Genetic control of acquired resistance to visceral leishmaniasis in mice

A series of H-2 and non-H-2 congenic resistant (CR) strains on a C57BL/10Sn background were infected with 10(7) amastigotes of Leishmania donovani. Non-H-2 congenic strains B10.LP-H-3b and B10.CE(30NX) and (B10.LP-H-3b x B10)F1 hybrids showed a very rapid decrease in liver-parasite burdens beyond day 21. Parasite counts for these strains at day 35 were significantly lower than for all other strains tested. The rapid decrease in parasite numbers, massive lymphocellular infiltration into the liver and strong delayed hypersensitivity reactions to parasite antigens in strains congenic for a portion of chromosome 2 indicated that acquired immunity to L. donovani was controlled by a dominant gene at or near the Ir-2 locus. In addition, B10.129(10M) mice, which differ from C57BL/10Sn at the H-11 locus, showed highly significant increases in parasite numbers at day 35. Other observations supporting the absence of acquired immunity in B10.129(10M) included negative delayed hypersensitivity tests to parasite antigens and the absence of lymphocellular infiltrate into the liver. Although the differences were not as pronounced, H-2 CR strains with H-2b, H-2a, and H-2k haplotypes also showed significantly greater decreases in parasite numbers by day 35 as compared to other H-2 CR strains.     

A role for Lyt-2+ T cells in resistance to cutaneous leishmaniasis in immunized mice

The role of Lyt-2+ T cells in immunologic resistance to cutaneous leishmaniasis was analyzed by comparing infection patterns in resistant C57BL/6 mice and susceptible BALB/c mice induced to heal their infections after sub-lethal irradiation or i.v. immunization, with similar mice treated in vivo with anti-Lyt-2 antibodies. Administration of anti-Lyt-2 mAb resulted in a dramatic reduction in the number of lymphoid cells expressing the Lyt-2+ phenotype. Such treatment led to enhanced disease in both resistant C57BL/6 and irradiated BALB/c mice, as assessed by lesion size, but did not affect the capacity of these mice to ultimately resolve their infections. In contrast, anti-Lyt-2 treatment totally blocked the induction of resistance in i.v. immunized mice. These results suggest, that Lyt-2+ T cells may play a role in immunity to a Leishmania major infection and that their relative importance to resistance may depend on how resistance is induced.     

Cytokine gene polymorphisms and susceptibility to cutaneous leishmaniasis in Iranian patients

Cutaneous Leishmaniasis (CL) is one of the most prevalent clinical forms of leishmaniasis. Preliminary data suggest that cytokine gene polymorphisms can contribute to resistance or susceptibility to CL. Therefore, we investigated the association of functional polymorphisms in four cytokine genes with susceptibility to, and clinical outcome of CL. A total of 201 patients with self-healing cutaneous leishmaniasis (SCL) and 92 asymptomatic infected controls (AIC) from Fars province as well as 58 patients with chronic cutaneous leishmaniasis (CCL) and their 688 normal controls (normal Iranian population or NIP) who were collected from the different areas of Iran were included in the study. The allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) or PCR-RFLP (restriction fragment length polymorphism) methods were used for genotyping. The frequency of TNF-alpha -308 G-->A and TNF-beta +252 G-->A gene polymorphisms were not different between studied groups. Distribution of IFN-gamma +874 A-->T and IL-4 -590 C-->T polymorphism were also compared between SCl or CCL patients and their controls. IFN-gamma +874 A-->T polymorphism was less common in CCL patients compared to the NIP (chi(2)=12.53, p=0.0019). Significant differences in frequency of IL-4 -590 C -->T polymorphism were also found between the SCL and AIC (chi(2)=8.64, p=0.003). In conclusion, our results suggest that functional genetic variants in the IL-4 promoter could influence the risk of developing CL while the polymorphism in the first intron of the IFN-gamma gene might influence the progression of disease towards CCL.     

Immunologic memory in cutaneous leishmaniasis

Leishmania major infections induce solid immunity to reinfection. Experimental studies in mice indicate that the CD4+ T cells responsible for this immunity include two populations: parasite-dependent T effector cells and parasite-independent central memory T (Tcm) cells. While there currently is no vaccine for leishmaniasis, the existence of a long-lived population of Tcm cells that does not require the continued presence of live parasites suggests that a vaccine that expands these cells might be efficacious.     

