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Role of human infection in domestic transmission of dermal leishmaniasis and drug resistance

Applicant Fasel Nicolas Joseph
Number 131421
Funding scheme Resource not found: 'bd31932a-e257-46d9-9dba-079f6f2c77c6'
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Biochemistry
Start/End 01.09.2010 - 31.08.2013
Approved amount 500'000.00
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All Disciplines (2)

Discipline
Biochemistry
Infectious Diseases

Keywords (5)

molecular markers; anthroponotic transmission; leishmaniasis; drug resistance; epidemiology

Lay Summary (English)

Lead
Lay summary
The human protozoan parasites Leishmania are the causative agents of leishmaniasis, which can lead, depending on the species, to either cutaneous or mucocutaneous lesions, or fatal generalized visceral infection.Among the countries of Latin America, Colombia is second only to Brazil in the number of reported cases of leishmaniasis. Approximately 20,000 cases of leishmaniasis have been reported annually in Colombia during the past 6 years. Furthermore because most cases occur in areas with poor access to medical care, a substantial yet undetermined proportion of cases are not detected by the public health system. Consequently, the true magnitude of the problem is unknown. Thus, the public health problem generated by leishmaniasis is compounded by the large number of unreported, untreated and inadequately treated cases and the high proportion of infections that are initially asymptomatic. These infections can be activated by circumstances that alter immunological homeostasis such as local trauma, immunosuppressive pharmacotherapy and co-infections.Transmission has expanded into the domestic setting of rural communities and periphery of urban centers, where children, women and older adults are most affected. The phenomenon of domestic transmission is common to endemic areas throughout Central and South America and its impact widespread.The goal of our project is to obtain the evidence base to prevent domestic transmission of dermal leishmaniasis and preserve the useful life of first line drugs, by defining the burden of Leishmania infection (symptomatic and asymptomatic) in domestically exposed populations and the role of this reservoir of human infection in transmission and the development and dissemination of drug resistance. This goal will be pursued through the concerted research of teams in Colombia and Switzerland that have a history of productive collaboration.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
A functional BH3 domain in an aquaporin from Leishmania infantum
Genes C M, de Lucio H, González V M, Sánchez-Murcia P A, Rico E, Gago F, Fasel N, Jiménez-Ruiz A (2016), A functional BH3 domain in an aquaporin from Leishmania infantum, in Cell Death Discovery, 2, 16043-16043.
Caspase-mediated cleavage of raptor participates in the inactivation of mTORC1 during cell death
Martin R, Desponds C, Eren R O, Quadroni M, Thome M, Fasel N (2016), Caspase-mediated cleavage of raptor participates in the inactivation of mTORC1 during cell death, in Cell Death Discovery, 2, 16024-16024.
Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A
Hartley Mary-Anne, Bourreau Eliane, Rossi Matteo, Castiglioni Patrik, Eren Remzi Onur, Prevel Florence, Couppié Pierre, Hickerson Suzanne M., Launois Pascal, Beverley Stephen M., Ronet Catherine, Fasel Nicolas (2016), Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A, in PLOS Pathogens, 12(9), e1005852-e1005852.
Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus
Parmentier L., Cusini A., Muller N., Zangger H., Hartley M.-A., Desponds C., Castiglioni P., Dubach P., Ronet C., Beverley S. M., Fasel N. (2016), Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus, in American Journal of Tropical Medicine and Hygiene, 94(4), 840-843.
Tilting the balance between RNA interference and replication eradicates Leishmania RNA virus 1 and mitigates the inflammatory response
Brettmann Erin A., Shaik Jahangheer S., Zangger Haroun, Lye Lon-Fye, Kuhlmann F. Matthew, Akopyants Natalia S., Oschwald Dayna M., Owens Katherine L., Hickerson Suzanne M., Ronet Catherine, Fasel Nicolas, Beverley Stephen M. (2016), Tilting the balance between RNA interference and replication eradicates Leishmania RNA virus 1 and mitigates the inflammatory response, in Proceedings of the National Academy of Sciences, 113(43), 11998-12005.
