
Honors and Awards
- 2019 UC Davis Early Career Faculty Award for Creativity and Innovation
- 2017 American Society for Microbiology Young Investigator Award
- 2016 - 2020 Pew Scholar
- 2016 - 2017 Hellman Fellow
- 2014 - 2016 NIH K22 Career Transition Award
- 2013 - 2014 Hartwell Foundation Postdoctoral Fellowship
- 2012 American Society for Microbiology Career Development Grant for Postdoctoral Women
- 2010 - 2013 Howard Hughes Medical Institute Postdoctoral Fellowship from the Life Sciences Research Foundation
- 2010 - 2012 NIH Individual Postdoctoral Fellowship
- 2008 Dissertation Year Fellowship, UCLA
- 2005 Distinction in Teaching Award, UCLA
- 2000 Howard Hughes Medical Institute, Science Teaching Fellowship
- 2009 PhD Microbiology UCLA
- 2001 BS Genetics UC Davis
Full Publications List: https://www.ncbi.nlm.nih.gov/myncbi/1hMtH1fOrOeku/bibliography/public/
Bettadapur, A, Hunter, SS, Barbieri, CG, Settles, ML, and Ralston, KS. Establishment of quantitative RNAi-based forward genetics in Entamoeba histolytica and identification of genes required for growth. Preprint, bioRxiv.
Bettadapur, A, and Ralston, KS. Direct and high-throughput assays for human cell killing through trogocytosis by Entamoeba histolytica. Preprint, bioRxiv.
Bettadapur, A*, Miller, HW*, and Ralston, KS. (2020). Biting off what can be chewed: Trogocytosis in health, infection and disease. Infection and Immunity. In press. Journal Cover. *equal authorship
Gilmartin, AA, Ralston, KS, and Petri, WA, Jr. (2020). Inhibition of Amebic Cysteine Proteases Blocks Amebic Trogocytosis but not Phagocytosis. J Infect Dis. In press.
Miller, HW, Suleiman, RL, and Ralston, KS. (2019). Trogocytosis by Entamoeba histolytica mediates acquisition and display of human cell membrane proteins and evasion of lysis by human serum. mBio. 10(2):e00068-19.
Gilmartin, AA, Ralston KS, and Petri, WA, Jr. (2017). Inhibition of amebic lysosomal acidification blocks amebic trogocytosis and cell killing. mBio. 8(4):e01187-17.
Ralston, KS. (2015). Taking a bite: Amoebic trogocytosis in Entamoeba histolytica and beyond. Current Opinion in Microbiology. 28:26-35.
Ralston, KS. (2015). Chew on this: Amoebic trogocytosis and host cell killing by Entamoeba histolytica. Trends in Parasitology. 31(9):442-52.
Ralston, KS, Solga, MD, Mackey-Lawrence, NM, Somlata, Bhattacharya, A, and Petri, WA, Jr. (2014). Trogocytosis by Entamoeba histolytica contributes to cell killing and tissue invasion. Nature. 508(7497):526-530. Highlighted in: Guillen, N. (2014). Infection biology: Nibbled to death. Nature. 508(7497):462-463. Highlighted in: (2014). Tissue destruction in amebiasis: chew on it. Clinical Infectious Diseases. 15;59(2):iii-iv.
Naylor, C, Burgess, S, Madan, R, Buonomo, E, Razzaq, K, Ralston, K, and Petri, WA, Jr. (2014). Leptin receptor mutation results in defective neutrophil recruitment to the colon during Entamoeba histolytica infection. mBio. 5(6):e02046-14.
Kisalu, NK, Langousis, G, Bentolila, LA, Ralston, KS, Weiss, S and Hill, KL. (2014). Mouse infection and pathogenesis by Trypanosoma brucei motility mutants. Cellular Microbiology. 16(6):912-24.
Kato, K, Takegawa, Y, Ralston, KS, Gilchrist, CA, Hamano, S, Petri, WA, Jr. and Shinohara, Y. (2013). Sialic acid-dependent attachment of mucins from three mouse strains to Entamoeba histolytica. Biochemical and Biophysical Research Communication. 436(2):252-258.
Korpe, PS, Liu, Y, Siddique, A, Kabir, M, Ralston, KS, Ma, JZ, Haque, R and Petri, WA, Jr. (2013). A Prospective Cohort Study of Parasite-specific Breast Milk Antibodies and Protection from Enteric Protozoal Infection in Bangladeshi Infants. Clinical Infectious Diseases. 56(7):988-992.
Royer, TL, Gilchrist, C, Kabir, M, Ralston, KS, Haque, R, Clark, CG and Petri, WA, Jr. (2012). Entamoeba bangladeshi n. sp.: A novel Entamoeba species identified in children in Bangladesh. Emerging Infectious Diseases. 18(9): 1543-1545.
Hughes, LC, Ralston, KS, Hill, KL and Zhou, ZH. (2012). Three-dimensional structure of the trypanosome flagellum suggests that the paraflagellar rod functions as a biomechanical spring. PLoS One. 7(1):e25700.
Ralston, KS, Kisalu, N and Hill KL. (2011). Structure-function analysis of dynein light chain 1 identifies viable motility mutants in bloodstream-form Trypanosoma brucei. Eukaryotic Cell. 10(7):884-894. Journal Cover.
Ralston, KS and Petri, WA, Jr. (2011). Tissue destruction and invasion by Entamoeba histolytica. Trends in Parasitology. 27(6): 254-263. Journal Cover.
Ralston, KS and Petri, WA, Jr. (2011). The ways of a killer: how does Entamoeba histolytica elicit host cell death? Essays in Biochemistry. 51:193-210.
Ralston KS, Kabututu ZP, Melehani JH, Oberholzer M and Hill KL. (2009). The Trypanosoma brucei flagellum: moving parasites in new directions. Annual Review of Microbiology. 63:335-362.
Oberholzer, M, Lopez, MA, Ralston, KS and Hill, KL. (2009). Approaches for functional analysis of flagellar proteins in African trypanosomes. Methods in Cell Biology. In: King, SM and Pazour, GJ editors; Cilia: Model Organisms and Intraflagellar Transport. p. 21-57. Academic Press. ISBN: 978-0-12-381377-0.
Ralston, KS and Hill, KL. (2008). The flagellum of Trypanosoma brucei: new tricks from an old dog. International Journal of Parasitology. 38(8-9):869-884.
Baron, DM, Ralston, KS, Kabututu, ZP and Hill, KL. (2007). Functional genomics in Trypanosoma brucei identifies evolutionarily-conserved components of motile flagella. Journal of Cell Science. 120(Pt 3):478-491.
Ralston, KS and Hill, KL. (2006). Trypanin, a component of the flagellar dynein regulatory complex, is essential in bloodstream form African trypanosomes. PLoS Pathogens. 2(9):873-882.
Ralston, KS, Lerner, AG, Diener, DR and Hill, KL. (2006). Flagellar motility contributes to cytokinesis in Trypanosoma brucei and is modulated by an evolutionarily-conserved dynein regulatory system. Eukaryotic Cell. 5(4):696-711.