A systematic review and meta-analysis of the prevalence of Leishmania infantum in sandflies in Iran

Objective:To determine the overall and pooled prevalence of Leishmania(L.)infantum in sandfly vectors in Iran.Methods:The present research conducted a systematic review and meta-analysis and searched regional databases such as PubMed,Scopus,Web of Science(WoS),Embase,PAHO Iris,LILACS,WHO Iris,and local databases named:SID,Magiran,Civilica,and also grey literatures.The current research included studies that were conducted in Iran and examined L.infantum in different sandfly vectors.The studies’quality assessment/risk of bias assessment was evaluated by the Joanna Briggs Institute Critical Appraisal Checklist for prevalence data studies,and the data were analyzed by Stata 14 software.In addition,we examined 22 primary studies to estimate the overall prevalence of L.infantum among various vectors of visceral leishmaniasis.Results:According to the meta-analysis,the pooled prevalence of Phlebotomus(Ph.)tobbi,Ph.alexandri,Ph.kandelaki,Ph.perfiliewi,Ph.major,Ph.keshishiani were 5.34%,4.36%,2.23%,1.79%,4.37%and 1.18%.Ph.tobbi has the highest infection rate(25.00%)of L.infantum among the sandfly vectors.Conclusions:Visceral leishmaniasis is widespread in Fars,Ardebil,and East-Azerbaijan provinces,which are the most important endemic regions in Iran.

American tegumentary leishmaniasis mimicking myiasis and granulomatous vasculitis:A case report

Rationale:American tegumentary leishmaniasis comprises cutaneous and mucocutaneous manifestations caused by parasitic infections by various Leishmania species.This report details the clinical interventions for a patient with American tegumentary leishmaniasis in Mendoza,Argentina,a non-endemic region.Patient concerns:A 43-year-old male was admitted to a tertiary care hospital in Mendoza,Argentina Republic with a history of progressive nasal discharge,septal perforation,facial pain,and pruritus.Despite treatment for presumed nasal myiasis and vasculitis with granulomatosis,symptoms persisted.Diagnosis:American tegumentary leishmaniasis.Interventions:Intravenous liposomal amphotericin B.Outcomes:Follow-up at 30 days showed no recurrence of symptoms with a remarkable clinical improvement of the nasal lesion.Lessons:This case sheds light on the necessity of accurate identification for timely intervention and the need to recognize the diverse manifestations of American tegumentary leishmaniasis to avoid misdiagnosis.

Immune response to inactivated bacterial vector carrying the recombinant K39 antigen of Leishmania infantum in mice

Objective:To evaluate the immunological response elicited by an inactivated bacterial vector carrying the K39 antigen of Leishmania infantum,and a purified antigen.Methods:Mice were subjected to the following treatments:(1)Purified recombinant K39(rK39)protein at a 20μg dose with complete Freund’s adjuvant;(2)Inactivated Escherichia coli(BL21 DE3)carrying the K39 protein at an equivalent total protein content of 200μg;(3)Inactivated bacteria lacking the K39 protein;(4)Non-immunized control animals.Serological monitoring was performed.All groups were challenged by intraperitoneal injection of 10^(7) Leishmania infantum promastigotes.After euthanasia,the liver and spleen were collected to analyze the levels of TNF,IFN-γ,IL-12,IL-4,and IL-10.Results:Mice immunized with purified rK39 or the inactivated bacterial vector carrying the K39 antigen of Leishmania infantum showed a long-lasting immune response with high levels of polyclonal antibodies specifically recognizing the recombinant proteins.The IgG1 subclass was the predominant immunoglobulin;however,the induction of IgG2a and the profile of cytokines produced were indicative of the induction of a mixed-type response.Conclusions:The inactivated bacterial vector carrying the K39 antigen,as well as the purified antigen can induce a long-lasting immune response in immunized mice,predominantly favouring a Th2 profile response.

