Entamoeba histolytica is a protozoan pathogen and the causative agent of amoebiasis in humans. The species name (histo-: tissue; lytic-: dissolving) derives from the ability to destroy host tissues. E. histolytica trophozoites (?amoebae?) invade the large intestine, causing ulceration and can spread to other tissues (e.g., liver, lungs, brain), causing fatal abscesses. Amoebae possess contact-dependent cell-killing activity that is likely to drive tissue damage, but the mechanism was unclear. We established a new paradigm by discovering that amoebae kill by biting off and ingesting human cell fragments, which we named ?amoebic trogocytosis? (trogo-: nibble) (Ralston, et al., Nature, 2014). Building on this discovery, here we propose to delineate the unexpected contribution of trogocytosis to immune evasion. We will apply imaging flow cytometry, host and amoeba mutants, and a variety of host cell types to dissect the contribution of trogocytosis to immune avoidance in vitro, and we will use the mouse model of amoebiasis to extend these findings to pathogenesis in vivo. Beyond E. histolytica, trogocytosis has far-reaching applications to eukaryotic biology. Several microbial eukaryotes appear to use trogocytosis for cell-killing. In multicellular eukaryotes, trogocytosis is used for cell-killing, cell-cell communication and cell-cell remodeling. Trogocytosis plays roles in the immune system, in the central nervous system, and during development. Therefore, an improved understanding of the mechanism and biology of E. histolytica trogocytosis will apply both directly to the pathogenesis of amoebiasis and broadly to eukaryotic trogocytosis in general. This work is significant and high-impact as it will define a novel strategy for immune evasion and an important aspect of amoebiasis pathogenesis. Moreover, these studies apply broadly to trogocytosis as a conserved mode of eukaryotic cell-cell interaction. !

Public Health Relevance

Entamoeba histolytica is the causative agent of amoebiasis in humans, and its ability to kill human cells is likely to underlie its capacity to invade and damage host tissues. We established a new paradigm by discovering that amoebae kill by biting off and ingesting human cell fragments, which we named ?amoebic trogocytosis? (trogo-: nibble). Building on this discovery, here we propose to delineate the unexpected contribution of trogocytosis to immune evasion, which will apply both directly to the pathogenesis of amoebiasis and broadly to eukaryotic trogocytosis in general. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI146914-01
Application #
9803739
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pesce, John T
Project Start
2019-06-01
Project End
2024-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618