Chronicity of Dermal Leishmaniasis Caused by Leishmania panamensis Is Associated with Parasite-Mediated Induction of Chemokine Gene Expression.
Navas Adriana, Vargas Deninson Alejandro, Freudzon Marina, McMahon-Pratt Diane, Saravia Nancy Gore, Gómez María Adelaida (2014), Chronicity of Dermal Leishmaniasis Caused by Leishmania panamensis Is Associated with Parasite-Mediated Induction of Chemokine Gene Expression., in Infection and immunity, 82(7), 2872-80.
Leishmania aethiopica Field Isolates Bearing an Endosymbiontic dsRNA Virus Induce Pro-inflammatory Cytokine Response
Zangger Haroun, Hailu Asrat, Desponds Chantal, Lye Lon-Fye, Akopyants Natalia S., Dobson Deborah E., Ronet Catherine, Ghalib Hashim, Beverley Stephen M., Fasel Nicolas (2014), Leishmania aethiopica Field Isolates Bearing an Endosymbiontic dsRNA Virus Induce Pro-inflammatory Cytokine Response, in PLoS Neglected Tropical Diseases, 8(4), e2836-e2836.
Miltefosine and antimonial drug susceptibility of Leishmania Viannia species and populations in regions of high transmission in Colombia.
Fernández Olga Lucía, Diaz-Toro Yira, Ovalle Clemencia, Valderrama Liliana, Muvdi Sandra, Rodríguez Isabel, Gomez María Adelaida, Saravia Nancy Gore (2014), Miltefosine and antimonial drug susceptibility of Leishmania Viannia species and populations in regions of high transmission in Colombia., in PLoS neglected tropical diseases, 8(5), 2871-2871.
MyD88 and TLR9 Dependent Immune Responses Mediate Resistance to Leishmania guyanensis Infections, Irrespective of Leishmania RNA Virus Burden
Ives Annette, Masina Slavica, Castiglioni Patrik, Prével Florence, Revaz-Breton Mélanie, Hartley Mary-Anne, Launois Pascal, Fasel Nicolas, Ronet Catherine (2014), MyD88 and TLR9 Dependent Immune Responses Mediate Resistance to Leishmania guyanensis Infections, Irrespective of Leishmania RNA Virus Burden, in PLoS ONE, 9(5), e96766-e96766.
Detection of Leishmania RNA Virus in Leishmania Parasites
Zangger Haroun, Ronet Catherine, Desponds Chantal, Kuhlmann F. Matthew, Robinson John, Hartley Mary-Anne, Prevel Florence, Castiglioni Patrik, Pratlong Francine, Bastien Patrick, Mueller Norbert, Parmentier Laurent, Gore Saravia Nancy, Beverley Stephen M., Fasel Nicolas (2013), Detection of Leishmania RNA Virus in Leishmania Parasites, in PLOS NEGLECTED TROPICAL DISEASES, 7(1), 1.
Leishmania panamensis infection and antimonial drugs modulate expression of macrophage drug transporters and metabolizing enzymes: impact on intracellular parasite survival.
Gómez Maria Adelaida, Navas Adriana, Márquez Ricardo, Rojas Laura Jimena, Vargas Deninson Alejandro, Blanco Victor Manuel, Koren Roni, Zilberstein Dan, Saravia Nancy Gore (2013), Leishmania panamensis infection and antimonial drugs modulate expression of macrophage drug transporters and metabolizing enzymes: impact on intracellular parasite survival., in The Journal of antimicrobial chemotherapy, 1.
Role of Toll-Like Receptor 9 Signaling in Experimental Leishmania braziliensis Infection
Weinkopff Tiffany, Mariotto Anita, Simon Gregoire, Hauyon-La Torre Yazmin, Auderset Floriane, Schuster Steffen, Zangger Haroun, Fasel Nicolas, Barral Aldina, Tacchini-Cottier Fabienne (2013), Role of Toll-Like Receptor 9 Signaling in Experimental Leishmania braziliensis Infection, in INFECTION AND IMMUNITY, 81(5), 1575-1584.
The therapeutic potential of immune cross-talk in leishmaniasis
Hartley M. -A., Kohl K., Ronet C., Fasel N. (2013), The therapeutic potential of immune cross-talk in leishmaniasis, in CLINICAL MICROBIOLOGY AND INFECTION, 19(2), 119-130.
Backseat drivers: the hidden influence of microbial viruses on disease.
Hartley Mary-Anne, Ronet Catherine, Fasel Nicolas (2012), Backseat drivers: the hidden influence of microbial viruses on disease., in Current opinion in microbiology, 15(4), 538-45.
Leishmania RNA virus: when the host pays the toll.
Hartley Mary-Anne, Ronet Catherine, Zangger Haroun, Beverley Stephen M, Fasel Nicolas (2012), Leishmania RNA virus: when the host pays the toll., in Frontiers in cellular and infection microbiology, 2, 99-99.
Muco-cutaneous leishmaniasis in the New World: the ultimate subversion.
Ronet Catherine, Beverley Stephen M, Fasel Nicolas (2011), Muco-cutaneous leishmaniasis in the New World: the ultimate subversion., in Virulence, 2(6), 547-52.
Un virus, hôte indésirable de L. guyanensis, détermine la gravité de la forme mucocutanée
Ronet Catherine (2011), Un virus, hôte indésirable de L. guyanensis, détermine la gravité de la forme mucocutanée, in Médecine/Sciences, 27(11), 924-926.

