Mechanisms of Resistance and Susceptibility to African Trypanosome Infection

Summary

Principal Investigator: Stephen L Hajduk
Abstract: DESCRIPTION (provided by applicant): Trypanosoma brucei brucei causes Nagana in cattle but is non-infectious to humans because of its susceptibility to the cytotoxic activity of normal human serum. This innate immune activity is due to a minor subclass of high-density lipoprotein (HDL) termed the Trypanosome Lytic Factor (TLF). TLF contains apolipoprotein A-1 (apoA-1), a protein found in all HDLs, and two primate specific proteins, haptoglobin related protein (Hpr) and apolipoprotein L-1 (apoL-1). Both Hpr and apoL-1 have been shown to be necessary for maximal trypanosome killing in vitro and in a transgenic mouse model. Hpr is a hemoglobin (Hb) binding protein and Hb is an essential co-factor for trypanosome killing by TLF. The cellular pathway of TLF mediated lysis of T. b. brucei initiates with binding of TLF to a high affinity receptor (Tb927.6.440) located in the flagellar pocket. Following binding TLF is rapidly taken up and localized to the lysosome. Within the acidified lysosome TLF is activated and kills T. b. brucei by destabilization of the lysosomal membrane. The human sleeping sickness parasite Trypanosoma brucei rhodesiense has evolved a defense against TLF. T. b. rhodesiense produces a potent inhibitor of TLF, Serum Resistance Associated protein (SRA), which binds apoL-1 and neutralizes the activity of TLF. Trypanosoma brucei gambiense also infects humans but lacks SRA and, as shown in this proposal, resists TLF killing by down regulation of the TLF receptor. In this proposal, we outline a number of experiments that will provide important information on the mechanism of assembly of TLF and how its composition might be altered to produce "variant TLFs" with activity against the human sleeping sickness parasites (Aim 1). To better understand the biophysical basis for membrane destabilization by native TLF and its constituent proteins we will use model liposomes of defined composition in fluorescence based assays to measure TLF induced changes in lipid dynamics (Aim 2). Finally, we will investigate the cellular, molecular and biochemical basis of SRA-dependent and SRA-independent resistance to TLF. In addition to resolving a longstanding question concerning how SRA inhibits TLF activity we will investigate the mechanism of T. b. gambiense resistance to TLF (Aim 3). Our long-term goals are to develop a better understanding of the mechanism of TLF killing and how the human sleeping sickness parasites evade this activity. This may allow us to develop novel approaches for the treatment of this important human disease.
Funding Period: 1996-02-15 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Late endosomal Rab7 regulates lysosomal trafficking of endocytic but not biosynthetic cargo in Trypanosoma brucei
    Jason S Silverman
    Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA
    Mol Microbiol 82:664-78. 2011

Detail Information

Publications1

  1. ncbi Late endosomal Rab7 regulates lysosomal trafficking of endocytic but not biosynthetic cargo in Trypanosoma brucei
    Jason S Silverman
    Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA
    Mol Microbiol 82:664-78. 2011
    ..Surprisingly, conditional knockout indicates that TbRab7 may be non-essential in procyclic insect form trypanosomes...

Research Grants30

  1. Multifunctional class I transcription in T. brucei
    ARTHUR GUNZL; Fiscal Year: 2013
    ..Such targets are urgently needed be- cause drugs to cure a T. brucei infection are few and toxic and parasite resistance to these drugs is on the rise. ..
  2. Selective Inhibitors of the Hexose Transporter from African Trypansomes
    Scott Landfear; Fiscal Year: 2013
    ..Kip Guy, who operates an internationally renowned compound screening and pharmaceutical chemistry facility at St. Jude and who has a strong track record of screening for anti-parasitic compounds. ..
  3. TRANSCRIPTOME ANALYSIS OF LEISHMANIA PANAMENSIS DEVELOPMENTAL STAGES
    Christian Tschudi; Fiscal Year: 2013
    ..The identified genes could be of interest as potential immunotherapeutic and pharmacological targets for treatment and disease control. ..
  4. Drug development of orally active anti-trypanosomiasis agents
    Bin Su; Fiscal Year: 2013
    ..3) Determine the in vivo anti-trypanosome activity and the bioavailability of the drug candidates. The oral activity and blood brain barrier passing ability of the drug candidates will be determined with animals. ..
  5. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  6. Middle Atlantic Regional Center for Excellence for Biodefense and Emerging Infect
    MYRON MAX LEVINE; Fiscal Year: 2013
    ..abstract_text> ..
  7. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  8. Parameters that govern initiation of VSG switching in T.brucei
    F Nina Papavasiliou; Fiscal Year: 2013
    ..The work we propose aims to understand the mechanism of T. brucei surface coat switching, which is the sole cause of pathogen persistence and chronic infection. ..
  9. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  10. An Integrative Genomic Approach to APOL1-Associated Nephropathy.
    BARRY IRA FREEDMAN; Fiscal Year: 2013
    ....
  11. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..