Insecticide impregnated curtains to control domestic transmission of cutaneous leishmaniasis in Venezuela: cluster randomised trial

ObjectiveTo measure the impact on transmission of leishmaniasis of curtains impregnated with insecticide.DesignCluster randomised controlled trial: household interview survey, observational study of people''s behaviour, entomological study with light trap captures of sandflies inside houses.Setting14 urban sectors in Trujillo, Venezuela.Participants2913 inhabitants of 569 houses.InterventionSectors were paired according to their 12 month cumulative incidence of cutaneous leishmaniasis, one sector in each pair was randomly allocated to receive polyester curtains impregnated with lambdacyhalothrin (intervention group) while the other sector received curtains without insecticide or no curtains (control groups). After 12 months a follow up household survey was conducted.ResultsTransmission of cutaneous leishmaniasis occurred mainly in the domestic setting, with the incidence over 12 months of 4%. The mean number of sandflies per trap per night was 16. After follow up the 12 month incidence of cutaneous leishmaniasis was 0% in the intervention group and 8% in the six pairs in the control group that received unimpregnated curtains (mean difference 8, 95% confidence interval 4.22 to 11.78; P=0.001). There were significantly fewer sandflies in the intervention group (2 v 15, mean difference 13 sandflies per trap; 9 to 17; P<0.001).ConclusionCurtains impregnated with insecticide provide a high degree of protection against indoor transmission of cutaneous leishmaniasis.

What is already known on this topic

The transmission of cutaneous leishmaniasis is increasingly in urban and domestic settingsHouse spraying, space spraying, and insecticide treated material reduce the number of vectors

What this paper adds

Pyrethroid impregnated curtains can considerably reduce the incidence rate of cutaneous leishmaniasis in areas where indoor transmission is predominant     

Murine cutaneous leishmaniasis: resistance correlates with the capacity to generate interferon-gamma in response to Leishmania antigens in vitro

The kinetics of cell-mediated immunity developed during the course of Leishmania major infection in resistant (C57BL/6) and susceptible (BALB/c) mice were determined by using in vitro bioassays. Cells isolated from the lymph nodes draining the infected footpads were assayed for their proliferative responses to leishmania antigens (promastigote and amastigote) or to concanavalin A (Con A). Although lymph node cells (LNC) from both mouse strains proliferated to mitogen and antigen early after infection, both C57BL/6 and BALB/c mice developed diminished in vitro proliferative reactivity within 3 to 5 wk after infection. LNC from both mouse strains recovered lymphoproliferative reactivity to Con A (week 6), but only C57BL/6 mice regained reactivity to leishmania antigens. BALB/c cells remained unresponsive to leishmania antigens throughout the subsequent course of the infection. Supernatants derived from cultures of LNC that had been stimulated with Con A or leishmania antigens were assayed for interferon-gamma (IFN-gamma) by analyzing three distinct activities associated with IFN-gamma. Culture supernatants derived from leishmania antigen stimulation of LNC from infected C57BL/6 mice, but not BALB/c mice, were able to induce surface Ia on murine P388D1 cells. Ia-inducing activity was detectable in supernatants from C57BL/6 cells as early as 3 wk, and peaked by 5 wk after infection. Although cells from infected BALB/c mice never produced detectable IFN-gamma in response to leishmania antigens, LNC from both mouse strains produced readily detectable IFN-gamma in response to Con A throughout the course of infection. Culture supernatants that induced Ia on P388D1 cells were also capable of activating resident peritoneal macrophages to display leishmanicidal activity and of inhibiting encephalomyocarditis virus replication in murine fibroblasts. Each of these activities could be removed by prior incubation of the supernatants with rabbit heterologous anti-murine IFN-gamma sera or monoclonal rat-anti-murine IFN-gamma. The correlation of healer status with the capacity to generate IFN-gamma in vitro in response to leishmania antigens was examined in BALB/c mice that had been exposed to sublethal irradiation (550 rad) before infection. These animals have been previously shown to effectively resist L. major infection. Consistent with observations in the genetically resistant C57BL/6 mice, LNC from these animals demonstrated the capacity to respond to in vitro leishmania antigen stimulation with lymphoproliferation, and more importantly, by producing IFN-gamma.(ABSTRACT TRUNCATED AT 400 WORDS)     

