Jean-Loup Lemesre

Institute of Research for Development, UMR 177 "INTERTRYP" · Société et Santé

High-throughput screening of available genomic data and identification of potential antigenic candidates have promoted the development of epitope-based vaccines and therapeutics. Several immunoinformatic tools are available to predict potential epitopes and other immunogenicity-related features, yet it is still challenging and time-consuming to com...

Human leishmaniasis is a public health problem worldwide for which the development of a vaccine remains a challenge. T cell-mediated immune responses are crucial for protection. Peptide vaccines based on the identification of immunodominant T cell epitopes able to induce T cell specific immune responses constitute a promising strategy. Here, we rep...

Dogs are the main reservoir of zoonotic visceral leishmaniasis. Vaccination is a promising approach to help control leishmaniasis and to interrupt transmission of the Leishmania parasite. The promastigote surface antigen (PSA) is a highly immunogenic component of Leishmania excretory/secretory products. A vaccine based on three peptides derived fro...

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease that is fatal if untreated, caused by Trypanosoma brucei gambiense and T. brucei rhodesiense. In its 2012 roadmap, WHO targeted HAT for elimination as a public health problem in 2020 and for zero transmission in 2030. Diagnosis of HAT is a multistep procedure...

Comment, depuis plusieurs décennies, la recherche scientifique contribue-t-elle au développement des pays du Sud ? À travers plus de 100 succès emblématiques de la recherche en partenariat, cet ouvrage nous plonge au coeur des grandes questions de développement : oeuvrer pour des sociétés plus justes, lutter contre les maladies, faire face aux risq...

Vaccination is a promising approach to interrupt Leishmania parasite transmission and help eliminate leishmaniasis. A vaccine formulation based on three peptides derived from the soluble promastigote surface antigen (PSA) of Leishmania infantum, was tested on naive Beagle dogs in a preclinical trial. The trial consisted in three immunizations of ei...

Clinical manifestations of American Tegumentary Leishmaniasis (ATL) include cutaneous (CL) and mucous forms (ML); however, there are asymptomatic individuals who despite being infected do not present any clinical manifestations. This study characterized the cell-mediated immunity of travelers who lived in the Andean highlands of Cusco, free of leis...

C-0348 joana.pissarra@ird.fr joana.s.pissarra@gmail.com This research is funded by the European Union's H2020 Programme under the MSCA GA nº 642609 Leishmaniases are vector-borne parasitic diseases endemic to 98 countries worldwide. Still, no preventable vaccine is available, a feasible and important tool to control transmission and possibly achiev...

Mononuclear phagocytes (monocytes, dendritic cells, and macrophages) are among the first host cells to face intra- and extracellular protozoan parasites such as trypanosomatids, and significant expansion of macrophages has been observed in infected hosts. They play essential roles in the outcome of infections caused by trypanosomatids, as they can...

Clinical manifestations of American Tegumentary Leishmaniasis (ATL) include cutaneous (CL) and mucous forms (ML); however, there are asymptomatic individuals who despite being infected do not present any clinical manifestations. This study characterized the cell-mediated immunity of travelers who lived in the Andean highlands of Cusco, free of leis...

In recent years, plants have been shown to be an efficient alternative expression system for high-value pharmaceuticals such as vaccines. However, constitutive expression of recombinant protein remains uncertain on their level of production and biological activity. To overcome these problems, transitory expression systems have been developed. Here,...

Arginase activity induction in macrophages is an escape mechanism developed by parasites to cope with the host's immune defense and benefit from increased host-derived growth factor production. We report that arginase expression and activity were induced in macrophages during mouse infection by Trypanosoma musculi, a natural parasite of this host....

Leishmaniasis is among the most severe parasitic infections affecting humans in the world. It is the second-highest number of deaths caused by parasites worldwide. Infection is provoked by protozoans of the genus Leishmania, transmitted by the bite of different species of phlebotomine sandflies, which replicate within host mononuclear phagocytes. V...

