Principal Investigator: Alain Debrabant, PhD
Office / Division / Lab: OBRR / DETTD / LEP
The blood supply of the US is a valuable resource that must be kept safe and available for surgical patients, accident victims, wounded soldiers, patients being treated for blood diseases, and other people in need of transfusions and products derived from blood. Therefore, donated blood is tested for a variety of infectious agents, such as the viruses HIV, West Nile Virus (WNV), and hepatitis B and C.
Blood collection facilities also test potential blood donors for the parasite Trypanosoma cruzi (T. cruzi), which causes Chagas disease. This infectious disease, which is spread by the bite of certain bugs, occurs in Mexico, Central and South America and, rarely in North America. The parasite infects mostly the heart tissues but can also be detected in the blood of infected persons.
About one third of the people infected with T. cruzi will develop serious disease later in their life; but everyone who is infected will remain infected for life.
Infected individuals can show no sign of disease; so if they become blood donors there is a risk that they can transmit the parasite to another person by blood transfusion. Experts estimate that about 300,000 persons living in the US are unknowingly infected with T. cruzi. Therefore, in order to protect the blood supply, all blood donors are tested to see if they are infected with T. cruzi.
The test licensed by FDA determines if a person is infected with T. cruzi by detecting antibodies to this parasite in blood. However, this test cannot determine if blood already donated by that person contains T. cruzi parasites. This is important because blood donated by infected individuals might be free of parasites and safe to use. However, until a test is available to ensure that such donated blood is safe to use, it must be discarded if the current test gives a positive result.
In order to help prevent the unnecessary disposal of such a valuable resource, our laboratory is studying how to better detect T. cruzi directly in blood from infected donors and to better understand how T. cruzi causes disease in humans. Our strategy has two goals: first, to develop ways to detect the DNA of this parasite in donated blood when there are only a few parasites present; and second, to develop methods to filter out T. cruzi parasites from whole blood donations without affecting the quality of the blood. In order to achieve these goals we are using recently developed technologies designed to select unique molecules in a complex mixture of molecules that bind strongly and exclusively to T. cruzi parasites. These unique molecules will be used to find and/or remove parasites from infected blood.
This research supports the regulatory work of the Division of Emerging and Transfusion Transmitted Diseases, which is responsible for licensing blood screening tests for blood-borne pathogens and HIV diagnostics. The new understanding of T cruzi biology and development of methods for detecting the parasite in blood will help the division to make informed regulatory decisions about such products.
Our goal is to increase the safety of the US blood supply and decrease the risk of transmission of parasitic agents by blood transfusion or organ transplantation.
The blood borne protozoan parasite Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas disease. An estimated 90 million people are at risk for this disease, mostly in Mexico, Central and South America. Among this population about 11 million persons carry the parasite chronically and present a potential source of infection through blood donation.
Some experts estimate that about 300,000 persons unknowingly infected with T. cruzi currently live in the US. Several documented cases of T. cruzi transmission by blood transfusion or organ transplantation have been reported in North America.
In order to reduce the risk of transmission by blood transfusion in the US, the FDA licensed in December 2006 the first blood screening test for the presence of T. cruzi antibodies in blood. Among donors tested up to February 2010, 1,134 were confirmed positive and removed from the donor pool, significantly reducing the risk of blood transmission.
The goal of our research program is to improve our knowledge of the cell and molecular biology of T. cruzi parasites, to study disease pathogenesis using animal models, and to better detect this parasites in blood of infected people.
We are working to identify new parasite targets that could be exploited for drug and vaccine development, or for parasite detection in blood and blood products. The selection of targets for detection assays is based on the high copy number of nucleic acid sequences in the parasite genome for nucleic acid-based assays and on secreted/excreted parasite proteins for protein-based assays. In addition, we are evaluating new technologies to concentrate parasites from infected blood prior to testing or to eliminate parasites by filtration. Our current approach is to use RNA aptamers (random, approximately 100-nucleotide-long RNA sequences) as T. cruzi -specific ligands. A major goal in our research is to improve the sensitivity of nucleic-acid- or parasite-protein-based assays and further enhance blood safety.
This research program contributes to a better understanding of T. cruzi biology and pathogenesis, which will enable FDA to make informed regulatory decisions regarding this pathogen. Our studies provide scientific and technical expertise relevant to the evaluation of the sensitivity and specificity of blood screening tests and new testing platforms for T. cruzi and other related blood borne pathogens.
Our research program aims to increase the safety of the US blood supply and decrease the risk of transmission of parasitic agents by blood transfusion or organ transplantation.
PLoS Negl Trop Dis 2016 Aug 31;10(8):e0004963
Live attenuated Leishmania donovani centrin knock out parasites generate non-inferior protective immune response in aged mice against visceral leishmaniasis.
Bhattacharya P, Dey R, Dagur PK, Joshi AB, Ismail N, Gannavaram S, Debrabant A, Akue AD, KuKuruga MA, Selvapandiyan A, McCoy JP Jr, Nakhasi HL
Infect Immun 2016 Mar 24;84(4):1123-36
Trypanosoma cruzi causes paralyzing systemic necrotizing vasculitis driven by pathogen-specific Type I immunity in mice.
Roffe E, Marino AP, Weaver J, Wan W, de Araujo FF, Hoffman V, Santiago HC, Murphy PM
Cell Death Dis 2015 Dec 10;6:e2018
Apoptotic cell clearance of Leishmania major-infected neutrophils by dendritic cells inhibits CD8(+) T-cell priming in vitro by Mer tyrosine kinase-dependent signaling.
Ribeiro-Gomes FL, Romano A, Lee S, Roffe E, Peters NC, Debrabant A, Sacks D
Infect Immun 2015 Oct;83(10):3800-15
Genetically modified live attenuated L.donovani parasites induce innate immunity through classical activation of macrophages that direct Th1 response in mice.
