Kent L. Hill, Ph.D.
-Professor, Microbiology, Immunology & Molecular Genetics
-Member, Biochemistry, Biophysics & Structural Biology GPB Home Area, California NanoSystems Institute, Cell & Developmental Biology GPB Home Area, Immunity, Microbes & Molecular Pathogenesis GPB Home Area, Microbiology, Immunology & Molecular Genetics
Figure 1. African trypanosome in the bloodstream.
PMT = subpellicular microtubules, PFR = paraflagellar rod, FAZ = flagellum attachment zone.
A) Scanning EM (provided by J.E. Donelson, University of Iowa)
Figure 2. Tsetse fly taking a bloodmeal.
Figure provided by J.E. Donelson, University of Iowa
|Research Program: Parasites in Motion, Mechanism and Biology of Flagellar Motility in Trypanosomes
My laboratory is investigating flagellar motility in African trypanosomes (Figure 1). These protozoan parasites cause a disease that is commonly called “African Sleeping Sickness”. They are transmitted to the bloodstream of their mammalian hosts through the bite of an insect vector, the tsetse fly (Figure 2). Once in the bloodstream, these highly motile, unicellular parasites burrow through the blood vessel endothelium and eventually invade the central nervous system, where they initiate a cascade of events that ultimately results in fatal sleeping sickness. The two general, long-term objectives of our research are:
1) Provide a better understanding of the cellular and molecular biology of trypanosomes and related kinetoplastid parasites, thereby facilitating the development of more effective treatments for the diseases caused by these organisms. These parasites are the source of mortality and morbidity in several million people worldwide and current treatment regimens are antiquated, costly and ineffective.
2) Exploit trypanosomes as a model system to investigate the function of the eukaryotic flagellum. As early diverging eukaryotes, trypanosomes have historically been a rich source for the discovery of novel biological phenomena that are subsequently found to occur in other eukaryotic organisms.
Why Study Trypanosome Flagella?
Cilia and flagella are evolutionarily-conserved organelles that protrude like small appendages from the surface of a cell. They are biological “nanomachines” that are present on most tissues of the human body and on many single-celled microbes. They perform motility, transport and sensory functions.
Flagella are required for motility of human pathogens and defects in human cilia cause a variety of fatal and debilitating diseases.
Infectious Diseases caused by pathogens that require cilia include:
African sleeping sickness, Malaria, Epidemic Diarrhea and Trichomoniasis (the most common non-viral sexually transmitted disease in the world). These pathogens are responsible for mortality and morbidity in approximately 0.5 billion people world-wide.
Heritable Human Diseases caused by cilia defects include:
Hydrocephalus, Infertility, Left-Right Axis Defects, Eye Disorders, Polycystic Kidney Disease and Bardet-Biedle Syndrome (BBS).
Therefore, in addition to addressing fundamental questions in cell biology, our research directly impacts efforts to understand and treat infectious diseases and genetic diseases in humans.
Specific Research Projects include:
I. Cell Motility. We have used the novel methodology of RNA-interference to generate inducible gene “knockdowns” in trypanosomes. One of the genes that we have “knocked-down” encodes a recently discovered protein that is essential for cell motility. Since trypanosomes are named for their hallmark auger-like motility (“trypanon” is Greek for auger), we have named this protein “trypanin”. Ongoing studies on this project include:
i) Determining how cell motility influences parasite development and disease pathogenesis.
ii) Identification and characterization of other components of the trypanosome’s motility apparatus.
iii) Elucidation of the mechanisms by which trypanin controls cell motility.
iv) Characterization of trypanin-related proteins that are present in other organisms.
II. Protein Trafficking. Formation of the eukaryotic flagellum is dependent upon an evolutionarily-conserved protein targeting process termed Intraflagellar Transport (“IFT”), in which newly synthesized proteins are delivered from the cytoplasm into the flagellum. Recent work has led to the identification of IFT motors and other components of the IFT pathway. However, a unifying explanation for how flagellar proteins are targeted to the flagellum is unknown. We have identified a set of 30 novel flagellar proteins and are using these proteins to elucidate mechanisms of protein targeting to the flagellum.
III. Additional areas of research include studies on a mammalian trypanin homologue and development of new methodologies for gene transfection and in situ gene tagging in trypanosomes. This latter project will benefit greatly from the recently completed trypanosome genome project.
a. DeMarco, S., Saada, E., Lopez, M., Hill, K.L. (2020). Identification of Positive Chemotaxis in the Protozoan Pathogen Trypanosoma brucei. mSphere 5(4), e00685-20. https://dx.doi.org/10.1128/msphere.00685-20 . PMCID: PMC7426175.
b. Shaw, S.*, DeMarco, S.*, Rehmann, R, Wenzler, T, Florini, F., Roditi, I† and Hill, K.L.† (2019) Flagellar cAMP signaling controls trypanosome progression through host tissues. (In Press) Nature Communications.10(1):803. doi: 10.1038/s41467-019-08696-y. *equal contributors; † co-corresponding authors
c. Imhof, S., Zhang, J., Wang, H., Bui, K., Nguyen, H., Atanosov, I., Hui, W., Yang, S., Zhou, Z., Hill, K.L. (2019). Cryo electron tomography with Volta phase plate reveals novel structural foundations of the 96-nm axonemal repeat in the pathogen Trypanosoma brucei. eLife 8(), e52058. https://dx.doi.org/10.7554/elife.52058
d. Imhof, S. and Hill, K.L. Dynein-based motility of pathogenic protozoa, in: S.M. King (Ed.), Dyneins: Structure, Biology And Disease: Dynein Mechanics, Dysfunction, and Disease. vol. 2, Academic Press, Elsevier, (2018), pp. 418–435.
e. Shimogawa, M.M., Ray, S.S., Kisalu, N., Zhang, Y., Geng, Q., Ozcan, A., and Hill, K.L. (2018) Parasite motility is critical for virulence of African trypanosomes. Scientific Reports, 8, 9122. PMCID: PMC6002391
f. Zhang, Y., Ceylan Koydemir, H., Shimogawa, M.M., Yalcin, S., Guziak, A., Liu, T., Oguz, I., Huang, Y., Bai, B., Luo, Y., Luo, Y., Wei, Z., Wang, H., Bianco, V., Zhang, B., Nadkarni, R., Hill, K.L. and Ozcan, A. (2018) Motility-based label-free detection of parasites in bodily fluids using holographic speckle analysis and deep learning. Light: Science & Applications 7(1), 108. https://dx.doi.org/10.1038/s41377-018-0110-1 . PMCID: PMC6290798