Raper Lab - Microbiology
Jayne Raper, Ph.D.
Associate Professor, Department of Microbiology
Medical Science Building
, Room 228
550 First Avenue, New York, NY 10016
Office: (212) 263-7632
Fax: (212) 263-8276
Lab: (212) 263-4372
Trypanosome, Leishmania, Salmonella, Bacillus, high density lipoprotein, innate immunity, antimicrobial peptide, intrinsic restriction factor, apoL-1, haptoglobin, Hpr, TLF1, TLF2, receptor, Africa, parasite, neglected tropical disease
PhD in Biochemistry in 1989, University of Cambridge, UK
1989-1993 Johns Hopkins University Medical School
Associate Professor New York University
2000-2006 Director, Advanced Topics in Microbial Pathogenesis
1985-1988 Science and Engineering Research Council Award
1988-1989 Cambridge Philosophical Society Award
1993-1995 ICP Postdoctoral Fellowship
1999-2003 Dewitt S. Goodman Award American Heart Association
1999-2004 K02 Independent Award (NIH/NIAID)
Trypanosome lytic factors, antimicrobial high-density lipoproteins and their role in intrinsic and innate immunity
Trypanosome lytic factors:
Our laboratory works on trypanosome lytic factors (TLFs), which are antimicrobial high-density lipoproteins that contribute to primate intrinsic and innate immunity. TLFs are characterized by their ability to kill African trypanosomes, which are extracellular protozoon parasites. TLFs are primate specific immune factors ONLY found in humans, some Great Apes and Old World Monkeys. Two subspecies of Trypanosoma brucei have evolved resistance to TLFs and can consequently infect humans and Great Apes, resulting sleeping sickness. The unique protein components of TLF are a hemoglobin binding protein, Haptoglobin-related protein (Hpr) and a pore forming protein, apolipoprotein L-I (apoL-I) (Fig.1).
Figure 1: Mechanism of killing of animal African trypanosomes by TLF.
TLF is bound via two of the protein components Hpr and hemoglobin in the flagellar pocket to a receptor and endocytosed by the parasite. TLF is activated in the acidic lysosome and apoL-I is released from the particle and inserts into the lysosomal membrane forming a monovalent ionic pore. The activation can be blocked by the weak base ammonium chloride (NH4Cl), which neutralizes acidic compartments within the parasite. The pore allows the equilibration of ions down their concentration gradients, leading to the dissipation of membrane potential and the influx of water, such that the parasite swells and bursts.
Recently we have discovered that TLF has broad-spectrum activity against other eukaryotic protozoa and prokaryotic pathogens, such as Leishmania sp., Salmonellatyphimurium (bacteriostatic) and Bacillus anthracis (bacteriocidal). The antimicrobial action requires that the pathogen and the TLF be taken up by macrophages and localize to the phagolysosome (Fig. 2), wherein apoL-I will be activated and form pores in the microbe. Therefore, we propose that TLF is one of our first lines of defense against intracellular pathogens.
Figure 2:Proposed mechanism of TLF intracellular antimicrobial action.
Transgenic cattle and trypanosomes:
Human African Trypanosomiasis, also known as sleeping sickness, is a tsetse fly-borne parasitic disease that is fatal if left untreated. Thirty-six sub-Saharan countries are endemic for trypanosomiasis. Both human and animal trypanosomiasis is considered a major obstacle to sustained economic growth. The animal disease causes immense human suffering through loss of the critical animal components, which are central to most African small scale agriculture. In the tsetse-infested areas, trypanosomiasis reduces the output of meat and milk by at least 50%. Accordingly, it isranked among the top 10 global cattle diseasesimpacting on the poor.
Some Old World Monkeys including baboons are naturally resistant to all African trypanosomes. We have recently isolated the baboon APOL1 orthologue, which is 60% similar to human APOL1. Mice transiently transfected with this gene are protected against human infective species T. b. rhodesiense as well as the cattle pathogens T. congolense and T. b. brucei. Due to this discovery we are developing transgenic cattle that carry baboon APOL1 and will evaluate their ability to resist infection.
Currently we are elucidating the critical changes in the baboon apoL-I protein that allow it to kill human infective parasites. We find that lysines in the C-terminus are required to evade neutralization by human infective trypanosomes.
Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model.
M.P. Molina Portela, M. Samanovic and J. Raper
J. Exp. Med. 2008 205:1721-1728
*Faculty of 1000 Biology: evaluations for Molina-Portela MP et al J Exp Med 2008 Aug 4 205 (8):1721-8 http://www.f1000biology.com/article/id/1120034/evaluation
Special commentary, In this Issue: Triple punch against trypanosomes by Hema Bashyam http://jem.rupress.org/cgi/content/full/205/8/1716
Trypanosome Lytic Factor, an Antimicrobial High Density Lipoprotein, Ameliorates Leishmania Infection.
M. Samanovic, M.P. Molina-Portela, A-D.C.Chessler, B.A.Burleigh, J. Raper
PLoS Pathogens (2009) Jan;5(1):e1000276
Identification of three classes of heteroaromatic compounds with activity against intracellular Trypanosoma cruzi by chemical library screening.
E. Bettiol, M. Samanovic, A. S. Murkin, J. Raper, F. Buckner and A. Rodriguez
PLoS Neglected Tropical Diseases 2009 Feb;3(2):e384
Activity of Trypanosome Lytic Factor- a novel component of innate immunity.
R. Thomson, M. Samanovic, J. Raper
Future Microbiology (2009) 4(7): 789-796
Hydrodynamic gene delivery of baboon TLF eradicates animal and human infective African trypanosomes.
R. Thomson, M.P. Molina-Portela, H. Mott, M. Carrington, J. Raper
Proc. Nat. Acad. Sci. (2009) 106: 19509-19514
Prophylactic antiparasitic transgenesis for human parasitic disease?
Lukeš J, Raper J., Mol Ther. (2010) 18(10):1745-1747.
Russell Thomson - Postdoctoral fellow
Daniella Kovacsics - Postdoctoral fellow
Ron Zipkin - Research Assistant
Cary Weiss - Undergraduate
Maria Nelson - Undergraduate
Chelsea Cannon - Undergraduate