Bhattacharya P, Dey R, Dagur PK, Kruhlak M, Ismail N, Debrabant A, Joshi AB, Akue A, Kukuruga M, Takeda K, Selvapandiyan A, McCoy JP Jr, Nakhasi HL
PLoS Negl Trop Dis 2015 Jan 8;9(1):e3451
Aptamer-based detection of disease biomarkers in mouse models for chagas drug discovery.
de Araujo FF, Nagarkatti R, Gupta C, Marino AP, Debrabant A
Proc Natl Acad Sci U S A 2014 Nov 25;111(47):16808-13
Cross-species genetic exchange between visceral and cutaneous strains of Leishmania in the sand fly vector.
Romano A, Inbar E, Debrabant A, Charmoy M, Lawyer P, Ribeiro-Gomes F, Barhoumi M, Grigg M, Shaik J, Dobson D, Beverley SM, Sacks DL
PLoS Pathog 2014 Feb 6;10(2):e1003923
Lundep, a sand fly salivary endonuclease increases Leishmania parasite survival in neutrophils and inhibits XIIa contact activation in human plasma.
Chagas AC, Oliveira F, Debrabant A, Valenzuela JG, Ribeiro JM, Calvo E
PLoS Negl Trop Dis 2014 Jan 16;8(1):e2650
Aptamer based, non-PCR, non-serological detection of Chagas disease biomarkers in Trypanosoma cruzi infected mice.
Nagarkatti R, de Araujo FF, Gupta C, Debrabant A
Eur J Immunol 2013 Feb;43(2):427-38
Tracking antigen-specific CD4(+) T cells throughout the course of chronic Leishmania major infection in resistant mice.
Pagan AJ, Peters NC, Debrabant A, Ribeiro-Gomes F, Pepper M, Karp CL, Jenkins MK, Sacks DL
PLoS One 2012;7(8):e43533
Development of an aptamer-based concentration method for the detection of Trypanosoma cruzi in blood.
Nagarkatti R, Bist V, Sun S, Fortes de Araujo F, Nakhasi HL, Debrabant A
Front Cell Infect Microbiol 2012 Jul;2:95
Programmed cell death in Leishmania: biochemical evidence and role in parasite infectivity.
Gannavaram S, Debrabant A
Mol Microbiol 2012 Mar;83(5):926-35
Involvement of TatD nuclease during programmed cell death in the protozoan parasite Trypanosoma brucei.
Gannavaram S, Debrabant A
PLoS Pathog 2012 Feb;8(2):e1002536
Efficient capture of infected neutrophils by dendritic cells in the skin inhibits the early anti-leishmania response.
Ribeiro-Gomes FL, Peters NC, Debrabant A, Sacks DL
Mol Biol Int 2011;2011:428486
Identification and Characterization of Genes Involved in Leishmania Pathogenesis: The Potential for Drug Target Selection.
Duncan R, Gannavaram S, Dey R, Debrabant A, Lakhal-Naouar I, Nakhasi HL
PLoS Negl Trop Dis 2011 Aug;5(8):e1288
Infection Parameters in the Sand Fly Vector That Predict Transmission of Leishmania major.
Stamper LW, Patrick RL, Fay MP, Lawyer PG, Elnaiem DE, Secundino N, Debrabant A, Sacks DL, Peters NC
J Exp Med 2011 Jun 6;208(6):1253-65
Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection.
Goncalves R, Zhang X, Cohen H, Debrabant A, Mosser DM
Science 2008 Aug 15;321(5891):970-4
In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies.
Peters NC, Egen JG, Secundino N, Debrabant A, Kimblin N, Kamhawi S, Lawyer P, Fay MP, Germain RN, Sacks D
Proc Natl Acad Sci U S A 2008 Jul 22;105(29):10125-30
Quantification of the infectious dose of Leishmania major transmitted to the skin by single sand flies.
Kimblin N, Peters N, Debrabant A, Secundino N, Egen J, Lawyer P, Fay MP, Kamhawi S, Sacks D
J Cell Sci 2008 Jan 1;121(Pt 1):99-109
Conservation of the pro-apoptotic nuclease activity of endonuclease G in unicellular trypanosomatid parasites.
Gannavaram S, Vedvyas C, Debrabant A
Eukaryot Cell 2007 Oct;6(10):1745-57
Characterization of metacaspases with trypsin-like activity and their putative role in the programmed cell death in the protozoan parasite Leishmania.
Lee N, Gannavaram S, Selvapandiyan A, Debrabant A
J Immunol 2006 Sep 15;177(6):3525-33
Leishmania antigens are presented to CD8+ T Cells by a transporter associated with antigen processing-independent pathway in vitro and in vivo.
Bertholet S, Goldszmid R, Morrot A, Debrabant A, Afrin F, Collazo-Custodio C, Houde M, Desjardins M, Sher A, Sacks D
Indian J Med Res 2006 Mar;123(3):455-66
Genetically modified live attenuated parasites as vaccines for leishmaniasis.
Selvapandiyan A, Duncan R, Debrabant A, Lee N, Sreenivas G, Salotra P, Nakhasi HL
Mol Biochem Parasitol 2006 Feb;145(2):147-57
Cloning and characterization of angiotensin converting enzyme related dipeptidylcarboxypeptidase from Leishmania donovani.
Goyal N, Duncan R, Selvapandiyan A, Debrabant A, Baig MS, Nakhasi HL
Infect Immun 2005 Oct;73(10):6620-8
Antigen requirements for efficient priming of CD8+ T cells by leishmania major-infected dendritic cells.
Bertholet S, Debrabant A, Afrin F, Caler E, Mendez S, Tabbara KS, Belkaid Y, Sacks DL