Toll-like receptor 4 polymorphisms predispose to cutaneous leishmaniasis

The clinical spectrum of cutaneous leishmaniasis (CL) is extremely variable. Studies in experimental leishmaniasis have revealed a role for TLR4 in control of infection. In the present study the associations between TLR4 mutations (Asp299Gly and Thr399Ile) with outcome of CL have been investigated. Genotyping for Asp299Gly and Thr399Ile was performed in patients with chronic (N?=?22) and acute (N?=?61) CL, asymptomatic (N?=?45) and healthy leishmanin skin test negative individuals (N?=?75). The results showed the frequency of the Asp299Gly genotype was increased in patients with chronic disease (OR 25.3, 95% CI 5.2-115.6, P?相似文献   

Immunobiology of experimental cutaneous leishmaniasis

The study of the murine model of infection with Leishmania major is providing important insights into the understanding of the complex interactions between the host and intracellular pathogens. Using this model system, basic research is actively leading to the identification of host factors promoting or circumventing the development of immunity to L. major. Here, Geneviève Milon, Giuseppe Del Giudice and Jacques A. Louis review recent results related to the characterization of immunological host factors determining resistance and susceptibility to this parasite, and try to identify areas where further research is required for a better understanding of the complex events triggered by intracellular parasites within their hosts. Extrapolation to the human leishmaniases of the rapid advances made in this murine model of infection, should pave the way to the rational design of future immunoprophylactic and immunotherapeutic measures.     

Impairment of alternative macrophage activation delays cutaneous leishmaniasis in nonhealing BALB/c mice

Expressed on various cell types, the IL-4Ralpha is a component of both receptors for IL-4 and IL-13. Susceptibility of BALB/c mice to Leishmania major is believed to be dependent on the development of IL-4- and IL-13-producing Th2 cells, while IFN-gamma secretion by Th1 cells is related to resistance. Despite a sustained development of Th2 cells, IL-4Ralpha-deficient BALB/c mice are able to control acute cutaneous leishmaniasis, suggesting that IL-4Ralpha-bearing cells other than Th2 cells contribute to susceptibility. To analyze the contribution of the IL-4Ralpha on macrophages, recently generated macrophage/neutrophil-specific IL-4Ralpha-deficient mice on a susceptible BALB/c genetic background were infected with L. major. Strikingly, macrophage/neutrophil-specific IL-4Ralpha-deficient mice showed a significantly delayed disease progression with normal Th2 and type 2 Ab responses but improved macrophage leishmanicidal effector functions and reduced arginase activity. Together, these results suggest that alternative macrophage activation contributes to susceptibility in cutaneous leishmaniasis.     

Dendritic cell-derived IL-12p40 homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice

Protection against Leishmania major in resistant C57BL/6 mice is mediated by Th1 cells, whereas susceptibility in BALB/c mice is the result of Th2 development. IL-12 release by L. major-infected dendritic cells (DC) is critically involved in differentiation of Th1 cells. Previously, we reported that strain differences in the production of DC-derived factors, e.g., IL-1alphabeta, are in part responsible for disparate disease outcome. In the present study, we analyzed the release of IL-12 from DC in more detail. Stimulated DC from C57BL/6 and BALB/c mice released comparable amounts of IL-12p40 and p70. In the absence of IL-4, BALB/c DC produced significantly more IL-12p40 than C57BL/6 DC. Detailed analyses by Western blot and ELISA revealed that one-tenth of IL-12p40 detected in DC supernatants was released as the IL-12 antagonist IL-12p40 homodimer (IL-12p80). BALB/c DC released approximately 2-fold more IL-12p80 than C57BL/6 DC both in vitro and in vivo. Local injection of IL-12p80 during the first 3 days after infection resulted in increased lesion volumes for several weeks in both L. major-infected BALB/c or C57BL/6 mice, in higher lesional parasite burdens, and decreased Th1-cytokine production. Finally, IL-12p40-transgenic C57BL/6 mice characterized by overexpression of p40 showed increased levels of serum IL-12p80 and enhanced disease susceptibility. Thus, in addition to IL-1alphabeta, strain-dependent differences in the release of other DC-derived factors such as IL-12p80 may influence genetically determined disease outcome.     

