Leishmaniasis remains a public health problem worldwide, affecting approximately 12 million people in 88 countries; 50 000 die of it each year. The disease is caused by Leishmania, obligate intracellular vector-borne parasites. In spite of its huge health impact on the populations in vast areas, leishmaniasis is one of the most neglected diseases. No safe and effective vaccine currently exists against any form of human leishmaniasis. The spectrum and efficacy of available antileishmanial drugs are also limited. First part of this review discusses the approaches used for the vaccination against leishmaniasis that are based on the pathogen and includes virulent or attenuated parasites, parasites of related nonpathogenic species, whole killed parasites, parasites' subunits, DNA vaccines, and vaccines based on the saliva or saliva components of transmitting phlebotomine vector. Second part describes parasite detection and quantification using microscopy assays, cell cultures, immunodetection, and DNA-based methods, and shows a progress in the development and application of these techniques. In the third part, first-line and alternative drugs used to treat leishmaniasis are characterized, and pre-clinical research of a range of natural and synthetic compounds studied for the leishmanicidal activity is described. The review also suggests that the application of novel strategies based on advances in genetics, genomics, advanced delivery systems, and high throughput screenings for leishmanicidal compounds would lead to improvement of prevention and treatment of this disease.
- MeSH
- antiprotozoální látky terapeutické užití MeSH
- DNA vakcíny imunologie terapeutické užití MeSH
- ELISA MeSH
- kožní testy MeSH
- Leishmania imunologie patogenita MeSH
- leishmanióza * diagnóza farmakoterapie prevence a kontrola MeSH
- lidé MeSH
- mikroskopie MeSH
- protozoální DNA analýza MeSH
- protozoální vakcíny * imunologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- antiprotozoální látky MeSH
- DNA vakcíny MeSH
- protozoální DNA MeSH
- protozoální vakcíny * MeSH
Sand flies are bloodsucking insects transmitting parasites of genus Leishmania, the causative agents of diseases in humans and dogs. Experimental hosts repeatedly exposed to sand fly saliva can control Leishmania infection. Cell-mediated anti-saliva immune response is most likely responsible for this protective effect; however, there is no study so far concerning its antigenic specificity towards different sand fly vectors. In this study, splenocytes from BALB/c mice repeatedly exposed to the bites of Phlebotomus sergenti were challenged ex vivo with salivary gland homogenates from three different sand fly vectors -P. sergenti, P. papatasi, or P. arabicus. Mice bitten by P. sergenti had higher proliferative response to homologous antigen than splenocytes from naive mice. Splenocytes from P. sergenti bitten mice as well as anti-P. sergenti antibodies partially cross-reacted with P. papatasi saliva. In contrast, no cross-reactivity was found with P. arabicus saliva. Our data indicate that both arms of the immune system, cellular and humoral, react in a species-specific manner. Therefore, the presence of antibodies against salivary components of a certain species indicates the specificity of cell-mediated immune response as well. The data suggest that unique transmission-blocking vaccine would be required for each vector -Leishmania combination.
- MeSH
- druhová specificita MeSH
- hmyz - vektory imunologie MeSH
- kousnutí a bodnutí hmyzem imunologie MeSH
- Leishmania imunologie MeSH
- leishmanióza imunologie prevence a kontrola přenos MeSH
- lidé MeSH
- lymfocyty imunologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- Phlebotomus imunologie parazitologie MeSH
- proliferace buněk MeSH
- protilátky protozoální imunologie MeSH
- psi MeSH
- slezina imunologie MeSH
- sliny imunologie MeSH
- vakcína proti leishmanióze imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- protilátky protozoální MeSH
- vakcína proti leishmanióze MeSH
Symptoms of human leishmaniasis range from subclinical to extensive systemic disease with splenomegaly, hepatomegaly, skin lesions, anemia and hyperglobulinemia, but the basis of this variation is unknown. Association of progression of the disease with Th2 lymphocyte response was reported in mice but not in humans. As most genetic studies in Leishmania major (L. major)-infected mice were restricted to skin lesions, we analyzed the symptomatology of leishmaniasis in mice by monitoring skin lesions, hepatomegaly, splenomegaly and seven immunological parameters. We detected and mapped 17 Leishmania major response (Lmr) gene loci that control the symptoms of infection. Surprisingly, the individual Lmr loci control 13 different combinations of pathological and immunological symptoms. Seven loci control both pathological and immunological parameters, 10 influence immunological parameters only. Moreover, the genetics of clinical symptoms is also very heterogeneous: loci Lmr13 and Lmr4 determine skin lesions only, Lmr5 and Lmr10 skin lesions and splenomegaly, Lmr14 and Lmr3 splenomegaly and hepatomegaly, Lmr3 (weakly) skin lesions, and Lmr15 hepatomegaly only. Only two immunological parameters, IgE and interferon-gamma serum levels, correlate partly with clinical manifestations. These findings extend the paradigm for the genetics of host response to infection to include numerous genes, each controlling a different set of organ-specific and systemic effects.