Collaboration

Group / person Country
Types of collaboration
Prof. Stephen M. Beverley, Dept Molecular Microbiology, Washington University, St Louis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Norbert Müller, Institute of Parasitology, Vetsuisse Faculty Bern, Univ. Bern Switzerland (Europe)
- Publication
Prof. Fabienne Tacchini-Cottier, Département de Biochimie, UNIL, Epalinges, Suisse Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Laurent Falquet, Swiss Institute of Bioinformatics, Vital-IT, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Patrick Bastien, Laboratoire de Parasitologie-Mycologie, Université Montpellier 1 France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Asrat Hailu Mekuria, Immunoparasitology, Addis Ababa University Ethiopia (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Virology Meeting Talk given at a conference Swiss Virology Meeting 09.01.2014 Thun, Switzerland Fasel Nicolas Joseph;
NIH/NIAID Twinbrook Seminar Series Talk given at a conference NIH/NIAID Twinbrook Seminar Series 03.01.2014 Rockville, United States of America Fasel Nicolas Joseph;
ASTMH 62nd Annual Meeting Poster Parasitological confirmation of asymptomatic infection in endemic areas for cutaneous Leishmaniasis in Colombia. 13.11.2013 Washington, United States of America Saravia Nancy;
88th Annual Meeting of the American Society of Parasitologists and 13th Annuel Québec Molecular Parasitology Meeting Talk given at a conference Leishmania RNA virus: a backseat driver to metastatic leishmaniasis 26.06.2013 Québec City, Canada Fasel Nicolas Joseph;
5th World Congress on Leishmaniasis - Worldleish 5 Talk given at a conference An endemic community perspective of systemic dissemination and persistent infection with Leishmania viannia species. 13.05.2013 Porto de Galinhas, PE, Brazil Saravia Nancy;
5th World Congress on Leishmaniasis - Worldleish 5 Poster Burden of infection in communities experiencing domestic transmission of dermal leishmaniasis in Risaralda Colombia. 13.05.2013 Porto de Galinhas, PE, Brazil Saravia Nancy;
5th World Congress on Leishmaniasis - Worldleish 5 Talk given at a conference Role of interferon-beta in Leishmania RNA Virus-positive Leishmania guyanensis infection 13.05.2013 Porto de Galinhas, PE, Brazil Fasel Nicolas Joseph;
5th World Congress on Leishmaniasis - Worldleish 5 Poster Warileya rotundipennis (diptera, psychodidae, phlebotominae) potencial vector de Leishmania panamensis? 13.05.2013 Porto de Galinhas, PE, Brazil Saravia Nancy;
5th World Congress on Leishmaniasis - Worldleish 5 Talk given at a conference Antimony-mediated killing of intracellular Leishmania is modulated by the expression of pharmacological determinants in host macrophages. 13.05.2013 Porto de Galinhas, PE, Brazil Saravia Nancy;
European Society of Virology Talk given at a conference European Society of Virology 09.01.2013 Lyon, France Fasel Nicolas Joseph;
Pathogens' Survival Strategies: from fundamentals to field Talk given at a conference A tale of a virus and of a parasite 03.12.2012 Antwerp, Belgium Fasel Nicolas Joseph;
Congreso Internacional del Colegio Nacional de Bacteriologia Poster Identificación de determinantes moleculares de patogenicidad mediante proteómica comparativa en cepas de Leishmania (Viannia) panamensis aisladas de pacientes con enfermedad crónica y autoresolutiva. 02.11.2012 Cali, Colombia Saravia Nancy;
Gordon Research Conference "Biology of Host-Parasite Interactions" Talk given at a conference Metastatic leishmaniasis 06.10.2012 Newport RI, United States of America Fasel Nicolas Joseph;
European Academy of Microbiology on “Co-infections 2012” Talk given at a conference A tale of a virus and of a parasite 07.06.2012 Halle, Germany Fasel Nicolas Joseph;
Lecture to graduate students Talk given at a conference A tale of a virus and a parasite 04.05.2012 Porto, Portugal Fasel Nicolas Joseph;
22nd Challenge in Virology and SAFE-ID Talk given at a conference A tale on a virus and a parasite 12.01.2012 Saanen Gstaad, Switzerland Fasel Nicolas Joseph;
Indo-Swiss Symposium on Parasitic Diseases / Infectious Diseases Talk given at a conference Muco-cutaneous leishmaniasis in the New World: the ultimate subversion 03.11.2011 New Delhi, India Fasel Nicolas Joseph;
XX Congreso FLAP y XV Congreso ACPMT Poster Análisis de diversidad poblacional de cepas de Leishmania panamensis a través de tipificación por microsatélites. 27.09.2011 Bogota, Colombia Saravia Nancy;
XX Congreso FLAP y XV Congreso ACPMT Poster Confirmación parasitológica de infección asintomática en tejidos extralesionales de individuos de áreas endémicas para leishmaniasis cutánea, a través de PCR. 27.09.2011 Bogota, Colombia Saravia Nancy;
XX Congress of the Latin American Federation of Parasitology and XV Colombian National Congress of Tropical Medicine and Parasitology Poster Confirmación parasitológica de infección asintomática de individuos de áreas endémicas para leishmaniasis cutánea, a través de PCR and Discriminación de cepas de Leishmania panamensis por microsatélites 27.09.2011 Bogota, Colombia Saravia Nancy;
Trypanosomatidés 2011: du terrain au laboratoire Talk given at a conference Virulence dans la leishmaniose mucocutanée 27.05.2011 Paris, France Fasel Nicolas Joseph;
Kinetoplastid Molecular and Biology Cell Meeting Talk given at a conference Leishmania RNA Virus Controls the Severity of Mucocutaneous Leishmaniasis 08.04.2011 Woods Hole, MA, United States of America Fasel Nicolas Joseph;
Gordon Research Conference on "Tropical Infectious Disease: From Bench to Field" Talk given at a conference Virulence in mucocutaneous leishmaniasis 13.03.2011 Galveston, Texas, United States of America Fasel Nicolas Joseph;