Hematological picture of pediatric Sudanese patients with visceral leishmaniasis and prediction of leishmania donovani parasite load

BACKGROUND Visceral leishmaniasis(VL)is a systemic protozoan infection caused by Leishmania donovani(L.donovani)and transmitted by sand flies,causing macrophage invasion in the liver,spleen,and bone marrow.Diagnosis of VL is currently based on clinical signs,symptoms,and specific in-vitro markers and bone marrow investigations.However,VL's specific hematological and bone marrow manifestation in Sudanese pediatric patients is not well studied.AIM To examine the blood and bone marrow characteristics in pediatric patients from Sudan who have VL.METHODS This is a retrospective hospital-based study with a sample of 107 consecutive Sudanese pediatric patients.The data focused on hematological and bone marrow results.We included only the completed records of the pediatric patients with VL in the Tropical Disease Teaching Hospital in Khartoum,Sudan from the period of 2016 to 2020.RESULTS The majority of pediatric patients included in this study are below 5-years-old(n=59,55.2%).Moreover,anemia,thrombocytopenia,and leukopenia were among the prevalent characteristics in the population under study.To further analyze the data,we developed a machine learning model using boosted forest algorithms to predict L.donovani parasites load,with a mean accuracy of 0.88 for the training dataset and an accuracy of 0.46,0.50,and 0.74 for mild,moderate,and severe L.donovani parasite load in the validation dataset.CONCLUSION This study shows that the most common bone marrow change among Sudanese VL children was increased chronic inflammatory cells(n=88,82.2%)with present macrophage hemophagocytes(n=103,96.3%).While anemia and thrombocytopenia were the most common hematological changes.These results will hopefully lead to an early diagnosis and hence better management for Sudanese pediatric patients with suspected VL.

Leishmania in an Ecotourism Area in Rio de Janeiro: Still a Concern for Public Health?

We evaluated some eco-epidemiological characteristics of the sand fly fauna in an ecotourism area in the Atlantic Forest located in Rio de Janeiro, southeastern Brazil. During a period of one year, sandflies were collected in three different locations, where the sampled residences were located, respectively, one inside the forest, the other two, respectively at the edge of the forest and the other in a more urbanized area. These three types of ecotopes were evaluated: home, peridomicile and kennel. Four hundred and fifty-six sandflies were collected and six species belonging to five genera were identified: Migonemyia migonei, Lutzomyia longipalpis, Nyssomyia intermedia, Evandromyia sallesi, Evandromyia edwardsi and Brumptomyia wedge. The two most abundant species collected were M. migonei and L. longipalpis, contributing 70% and 18% respectively, totaling 88% of the individuals collected. The results suggested that modifications of the natural environment due to anthropic action probably resulted in changes in the composition of the sand fly population. At point (3), where spraying occurred irregularly, even representing a degraded environment, only one species was captured, M. migonei. Differently at points (1) and (2), areas located respectively in the interior and on the edge of the Atlantic Forest, a greater number of sand fly species was observed. However, after a few years, anthropic actions ceased, followed by the implementation of reforestation projects and currently the landscape is very different, showing considerable forest recovery. For this reason, ecotourism activities are increasing in the area, creating potentially dangerous conditions caused by the exposure of greater numbers of people and dogs to insect vectors. Therefore, the implementation of environmental education projects is essential. However, we suggest that the use of warning signs to be placed at the entrances to the main traffic routes, alerting tourists to the risk of infection and indicating protective measures, would be very useful.

陇南川北中华白蛉生物学及其与人、犬内脏利什曼病(Visceral leishmaniasis)关系的研究

本文报告陇南川北山区中华白蛉若干生物学观察的结果及其与人、犬内脏利什曼病的关系。中华白蛉为本区的优势种,具有野栖习性,发生季节自5月至10月,7月为高峰期,峰幅宽和持续时间长为其特点。我们对中华白蛉全季节的性营养周期变动作了观察和分析,指出它是阐明蛉口动力学、预报和预防疾病发生的重要指征。饲血测试表明中华白蛉吸犬血率为61.5%(198/322),当地犬感染内脏利什曼病是与当地中华白蛉吸犬血的习性密切相关。不同垂直高度中华白蛉的发育史比较观察,证明其发育期长短是受自然因素的严格制约。提高温度和增加光照并不能使滞育幼虫提前解除滞育;相反,在自然室温和自然光下饲养的滞育幼虫是实验室饲养越冬幼虫的理想方法。中华白蛉人工感染试验和自然感染调查数据表明,本区中华白蛉是传播人、犬内脏利什曼病的唯一媒介。同时证明本区存在黑热病的自然疫源地。调查说明了媒介生态习性与其传病有直接的关系,并可表达在相互间传播,它们是怎样起着不同的传播作用,因此,研究媒介的生物学及其传病的各种因素有重要的意义。