Antibodies directed against L-tryptophan epitope (WE - W for tryptophan, E for epitope), a constant epitope borne by variant surface glycoproteins (VSG), have been detected in sera of all 152 Human African Trypanosomosis (HAT) patients from Angola. The WE is present in VSG hydrophobic regions of the C terminal domains. In the assay, L-tryptophan wa...

Escaping Deleterious Immune Response in Their Hosts: Lessons from Trypanosomatids

Preventive vaccination is a highly promising strategy for interrupting leishmaniasis transmission that can, additionally, contribute to elimination. A vaccine formulation based on naturally excreted secreted (ES) antigens was prepared from L. infantum promastigote culture supernatant. This vaccine achieved successful results in Phase III trials and...

Post kala-azar dermal leishmaniasis (PKDL) is a chronic dermal complication that occurs usually after recovery from visceral leishmaniasis (VL). The disease manifests into macular, papular and/or nodular clinical types with mono- or polymorphic presentations. Here, we investigated differences in immunological response between these two distinct cli...

The Trypanosomatidae family includes the genera Trypanosoma and Leishmania, protozoan parasites displaying complex digenetic life cycles requiring a vertebrate host and an insect vector. Trypanosoma brucei gambiense, Trypanosoma cruzi, and Leishmania spp. are important human pathogens causing human African trypanosomiasis (HAT or sleeping sickness)...

So far, research on trypanosomatid infections has been driven by 'disease by disease' approaches, leading to different concepts and control strategies. It is, however, increasingly clear that they share common features such as the ability to generate long-lasting asymptomatic infections in their mammalian hosts. Trypanotolerance, long integrated in...

Background Majority of individuals with history of visceral leishmaniasis (VL) exhibit strong immunity to re-infection, however, the mechanism of resistance is poorly understood. It is unclear whether CD8+ T cells contribute to protection against Leishmania donovani infection through cytotoxic activity. The present study aims to evaluate immunologi...

PSA (Promastigote Surface Antigen) belongs to a family of membrane-bound and secreted proteins present in several Leishmania (L.) species. PSA is recognized by human Th1 cells and provides a high degree of protection in vaccinated mice. We evaluated humoral and cellular immune responses induced by a L. amazonensis PSA protein (LaPSA-38S) produced i...

Trypanosoma brucei gambiense, a parasitic protozoan belonging to kinetoplastids, is the main etiological agent of human African trypanosomiasis (HAT), or sleeping sickness. One major characteristic of this disease is the dysregulation of the host immune system. The present study demonstrates that the secretome (excreted-secreted proteins) of T. b....

Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1β (IL-1β). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in...

Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1β (IL-1β). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in...

The invention provides a composition for the inoculation in a plant of agrobacteria transfected by expression vectors, in order to produce in said plant a protein of interest or a derivative of said protein, by deletion or by mutation, characterised in that it comprises agrobacteria transfected by at least one expression vector, comprising a nucleo...

Many tools used to analyze microarrays in different conditions have been described. However, the integration of deregulated genes within coherent metabolic pathways is lacking. Currently no objective selection criterion based on biological functions exists to determine a threshold demonstrating that a gene is indeed differentially expressed. To imp...

Many scientists working on pathogens (viruses, bacteria, fungi, parasites) are betting heavily on data generated by longitudinal genomic-transcriptomic-proteomic studies to explain biochemical host-vector-pathogen interactions and thus to contribute to disease control. Availability of genome sequences of various organisms, from viruses to complex m...

Cell-mediated and humoral immunity were explored in LiESAp-MDP vaccinated protected dogs versus susceptible placebo dogs 2 months and 8 months post-vaccination. As previously described, a strong and long-lasting cell-mediated immunity, critical for protection against Leishmania infantum was exclusively revealed in vaccinated dogs as confirmed by a...

Many scientists working on pathogens (viruses, bacteria, fungi, parasites) are betting heavily on data generated by longitudinal genomic–transcriptomic–proteomic studies to explain biochemical host–vector–pathogen interactions and thus to contribute to disease control. Availability of genome sequences of various organisms, from viruses to complex m...