Vectors of cutaneous leishmaniasis in north-central Venezuela

Abstract. An entomological survey was undertaken from January 1991 to February 1992 in El Ingenio, Miranda State, Venezuela, an endemic area of cutaneous leishmaniasis: prevalence of 10.7 cases per 100,000 inhabitants.
A total of 4863 female sandflies (Phlebotominae) of fourteen species were collected in Shannon traps, then dissected and examined for leishmanial infections.
Lutzomyia ovallesi (85.4%) and Lu. gomezl (11.2%) were the predominant anthropophilic species of sandfly. Fifty-one (1.19%) Lu. ovallesi and two(0.47%) Lu. gomezi had natural infection with Leishmania promastigotes. Identification of the parasites was done by using the polymerase chain reaction (PCR) and DNA hybridization. Two isolates from Lu. gomezi and forty-nine from Lu. ovallesi were typed as Leishmania braziliensis and three of the latter reacted with Le. mexicana also. This is the first report of Lu. gomezi with parasites typed as Le. braziliensis.
We concluded that Lu. ovallesi is the primary vector of cutaneous leishmaniasis in the north-central area of Venezuela and Lu. gomezi should be regarded as an additional vector.     

Concordance of leishmaniasis cutaneous tests in Tunisia

A cross sectional study aimed to evaluate the effect of antigenic preparation (Leishmania infantum versus Leishmania major) and dose of leishmania antigens (5 x 10(6) versus 2.5 x 10(6) parasites in the same volume) on the reproducibility of delayed type hypersensitivity leishmania skin test. Results showed that among 34 individuals involved from visceral leishmaniasis endemic area. 26 (76.5%) had a positif Leishmania infantum leishmania (L-L. infantum) test and 27 (79.4%) to Leishmania major leishmania (L-L. major). Mean size of cutaneous reaction was 5.94 +/- 2.86 mm for L-L. infantum and 5.41 +/- 3.23 mm for L-L. major, with a significant positive linear association (p < 10-3). Intra-class correlation coefficient was 0.80 (CI95% = [0.64-0.93]) and concordance Kappa (kappa) was 0.57 (CI95% = [0.40-0.74]). Among 153 individuals from zoonotic cutaneous leishmaniasis. 92.9% revealed a positive test for both types of leishmanin (L-L. major full dose versus L-L. major half dose). Mean size of cutaneous reaction was 12.61 +/- 4.65 mm for the reference test and 11.30 +/- 3.95 mm for diluted one, with a positive linear association (p < 10-3). Intra-class correlation coefficient was 0.78 (IC95% = [0.71-0.84]) and concordance Kappa (kappa) was 0.82 (IC95% = [0.73-0.91]). These results demonstrate a limited effect of leishmania antigenic variation and antigen dose on the reproducibility of delayed type hypersensitivity induced by the leishmanin test.     

Genetic control of acquired resistance to visceral Leishmaniasis in mice

A series ofH-2 and non-H-2 congenic resistant (CR) strains on a C57BL/10Sn background were infected with 10⁷ amastigotes ofLeishmania donovani. Non-H-2 congenic strains B10.LP-H-3 ^b and B10.CE(30NX) and (B10.LP-H-3 ^b × B10)F₁ hybrids showed a very rapid decrease in liver-parasite burdens beyond day 21. Parasite counts for these strains at day 35 were significantly lower than for all other strains tested. The rapid decrease in parasite numbers, massive lymphocellular infiltration into the liver and strong delayed hypersensitivity reactions to parasite antigens in strains congenic for a portion of chromosome 2 indicated that acquired immunity toL. donovani was controlled by a dominant gene at or near theIr-2 locus. In addition, B10.129(10M) mice, which differ from C57BL/10Sn at theH-11 locus, showed highly significant increases in parasite numbers at day 35. Other observations supporting the absence of acquired immunity in B10.129(10M) included negative delayed hypersensitivity tests to parasite antigens and the absence of lymphocellular infiltrate into the liver. Although the differences were not as pronounced,H-2 CR strains withH-2 ^b ,H-2 ^a , andH-2 ^k haplotypes also showed significantly greater decreases in parasite numbers by day 35 as compared to otherH-2 CR strains.     