Communication with the public

Communication Title Media Place Year
Print (books, brochures, leaflets) Article in Horizons/FNS by Fabio Bergani December 2012 ( p.25) Western Switzerland German-speaking Switzerland 2012
Talks/events/exhibitions Asociacion Colombiana de Investigadores en Suiza (ACIS), Symposium 2012 International 2012
Media relations: radio, television Public intervention with the radio and TV rts Western Switzerland 2012

Associated projects

Number Title Start Funding scheme
135616 Impact of Leishmania dsRNA virus on mucocutaneous leishmaniasis 01.04.2011 Project funding (Div. I-III)
137340 Leishmania genomics 01.10.2011 International Exploratory Workshops
153204 Impact of Leishmania dsRNA virus on metastatic leishmaniases 01.04.2014 Project funding (Div. I-III)

Abstract

Tens of thousands of cases of dermal leishmaniasis occur each year in Colombia. Transmission has expanded into the domestic setting of rural communities and periphery of urban centers, where children, women and older adults are most affected. The phenomenon of domestic transmission is common to endemic areas throughout Central and South America and its impact widespread. Control of dermal is largely limited to passive case detection and treatment in health facilities far from rural settlements. In the domestic setting of transmission many cases go undetected and without treatment because of the economic and logistical constraints of leaving homes and crops unattended and travelling with children to urban centers for diagnosis and the 20 day parenteral treatment. Clinical follow-up to determine whether treatment was successful is seldom possible for similar reasons. Available data indicate that treatment failure is frequent and multifactorial. Loss of susceptibility to antimonial drugs has been shown to be a contributing factor and higher rates of elimination in children reduces exposure to antimony to levels that can be sub-therapeutic.Molecular amplification technology has allowed the presence of Leishmania to be detected in blood and healthy skin of patients before and after treatment, and swab sampling has provided access to mucosal sites revealing parasites in apparently healthy nasal mucosa, conjunctiva and tonsils. Viability of parasites in these sites has been confirmed by amplification of Leishmania 7SLRNA transcripts. This technology and the high frequency of symptomatic and asymptomatic infections in communities experiencing transmission in and around their homes make it feasible to measure the burden of infection and to assess the participation of the infected population in domestic transmission. In addition, recent evidence supporting the participation of Leishmania virus RNA in the hyper-reactivity response associated with the development of mucosal disease and the elucidation of mechanisms of intracellular survival via resistance to oxidative stress during the initial stages of infection allow aspects of the Leishmania-host relationship that promote persistent infection and pathogenesis to be investigated in clinical strains of Leishmania.The goal of this project is to obtain the evidence base to prevent domestic transmission of dermal leishmaniasis and preserve the useful life of first line drugs. by defining the burden of Leishmania infection (symptomatic and asymptomatic) in domestically exposed populations and the role of this reservoir of human infection in transmission and the development and dissemination of drug resistance. This goal will be pursued through the concerted research of teams in Colombia and Switzerland that have a history of productive collaboration, with the following Specific Aims:1.) To determine the age-specific prevalence of parasites in blood, mucosa and dermal aspirates of the inhabitants of foci of domestic transmission of leishmaniasis. 2.) To discern the relationship between immunological evidence of infection (DTH response to intradermal leishmanin) and the presence of parasites in host tissues (blood, mucosa and healthy skin). 3.) To determine the diversity and interrelationship of Leishmania populations circulating among the inhabitants of a focus of domestic transmission. 4.) To define the drug susceptibility and virulence characteristics associated with intracellular survival and persistence in parasites isolated from lesions and extralesional tissues before and after treatment. Capacity building will target community health promoters, graduate and postdoctoral trainees and national post graduate programs biomedical science.
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