Extracts of seven medicinal plants used specifically against cutaneous leishmaniasis in the Madre de Dios region of Peru were evaluated in vitro against promastigote and axenic amastigote forms of Leishmania amazonensis. One of them showed interesting leishmanicidal activities (IC(50)=5 microg/ml in amastigotes). Bio-guided isolation of the stem ba...

Vaccination against visceral leishmaniasis has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine against visceral leishmaniasis is pressing. Dogs constitute the major reservoir of Leishmania infantum/chagasi responsible for human visceral leishmaniasis. We have recently demonstrated that th...

Antibodies (Ab) directed against a tryptophan-like epitope (WE) were previously detected in patients with human African trypanosomiasis (HAT). We investigated whether or not these Ab resulted from immunization against trypanosome antigen(s) expressing a WE. By Western blotting, we identified an antigen having an apparent molecular weight ranging fr...

Generalities on LeishmaniasisImpact of Sand Fly Vectors on LeishmaniasisBiodiversity and Genetics of Parasites: Implications in Virulence and Pathogenicity in HumansThe Immune Response and Genetic Factors from the Mammalian HostThe Need for an Integrated Approach: The Kala-Azar Example in IndiaConclusion AcknowledgmentsAbbreviationsGlossaryReferenc...

Nitric oxide (NO) has been demonstrated to be the principal effector molecule mediating intracellular killing of Leishmania. The free radical characteristic of NO prevented direct induction of resistance in Leishmania wild-type parasites. Starting from the previous observation that antimony-resistant amastigotes of Leishmania infantum were not affe...

Nitric oxide (NO) has been demonstrated to be the principal effector molecule mediating intracellular killing of Leishmania, both in vitro and in vivo. We investigated the type of cell death process induced by NO for the intracellular amastigote stage of the protozoa Leishmania. Specific detection methods revealed a rapid and extensive cell death w...

Résultats de la vaccination contre la leishmaniose canine (Leishmania infantum) en zone d'enzootie Results of vaccination against canine visceral leishmaniasis (Leishmania infantum) in enzootic areas Par Christophe HUGNET (1) , Jean-Loup LEMESRE (2) , Gérard PAPIEROK (3) et Gilles BOURDOISEAU (4) (communication présentée le 2 février 2006) La prote...

We previously documented the induction of Leishmania amastigote apoptosis by trivalent antimony (SbIII) and nitric oxide (NO). We demonstrate here that SbIII-resistant amastigotes were resistant to NO toxicity when delivered extracellularly by NO donors or intracellularly via macrophage activation. Shared biochemical targets for SbIII and NO resist...

The role of nitric oxide (NO) in the anti-leishmanial activity has been confirmed both in vitro and in vivo. Recently, we demonstrated that NO-mediated apoptosis-like amastigote death pathway is an important and highly regulated mechanism used for the clearance of Leishmania within infected murine macrophages stimulated to produce NO endogenously....

The capacity of naturally excreted secreted antigens easily purified from culture supernatant of Leishmania infantum promastigotes (LiESAp), successfully cultivated in completely defined medium called CDM/LP [Lemesre JL. Methods for the culture in vitro of different stages of tissue parasites. International publication WO 94/26899, 1994; Merlen T,...

Antibodies directed against nitrosylated epitopes have been found in sera from patients suffering from human African trypanosomiasis (HAT) but not in sera from control subjects living in the same endemic area or African control subjects living in France. We conjugated amino acids to albumin by glutaraldehyde (conjugates) and then nitrosylated the c...

As most methods currently available to treat and control canine leishmaniasis have a limited efficacy, researchers are testing immunotherapeutic methods with great interest. Excreted– secreted antigens (ES Ag) of promastigotes of Leishmania infantum cultured in a defined medium were selected. Three Leishmania– infected dogs received two intradermal...

The Silent Information Regulator (SIR2) family of genes have been cloned from a variety of species ranging from bacteria to man. In previous studies, we reported the characterization of a Leishmania major gene encoding a protein with extensive homology to yeast SIR2p and expressed by different Leishmania species and parasite developmental stages an...