- MeSH
- chromozomy genetika MeSH
- genetická predispozice k nemoci * MeSH
- hepatomegalie genetika patologie MeSH
- imunoglobulin E krev MeSH
- inbrední kmeny myší MeSH
- interferon gama krev MeSH
- kůže patologie MeSH
- Leishmania major imunologie MeSH
- leishmanióza genetika imunologie patologie MeSH
- mapování chromozomů MeSH
- myši MeSH
- splenomegalie genetika patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- imunoglobulin E MeSH
- interferon gama MeSH
- MeSH
- alergeny imunologie MeSH
- bronchiální astma etiologie MeSH
- imunoglobulin E krev MeSH
- kočky imunologie MeSH
- lidé MeSH
- zvířata MeSH
- Check Tag
- kočky imunologie MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alergeny MeSH
- imunoglobulin E MeSH
Saliva of sand flies (Diptera: Phlebotominae) plays an important role in transmission of Leishmania parasites by modulating host immune response. However, because of the different protein compositions of saliva, the immunomodulatory effects may vary among sand fly species. We have therefore analysed and compared the immunomodulation effects of salivary gland lysate (SGL) of three different sand flies. Spleen cells from BALB/c mice were incubated with SGL of Phlebotomus papatasi, P. sergenti or Lutzomyia longipalpis. Concanavalin A-stimulated lymphocyte proliferation was significantly suppressed with SGLs of all three sand fly species and all SGL doses tested. This result indicates that saliva from different sand fly species is able to suppress host proliferative response even to the potent mitogen. In parallel experiments, we analysed the effect of SGL on IFN-gamma, IL-2, and IL-4 production; in mitogen-stimulated cells SGLs markedly inhibited IFN-gamma production in all intervals tested (reduced up to 31%) and to a lesser degree impaired production of the other two cytokines as well. Despite some species-specific differences in the intensity of immunomodulatory effects, saliva of all sand fly species modulated cell proliferation as well as cytokine production in a similar way.
- MeSH
- aktivace lymfocytů MeSH
- buněčná imunita * MeSH
- cytokiny biosyntéza MeSH
- druhová specificita MeSH
- imunologické faktory imunologie MeSH
- interferon gama analýza MeSH
- interleukin-2 analýza MeSH
- interleukin-4 analýza MeSH
- kultivované buňky MeSH
- lymfocyty imunologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- Phlebotomus imunologie MeSH
- proliferace buněk MeSH
- Psychodidae imunologie MeSH
- slinné žlázy chemie imunologie MeSH
- sliny imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cytokiny MeSH
- imunologické faktory MeSH
- interferon gama MeSH
- interleukin-2 MeSH
- interleukin-4 MeSH
The strain BALB/cHeA (BALB/c) is a high producer, and STS/A (STS) a low producer of IgE after Leishmania major infection. We analyzed this strain difference using 20 recombinant congenic (RC) BALB/c-c-STS/Dem (CcS/Dem) strains that carry different random subsets of 12.5% of genes of the strain STS on the BALB/c background. Strains CcS-16 and -20 exhibit a high and a low IgE level, respectively. In their F(2) hybrids with BALB/c we mapped nine Leishmania major response (Lmr) loci. Two of them we previously found to influence IgE level in CcS-5. IgE production in CcS-16 is controlled by loci on chromosomes 2, 10, 16 and 18 and in CcS-20 by loci on chromosomes 1, 3, 4, 5 and 8. The STS alleles of loci on chromosomes 1, 4, 5, 8 and 10 were associated with a low, whereas the STS alleles on chromosomes 16 and 18 with a high IgE production. The loci on chromosomes 2 and 3 have no apparent individual effect, but interact with the loci on chromosomes 10 and 1, respectively. The loci on chromosomes 10 and 18 were mapped in the regions homologous with the human regions containing genes that control total serum IgE and intensity of infection by Schistosoma mansoni, suggesting that some Lmr loci may participate in the pathways influencing atopic reactions and responses to several parasites. The definition of genes controlling anti-parasite responses will permit a better understanding of pathways and genetic diversity underlying the disease phenotypes.
- MeSH
- imunoglobulin E genetika imunologie MeSH
- křížení genetické MeSH
- Leishmania major * imunologie MeSH
- leishmanióza kožní imunologie MeSH
- mapování chromozomů * MeSH
- myši inbrední BALB C MeSH
- myši kongenní imunologie MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- imunoglobulin E MeSH
The intensity of the mixed lymphocyte response (MLR) depends on the genetic disparity between the donors of responding and stimulating cells. Differences in the major histocompatibility complex (MHC) and Mls1 antigens induce the strongest responses. However, even with comparable incompatibilities in MHC and Mls antigens, some strains of genetically defined mice respond remarkably better than other strains. Apparently other, so far undefined, genetic factors contribute to the magnitude of the MLR. The strain OcB-9 (H2pz) has 87.5% genes from the strain O20/A (O20) and 12.5% genes from strain B10.O20 (both H2pz). In spite of the overal similarity of their genomes, OcB-9 mice differed from O20 mice in response to three different alloantigens C57BL/10 (H2b), BALB/c (H2d) and CBA (H2k). As both O20 and OcB-9 strains carry identical haplotype H2pz, their differences in alloantigen response depend only on non-MHC genes. We analyzed the genetic basis of these strain differences using (OcB-9 x O20)F2 hybrids, and we mapped a novel locus Alan2 (Alloantigen response 2) on chromosome 4 near D4Mit72 that influences the response to all alloantigens tested. This linkage was significant for C57BL/10 and for BALB/c alloantigens (corrected P values 0.0475 and 0.0158, respectively) and highly suggestive for CBA (corrected P = 0.0661). The response to DBA/1 (H2q) alloantigens exhibited a similar pattern but the linkage was not significant. As MLR reflects the recognition phase of transplantation reaction, identification of human counterparts of the Alan genes and a better understanding of the regulation of alloresponsiveness might lead to a better prediction of patients' reactions to allografts and to a more individualized measures to prevent rejection.