Effectiveness of vector control methods for the control of cutaneous and visceral leishmaniasis: A meta-review

Elimination of visceral leishmaniasis (VL) in Southeast Asia and global control of cutaneous leishmaniasis (CL) and VL are priorities of the World Health Organization (WHO). But is the existing evidence good enough for public health recommendations? This meta-review summarises the available and new evidence for vector control with the aims of establishing what is known about the value of vector control for the control of CL and VL, establishing gaps in knowledge, and particularly focusing on key recommendations for further scientific work. This meta-review follows the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria, including (1) systematic reviews and meta-analyses (SRs/MAs) for (2) vector control methods and strategies and (3) for the control of CL and/or VL. Nine SRs/MAs were included, with different research questions and inclusion/exclusion criteria. The methods analysed for vector control can be broadly classified into (1) indoor residual spraying (IRS); (2) insecticide-treated nets (ITNs; including insecticide-impregnated bednets); (3) insecticide-treated curtains (ITCs; including insecticide-treated house screening); (4) insecticide-treated bedsheets (ITSs) and insecticide-treated fabrics (ITFs; including insecticide-treated clothing) and (5) durable wall lining (treated with insecticides) and other environmental measures to protect the house; (6) control of the reservoir host; and (7) strengthening vector control operations through health education. The existing SRs/MAs include a large variation of different primary studies, even for the same specific research sub-question. Also, the SRs/MAs are outdated, using available information until earlier than 2018 only. Assessing the quality of the SRs/MAs, there is a considerable degree of variation. It is therefore very difficult to summarise the results of the available SRs/MAs, with contradictory results for both vector indices and—if available—human transmission data. Conclusions of this meta-review are that (1) existing SRs/MAs and their results make policy recommendations for evidence-based vector control difficult; (2) further work is needed to establish efficacy and community effectiveness of key vector control methods with specific SRs and MAs (3) including vector and human transmission parameters; and (4) attempting to conclude with recommendations in different transmission scenarios.     

Immunologic responsiveness in American cutaneous leishmaniasis lesions

American cutaneous leishmaniasis is a disease of skin and mucous membranes in which T lymphocytes reactive to Leishmania (Viannia) braziliensis are thought to contribute to protective immunity. To characterize the nature of the T cell inflammatory infiltrate in American cutaneous leishmaniasis lesions, immunohistochemistry with mAb that define T cell subpopulations and in situ hybridization to detect mRNA coding for IFN-gamma were performed. In both localized cutaneous (LCL) and mucocutaneous (MCL) lesions, we observed a predominance of T memory (CD4+CD45RO+) as compared to T naive cells (CD+CD45RA+). The percentages of cells containing IFN-gamma mRNA were equivalent in both LCL and MCL lesions. T cells were extracted from LCL and MCL lesions and analysis indicated that T cells from both lesions had been stimulated by L. (V.) braziliensis in vivo and gave equivalent proliferative responses in vitro. The present data suggest that T memory cells, which are likely to elaborate IFN-gamma, are components of DTH response to L. (V.) braziliensis and participate in the pathogenesis of both LCL and MCL lesions.     

Leishmania (Leishmania) amazonensis: experimental cutaneous leishmaniasis associated with systemic amyloidosis in mice

We infected Swiss and C57BL/6 female mice in the left hind footpad with 10⁴Leishmania (L.) amazonensis promastigotes in stationary phase. The macroscopic examination showed a nodular non-ulcerated lesion at the site of inoculation and hepatic and spleenic enlargement. Histopathologically, the primary lesion showed an extensive liquefactive necrosis and inflammatory infiltrate, mainly consisting of macrophages filled with amastigotes, and rare lymphocytes. The inflammatory reaction in liver, spleen and kidney showed amyloid deposits. Additionally, C57BL/6 had accentuated amyloidosis in both ovarian cortical and medullar region and inflammatory infiltrates in the pancreas and adrenal gland.     

Experimental models of cutaneous leishmaniasis in laboratory animals

A survey of literature on modelling cutaneous leishmaniasis of man (common and metastatic) on some lines of mice, guinea pigs, golden hamsters infected with different species of Leishmania is given. Merits and demerits of each described model are pointed out.