砂鼠利什曼原虫(Leishmania gerbilli)的亚显微结构

砂鼠利什曼原虫(Leishmania gerbilli)存在于我国西北甘肃某地的砂土鼠或大砂鼠(Rhombomys opimus)体内,是中国特有的种类,王捷等60年代分离培养成功。对L.gerbilli的前鞭毛体的亚显微结构的观察表明:1.质膜下微管间距约为50nm,比别的利什曼原虫的宽;2.鞭毛基部极少观察到基板(basal plate);3.线粒体发达,从动基体所在部位伸向虫体各个部位,内有复杂的结构;4.在通常情况下,L.gerbilli的动基体呈棒状,但当细胞膨胀后则无论在光镜或电镜下动基体均呈扁环结构;5.虫体后部有发达的复片层结构。这一结构由一系列的膜卷绕成,其意义不明。

Cutaneous leishmaniasis in Iran: Results from an epidemiological study in urban and rural provinces

Objective: To examine the prevalence and clinical manifestations of cutaneous leishmaniasis(CL) in Iran.Methods: This study was conducted in Iran between 2011 and 2013. Sampling, preparing, developing, and fixing of suspicious skin lesions were completed in healthcare centers in 31 Iranian provinces as well as in the Academic Reference Laboratory and the National Reference Laboratory. The information was then analyzed at the Ministry of Health's Information Management Center of Contagious Diseases.Results: Over a three-year period, the number of people identified with CL was 56 546.The highest incidence was reported in 2011(27.5 per 100 000). Wet CL accounted for 43.7% of cases while 43.3% resulted from sporotrichoid leishmaniasis. The results showed that there was a higher incidence of CL due to Leishmania major(50.2%) than to Leishmania tropica. The results of this study found that the highest incidence of CL had happened respectively in Ilam, Fars and, Khorasan Razavi Provinces between 2011 and 2013.Conclusions: Although the incidence of the disease is declining, CL is still a public health concern and disease control protocols need to be established. Therefore, further studies are needed to identify the vectors, reservoirs, and disease species as well as to develop appropriate disease control strategies.

In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis

The present study evaluated the in vitro activity and in vivo efficacy of diminazene combined with chloroquine as a potential drug against Leishmania donovani. Amphotericin B was used as a positive control drug. In vitro activity involved incubation of various drug concentrations with promastigotes or vero cells in culture before determination of parasite growth inhibition or cell death while in vivo evaluations involved infection of various mice groups with virulent L. donovani parasites and treatment with test drug compounds following disease establishment. Weight changes in experimental mice were also evaluated before infection and throughout the experiment. The results indicated that the diminazene-chloroquine combination was at least nine times more efficacious than individual drugs in killing promastigotes in culture. The diminazene-chloroquine combination was safer （Ld50=0.03±0.04） than Amphotericin B （Ld50=0.02±0.01）. Body weight in infected mice increased significantly （P=0.0007） from day 7 to day 37 following infection （P=0.026）. However, body weight remained comparable in all mice groups during treatment （P=0.16）. The diminazene-chloroquine combination significantly reduced splenic parasite numbers as compared to individual drug therapies （P=0.0001） although Amphotericin B was still more efficacious than any other treatment （P=0.0001）. Amongst the test compounds, the diminazene-chloroquine combination showed the lowest level of IgG antibody responses with results indicating significant negative correlation between antileishmanial antibody responses and protection against disease. These findings demonstrate the positive advantage and the potential use of a combined therapy of diminazene-chloroquine over the constituent drugs. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.

Development ofLeishmania vaccines:predicting the future from past and present experience

Leishmaniasis is a disease that ranges in severity infection. Resistance to infection is associated with from skin lesions to serious disfigurement and fatal systemic a T-helper-1 immune response that activates macrophages to kill the intracellular parasite in a nitric oxide-dependent manner. Conversely, disease progression is generally associated with a T-helper-2 response that activates humoral immunity. Current control is based on chemothera- peutic treatments which are expensive, toxic and associated with high relapse and resistance rates. Vaccination remains the best hope for control of all forms of the disease, and the development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunization with defined subunit vaccines or live-at- tenuated strains of Leishmania. However, to date, no vaccine is available despite substantial efforts by many laboratories. Major impediments in Leishmania vaccine development include： lack of adequate funding from national and international agencies, problems related to the translation of data from animal models to human disease, and the transition from the laboratory to the field. Furthermore, a thorough understanding of protective immune responses and generation and maintenance of the immunological memory, an important but least-studied aspect of antiparasitic vaccine development, during Leishmania infection is needed. This review focuses on the progress of the search for an effective vaccine against human and canine leishmaniasis.