- MeSH
- genetická vazba MeSH
- H-2 antigeny imunologie MeSH
- histokompatibilní antigen H-2D MeSH
- inbrední kmeny myší genetika imunologie MeSH
- isoantigeny imunologie MeSH
- křížení genetické MeSH
- kultivované buňky MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši inbrední CBA MeSH
- myši MeSH
- slezina cytologie MeSH
- test smíšené lymfocytární kultury MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- H-2 antigeny MeSH
- H-2Kb protein, mouse MeSH Prohlížeč
- histokompatibilní antigen H-2D MeSH
- isoantigeny MeSH
- MeSH
- isoantigeny imunologie MeSH
- mapování chromozomů * MeSH
- mikrosatelitní repetice * MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- test smíšené lymfocytární kultury MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- isoantigeny MeSH
Susceptibility as opposed to resistance of mouse strains (e.g., BALB/c vs C57BL/6) to Leishmania major has been attributed to a defective Th1 and a predominant Th2-response, resulting in increased IL-4 and IgE production, and decreased interferon gamma (IFN gamma) production, macrophage activation and elimination of parasites. Here we report dissection of genetic and functional aspects of susceptibility to leishmaniasis using two contrasting inbred strains BALB/cHeA (susceptible) and STS/A (resistant) and a resistant Recombinant Congenic (RC) Strain, CcS-5/Dem, which carries a random set of 12.5% of genes from the strain STS and 87.5% genes from the susceptible strain BALB/c. Linkage analysis of F2 hybrids between the resistant RC strain CcS-5 and the susceptible strain BALB/c revealed five loci affecting the response to the infection, each apparently associated with a different combination of pathological symptoms and immunological reactions. The correlation between Th2-type immune reactions and the disease in the F2 mice was either absent, or it was limited to mice with specific genotypes at loci on chromosomes 10 and 17. This suggests that the resistance vs susceptibility is influenced by mechanisms additional to the postulated antagonistic effects of Th1 and Th2 responses, and that the host's genotype affects the development of leishmaniasis in a complex way.
- MeSH
- aktivace lymfocytů MeSH
- druhová specificita MeSH
- fenotyp MeSH
- genetická vazba MeSH
- genotyp MeSH
- hybridizace genetická MeSH
- inbrední kmeny myší MeSH
- Leishmania major * MeSH
- leishmanióza kožní genetika imunologie patologie MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- polymorfismus genetický MeSH
- techniky in vitro MeSH
- Th1 buňky imunologie MeSH
- Th2 buňky imunologie MeSH
- zvířata kongenní MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Lymphocytes of mouse strains BALB/cHeA (BALB/c) and STS/A (STS) differ in their response to CD3 antibody (anti-CD3). We analyzed the genetic basis of this strain difference, using the Recombinant Congenic Strains (RCS) of the BALB/c-c-STS/Dem (CcS/Dem) series. Each of the 20 CcS/Dem strains carries a different, random combination of 12.5% genes from the nonresponding strain STS and 87. 5% genes of the intermediate responder strain BALB/c. Differences in the magnitude of anti-CD3-induced response among CcS/Dem strains indicated that in addition to Fcgamma receptor 2 (Fcgr2) other genes are involved in the control of this response as well, and we have already mapped loci Tria1 (T cell receptor-induced activation 1), Tria2, and Tria3. In order to map additional Tria genes, we tested F2 hybrids between the high responder RC strain CcS-9 and the low responder strain CcS-11. Proliferation in complete RPMI medium without anti-CD3 is controlled by locus Sprol1 (spontaneous proliferation 1) linked to the marker D4Mit23 on Chr 4. At concentration 0.375 microg/ml anti-CD3 mAb, the response was controlled by a locus Tria4, which maps to the marker D7Mit32 on Chr 7. The response to the higher concentration of mAb, 3 microg/ml, was controlled by Tria5, which mapped to the marker D9Mit15 on Chr 9. Anti-CD3 is being used for modulation of lymphocyte functions in transplantation reactions and in cancer treatment. Study of mechanisms of action of different Tria loci could lead to better understanding of genetic regulation of these reactions.