Resistance to leishmanial infections depends on intracellular parasite killing by activated host macrophages through the l-arginine-nitric oxide (NO) metabolic pathway. Here we investigate the cell death process induced by NO for the intracellular protozoan Leishmania amazonensis. Exposure of amastigotes to moderate concentrations of NO-donating co...

Pentavalent antimonial unresponsiveness is an emerging problem in endemic areas and information on factors which could modulate the transmission of drug-resistant phenotypes and parasites during life cycle are warranted. Using axenic amastigotes resistant to potassium antimonyl tartrate (Sb(III)) we investigated the modulation of antimonyl resistan...

The basic treatment of leishmaniasis consists in the administration of pentavalent antimonials. The mechanisms that contribute to pentavalent antimonial toxicity against the intracellular stage of the parasite (i.e., amastigote) are still unknown. In this study, the combined use of several techniques including DNA fragmentation assay and in situ an...

The in vitro growth of promastigote cells of Leishmania amazonensis was found to strongly depend on interactions among strains that differed in their pentamidine resistance. In particular, the growth of resistant strains was reduced when they shared the same environment with a less-resistant strain.

Protocols for DNA electroporation in Leishmaniapromastigote cells are well established. More recently, in vitro culture of axenic Leishmania amastigotes became possible. We have established conditions for DNA transformation of axenically grown Leishmania infantum amastigotes. Parameters for DNA electroporation of Leishmania axenic amastigotes were...

Trypanosoma brucei gambiense a causative agent of sleeping sickness, induced a dose-dependent production of tumor necrosis factor (TNF)–α by human macrophages in vitro. TNF-α was also induced in the Mono Mac 6 cell line, which indicates a direct effect of parasite components on macrophages. Parasite-soluble factors were also potent inducers of TNF-...

In a previous paper we have demonstrated that the induction, by direct drug pressure, of a resistance to Sb(III) antimony at physiological concentration in the amastigote stage of the parasite, led to a high cross-resistance to Sb(V) species in the form of Glucantime. In this paper, further chemoresistant clones were characterized. Axenic amastigot...

Following purification by affinity chromatography, a Leishmania majorS-hexylglutathione- binding protein of molecular mass 66 kDa was isolated. The immune serum against the parasite 66 kDa polypeptide when used to screen a L. major cDNA library could identify clones encoding for the human v-fos transformation effector homologue, namely ribosomal pr...

To study the antigens secreted by promastigote and amastigote forms of Leishmania infantum which are able to induce a humoral response in human patients and dogs, we have carried out immunoprecipitation assays with different supernatants of in vitro cultured parasites, metabolically labelled with [35S]methionine, using serum samples from human pati...

The elimination of serum or of serum-derived macromolecules that supplant the fetal calf serum requirement from Leishmania culture media could decrease costs and improve the feasibility of large-scale production of well-defined parasite material. We report a completely defined medium, without serum-derived protein and/or macromolecules as a serum s...

The mechanism(s) of activity of pentavalent antimony [Sb(V)] is poorly understood. In a recent study, we have shown that potassium antimonyl tartrate, a trivalent antimonial [Sb(III)], was substantially more potent than Sb(V) against both promastigotes and axenically grown amastigotes of three Leishmania species, supporting the idea of an in vivo m...

In previous studies we have characterized several Leishmania major polypeptides and showed that one member of this group (LmSIR2rp) shared significant homology to silent information regulator 2 (SIR2) of Saccharomyces cerevisiae, a protein playing a role in both telomeric and mating type loci repression in these organisms. In the present study, by...

Two clones of Leishmania mexicana resistant to 5 microM (LmR5CL2) and 20 microM (LmR20CL1) pentamidine, derived from a parental wild-type clone (LmWTCL3) were selected in vitro using a continuous drug pressure protocol. Both resistant clones expressed a cross-resistance to diminazene aceturate. No differences in their in-vitro infectivity for mouse...