Leishmania donovani whole cell antigen delivered with adjuvants protects against visceral leishmaniasis in vervet monkeys (Chlorocebus aethiops)

In a previous immunogenicity and efficacy study in mice, montanide ISA 720 （MISA） was indicated to be a better adjuvant than bacillus calmette guerin vaccine （BCG） for a Leishmania vaccine. In the present study, we report the safety, immunogenicity and efficacy of Leishmania donovani （L. donovani） sonicated antigen delivered with alum-BCG （A1BCG）, MISA or monophosphoryl lipid A （MPLA） in vervet monkeys following intradermal inoculums. Vaccinated and control animals were challenged with virulent L. donovani parasites and the parasitic burden was determined. Only animals vaccinated with alum-BCG adversely reacted to the inoculum by produc- ing ulcerative erythematous skin indurations. Non-parametric ANOVA followed by a post test showed signifi- cantly higher IgG antibodies, and revealed the presence of lymphoproliferative and interferon gamma responses in both AIBCG＋Ag and MISA＋Ag as compared to the MPLA＋Ag or other groups （P 〈 0.001）. We conclude that L. donovani sonicated antigen containing MISA is safe and is associated with protective immune response against Leishmania donovani infection in the vervet monkey model.

Anti-leishmanial,immunomodulatory and anti-oxidative activity of quercetin against cutaneous leishmaniasis caused by Leishmania major

Objective:To evaluate the in vitro and in vivo efficacy of quercetin and its immunomodulatory and anti-oxidative activity against Leishmania major(L.major).Methods:L.major promastigotes and amastigotes were incubated with different concentrations of quercetin to estimate EC_(50).For in vivo study,the base of tails of mice was infected with L.major.After developing ulcers in the inoculation site,mice were treated with 50 mg/kg quercetin orally for 28 consecutive days.The wound-healing potential of quercetin was evaluated by histopathological analysis of tissue sections stained by hematoxylin and eosin as well as Masson's trichrome.In addition,the levels of tumor necrosis factor-α,interleukin-6,malondialdehyde,and adiponectin,the ferric reducing ability of plasma,as well as superoxide dismutase and glutathione peroxidase activities were measured.Results:The EC_(50)values of quercetin against L.major promastigotes and intracellular amastigotes were 0.27 and 0.85μM,respectively.Histopathological analysis showed that fewer inflammatory cells,more fibroblasts,and more collagen deposition were observed in tissue sections of quercetin-treated mice.In addition,treatment with quercetin markedly increased glutathione peroxidase activity,the ferric reducing ability of plasma and adiponectin levels while decreasing malondialdehyde,interleukin-6,and tumor necrosis factor-αlevels.Conclusions:Quercetin shows anti-leishmanial activity,immunomodulatory,anti-oxidative,and anti-inflammatory effects.Therefore,it may be further explored as an effective drug in treating leishmaniasis.

Caffeic acid and quercetin exert caspases-independent apoptotic effects on Leishmania major promastigotes, and reactivate the death of infected phagocytes derived from BALB/c mice

Objective: To investigate the leishmanicidal effects of two antioxidants, caffeic acid and quercetin on Leishmania major(L.major) promastigotes in vitro, and their immunomodulatory effects on infected phagocytes derived from susceptible BALB/c mice.Methods: Caffeic acid and quercetin-induced cell death was examined by Pi-Hoechst double staining of L.major promastigotes and MTT assay, in the presence or absence of protease inhibitors in vitro.Caffeic acid or quercetin were administered subcutaneously to BALB/c mice infected with L.major promastigotes through a dorsal air pouch.Nitric oxide and superoxide anion production by phagocytes infiltrating the air pouch and the expression of inducible nitric oxide synthase(i NOS), tumor necrosis factor alpha(TNF-a) and nuclear factor kappa B in the air pouch membrane were therefore evaluated using appropriate methods.Results: Caffeic acid and quercetin displayed a dose-dependent cytotoxic effect against L.major promastigotes, and induced cell death via caspases-independent pathways.In vivo, L.major promastigotes inoculation into air pouch cavity of BALB/c mice leads to a sequential influx of neutrophils(hours), followed by macrophages(days).Results showed that L.major delayed apoptosis of infected neutrophils and macrophages by the cleavage of the nuclear factor kappa B p65^(RelA) subunit, and persisted by inhibiting TNF-a and i NOS expression and reactive oxygen species generation.Caffeic acid or quercetin restored reactive oxygen species production and TNF-a-induced i NOS activity, and abrogate apoptosis delay of infected phagocytes.Conclusions: The leishmanicidal effect of caffeic acid and quercetin on promastigotes and amastigotes, as well as reactivation of infected phagocytes apoptosis, suggested a potential therapeutic role against cutaneous leishmaniasis.