Using a continuous drug pressure protocol, we induced pentamidine resistance in an active and dividing population of amastigote forms of Leishmania mexicana. We selected in vitro two clones with different levels of resistance to pentamidine, with clone LmPENT5 being resistant to 5 microM pentamidine, while clone LmPENT20 was resistant to 20 microM...

Babesia divergens was cultivated in RPMI 1640 (25 mM HEPES) supplemented with 10% human serum (RPMI-10% HS) with a high percentage of parasitized erythrocytes (PPE) (> or = 40%). Standardization of in vitro tests, purification of exoantigens, biochemical studies and the safety of the culture handler motivated the development of a serum-free defined...

Using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide microassay, previously described as a means of quantifying Leishmania amazonensis in vitro at the amastigote stage (D. Sereno and J. L. Lemesre, Parisitol. Res., in press), we have compared the activities of seven drugs, including those currently used to treat leishmaniasis, again...

The antimicrobial effect of activated macrophages on parasites involves nitric oxide (NO). NO induces intracellular parasite killing in murine leishmaniasis. Nevertheless, the mechanisms of action of NO as a final effector molecule on intracellular forms ofLeishmaniaare unknown. The recent development of axenically grown amastigote forms of differe...

Using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide microassay, previously described as a means of quantifying Leishmania amazonensis in vitro at the amastigote stage (D. Sereno and J. L. Lemesre, Parisitol. Res., in press), we have compared the activities of seven drugs, including those currently used to treat leishmaniasis, again...

In previous studies, we and others have shown utility of a 24-kDa #Trypanosoma cruzi$ recombinant antigen (rTc24) for serological diagnosis of Chagas' disease. Also, this molecule has been proved useful to evaluate cure of chagasic patients who submit to specific treatment. However, in all the studies done so far, the 24-kDa protein was used as a f...

The levels of tumor necrosis factor-alpha (TNF-alpha) in sera from Trypanosoma brucei gambiense-infected patients from the endemic region of Boko Songho (Bouenza focus in Congo) were measured. An increase was observed in sera from patients (geometric mean = 53.75 pg/ml, n = 69) compared with control subjects from the same endemic area (6.72 pg/ml,...

The levels of tumor necrosis factor-α (TNF-α) in sera from Trypanosoma brucei gambiense-infected patients from the endemic region of Boko Songho (Bouenza focus in Congo) were measured. An increase was observed in sera from patients (geometric mean = 53.75 pg/ml, n = 69) compared with control subjects from the same endemic area (6.72 pg/ml, n = 31)....

Human African trypanosomiasis is often associated with an intense proliferation of B lymphocytes, leading to polyclonal antibody synthesis. Using a modified enzyme-linked immunosorbent assay method, we have found highly significant levels of circulating anti-conjugated tryptophan-like epitope antibodies in sera of patients with sleeping sickness. T...

Neighteen Mbororo zebu herds were monitored to evaluate the impact of a trapping campaign against Glossina fuscipes fuscipes restricted to the watering places. This programme is part of the strategy of an integrated campaign against bovine trypanosomoses in the Central African Republic. Trapping reduces the densities of G. f. fuscipes and causes tr...

Le suivi d'un réseau d'élevage de 19 troupeaux zébus Mbororo a été mis en place pour évaluer l'impact d'une lutte par piégeage contre Glossina fuscipes fuscipes limitée aux abreuvoirs. Ce programme s'inscrit dans la stratégie d'une lutte intégrée contre les trypanosomoses bovines en République centrafricaine. Le piégeage permet d'abaisser les densi...

Macrophages collected from BCG-infected mice or exposed in vitro to interferon-γ plus lipopolysaccharide developed a cytostatic activity on Trypanosoma brucei gambiense and Trypanosoma brucei brucei. This trypanostatic activity of activated macrophages was inhibited by addition of N-monomethyl-l-arginine, an inhibitor of the l-arginine-nitric oxide...