Antileishmanial activities of caffeic acid phenethyl ester loaded PLGA nanoparticles against Leishmania infantum promastigotes and amastigotes in vitro

Objective: To investigate and compare the antileishmanial effects of CAPE and(CAPE)PLGA NPs on Leishmania infantum(L.infantum) promastigotes and amastigotes in vitro,Methods: Efficacies of CAPE,(CAPE)PLGA NPs and free PLGA nanoparticles(NPs) on promastigotes were evaluated using MTT and promastigote count assays,and their anti-amastigote effects were determined via infection index analysis,Griess reaction was also performed to calculate nitric oxide production of macrophages exposed to investigated molecules,Results: It was determined that CAPE and(CAPE)PLGA NPs demonstrated significant inhibitory effects on L.infantum promastigotes and amastigotes,while free NPs did not exhibit any meaningful antileishmanial effectiveness,The IC50 values of CAPE for L.infantum promastigotes and amastigotes were assessed as(51.0±0.8) and(19.0±1.4) μg/m L,respectively(P<0.05),On the other side,it was revealed that(CAPE)PLGA NPs had superior antileishmanial activity on both forms of parasites since its IC50 values for L.infantum promastigotes and amastigotes were(32.0±1.3) and(8.0±0.9) μg/m L,respectively(P<0.05),It was also determined that both agents strongly stimulated nitric oxide production of macrophages,Conclusions: The obtained results show that(CAPE)PLGA NPs have a great potential to be especially used in treatment of visceral leishmaniasis; however,in vivo antileishmanial screening of these molecules should be performed in the near future.

First report on molecular characterization of Leishmania species from cutaneous leishmaniasis patients in southern Khyber Pakhtunkhwa province of Pakistan

Objective: To report presence of Leishmania major in Khyber Pakhtunkhwa of Pakistan, where cutaneous leishmaniasis(CL) is endemic and was thought to be caused by Leishmania tropica only. Methods: Biopsy samples from 432 CL suspected patients were collected from 3 southern districts of Khyber Pakhtunkhwa during years 2011–2016. Microscopy on Giemsa stained slides were done followed by amplification of the ribosomal internal transcribed spacer 1 gene. Results: Leishmania amastigotes were detected by microscopy in 308 of 432 samples(71.3%) while 374 out of 432 samples(86.6%) were positive by ribosomal internal transcribed spacer 1 PCR. Subsequent restriction fragment length polymorphism confirmed Leishmania tropica in 351 and Leishmania major in 6 biopsy samples. Conclusions: This study is the first molecular characterization of Leishmania species in southern Khyber Pakhtunkhwa. It confirmed the previous assumptions that anthroponotic CL is the major CL form present in Khyber Pakhtunkhwa province. Furthermore, this is the first report of Leishmania major from a classical anthroponotic CL endemic focus identified in rural areas of Kohat district in southern Khyber Pakhtunkhwa.

A review of adjuvants forLeishmania vaccine candidates

Over the last decade, there has been a flurry of research on adjuvants for vaccines, and several novel adjuvants are now licensed products or in late stage clinical development. The success of adjuvants in enhancing the immune response to antigens has led many researchers to re-focus their vaccine development programs. Although several vaccine candidates have been tested against leishmaniasis, there is yet no effective vaccine against this parasitic disease. Recent research has documented that efforts to develop effective Leishmania vaccine have been limited due to lack of an appropriate adjuvant. In view of this, this review paper outlines some of the adjuvants that have been used in Leishmania vaccine candidates and cites a few of the responses obtained from these studies. The aim of the present review is to consolidate these findings to facilitate the application of these adjuvants in general and experimental vaccinology.