A total of 33 domestic animals living in close contact with man in a human trypanosomiasis focus in South Congo were examined parasitologically and tested for serological markers of Trypanosoma brucei gambiense infection. 84.8% of the animals presented detectable T. congolense parasitaemia. The high rate of seropositivity observed with CATT (81.8%)...

We have studied the serum lipoprotein system in human African trypanosomiasis (Trypanosoma brucei gambiense infection). The study was carried out on 74 Congolense patients suffering from sleeping sickness and 34 Congolense control subjects living in the endemic region of Boko Songho. We have determined the serum concentrations of lipids (triglyceri...

A gonad endocrine survey on 46 Congolese patients (15 women and 31 men) with parasitologically confirmed trypanosomiasis found amenorrhoea in 60% of the women and impotence in 70% of the men. The basic gonad endocrine examination showed a decrease in oestradiol levels in about 65% of the women. Both amenorrhoea and low oestrogen levels were observe...

Using immunofluorescence techniques and flow microfluorometry analysis, we have demonstrated that the binding of a monoclonal antibody (VD5/25) produced against GP65, the major surface antigen of Leishmania braziliensis, increased on the surface of stationary-phase promastigotes from all the New World Leishmania species causing mucocutaneous or cut...

Biological and biochemical characterization of 36 human and 5 animal congolese stocks of Trypanosoma brucei were performed. One human and all the animal stocks showed a quick adaptation to rodent host whereas the other 35 human stocks were characterized by a low virulence degree (Group 1 of T. gambiense). The virulent stocks showed hybridization pa...

The growth characteristics of L. chagasi (MHOM/BR/79/LI01) and L. braziliensis (MHOM/BR/72/1670), the causative agents of visceral and muco-cutaneous leishmaniases, respectively, were compared. Inoculum size clearly influences the growth course of both Leishmania species, whatever the culture medium used (serum-supplemented media: GLSH or RPMI, and...

Although the high frequency of hypogonadism was found during the sleeping sickness, the physiological properties of the gonads have been poorly studied. We reported here the exploration of the gonadotropic axis in 79 patients infected by Trypanosoma brucei gambiense. It has been noted a decrease in oestradiol for 50% of women, in testosterone level...

Three serological tests: the Card Agglutination Test (Testryp CATT), the Indirect Immunofluorescence Antibody Test (IFAT) and the Cellognost Indirect Haemagglutination technique (CIHA) were used to analyse the cerebrospinal fluid (CSF) of 41 patients infected with Trypanosoma gambiense and 30 uninfected persons. The authors reported the following d...

The card agglutination test for trypanosomiasis (CATT) was evaluated and compared to the classical immunofluorescent antibody test (IFAT) in the immunological diagnosis of Gambian trypanosomiasis. Tests were performed on serum and whole blood. Cross-reactions were found in the CATT with sera from patients suffering from parasitic infections other t...

In the present study, we report that a growth factor released by cultured Leishmania promastigotes plays a key role in the regulation of their growth in vitro. The factor stimulates growth at low concentrations but is inhibitory at high doses and these effects are not species-specific, also affecting other Trypanosomatidae growing in vitro. The dos...

A micro double diffusion test (MD), allowing the identification of precipitation brand 5 by identity reaction, using a rabbit specific anti-component 5 serum, was evaluated for the immunological diagnosis of Chagas' disease. The previous studies on the Trypanosoma cruzi specificity of component 5[g] were completed, showing it to be absent in Leishm...

The study of the surface antigens of Leishmania braziliensis braziliensis revealed a great homogeneity among ten strains isolated from Bolivia and two reference strains from Brazil and Belize. A 72 kDa major protein, present in all L. b. braziliensis strains, was recognized by both cutaneous and mucocutaneous human sera, but was not recognized by K...

Sequential development of Leishmania braziliensis promastigotes from a noninfective to an infective stage was demonstrated. The generation of infective forms was related to their growth cycle and restricted to stationary stage organisms. Using immunofluorescence techniques, we have noticed that the binding of a monoclonal antibody (mAb) against L....