Disseminated cutaneous leishmaniasis due to Leishmania(Leishmania) amazonensis in human immunodeficiency virus(HIV)-infected patients: A report of two cases

Rationale: Co-infection of human immunodeficiency virus(HIV) and Leishmania spp. has impact on clinical and therapeutic outcomes of leishmaniases. Most studies do not present the identification of Leishmania species causing American tegumentary leishmaniasis in co-infections. In the Americas, Leishmania(L.) Viannia(V.) braziliensis and L.(V.) guyanensis have been identified. Patient concerns: In this study, two cases of American tegumentary leishmaniasis in patients infected with HIV are described. Patients presented several lesions with rapid dissemination and mucosal involvement. Diagnosis: Disseminated cutaneous leishmaniasis caused by L. amazonensis was identified by molecular test. Interventions: The patients were treated with conventional therapies for HIV infection and American tegumentary leishmaniasis. Outcomes: In co-infection, the clinical manifestations are atypical and the treatment response can be impaired. Lessons: These cases show that HIV infection impacts L. amazonensis infection and point to the relevance of identifying Leishmania species, which can lead to a better patient management.

A new approach for development of vaccine against visceral leishmaniasis: Lipophosphoglycan and polyacrylic acid conjugates

Objective: To determine the antileishmanial vaccine effectiveness of lipophosphoglycan(LPG) and polyacrylic acids(PAA) conjugates on in vivo mice models.Methods: LPG molecule was isolated and purified from large-scale Leishmania donovani parasite culture. Protection efficacies of LPG alone, in combination with Freund's adjuvant, in a physical mixture and in conjugate(consisting of various LPG concentrations) with PAA, were comparatively determined by various techniques, such as cultivation with the micro-culture method, assessment of in vitro infection rates of peritoneal macrophages, determination of parasite load in liver with Leishman-Donovan Units, and detection of cytokine responses.Results: Obtained results demonstrated that the highest vaccine-mediated immune protection was provided by LPG-PAA conjugate due to all parameters investigated. According to the Leishman-Donovan Units results, the sharpest decline in parasite load was seen with a ratio of 81.17% when 35 mg LPG containing conjugate was applied. This value was 44.93% for the control group immunized only with LPG. Moreover, decreases in parasite load were 53.37%, 55.2% and 65.8% for the groups immunized with 10 mg LPG containing LPG-PAA conjugate, a physical mixture of the LPG–PAA, and a mixture of LPG + Freund's adjuvant, respectively. Furthermore, cytokine results supported that Th1 mediated protection occurred when mice were immunized with LPG-PAA conjugate.Conclusions: It has been demonstrated in this study that conjugate of LPG and PAA has an antileishmanial vaccine effect against visceral leishmaniasis. In this respect, the present study may lead to new vaccine approaches based on high immunogenic LPG molecule and adjuvant polymers in fighting against Leishmania infection.

B-1 cells modulate the murine macrophage response to Leishmania major infection

AIM To investigate the modulatory effect of B-1 cells on murine peritoneal macrophages infected with Leishmania major(L. major) in vitro.METHODS Peritoneal macrophages obtained from BALB/c andBALB/c XID mice were infected with L. major and cultured in the presence or absence of B-1 cells obtained from wild-type BALB/c mice. Intracellular amastigotes were counted, and interleukin-10(IL-10) production was quantified in the cellular supernatants using an enzymelinked immunosorbent assay. The levels of the lipid mediator prostaglandin E2(PGE2) were determined using a PGE2 enzyme immunoassay kit(Cayman Chemical, Ann Arbor, MI), and the number of lipid bodies was quantified in the cytoplasm of infected macrophages in the presence and absence of B-1 cells. Culturing the cells with selective PGE2-neutralizing drugs inhibited PGE2 production and confirmed the role of this lipid mediator in IL-10 production. In contrast, we demonstrated that B-1 cells derived from IL-10 KO mice did not favor the intracellular growth of L. major.RESULTS We report that B-1 cells promote the growth of L. major amastigotes inside peritoneal murine macrophages. We demonstrated that the modulatory effect was independent of physical contact between the cells, suggesting that soluble factor(s) were released into the cultures. We demonstrated in our co-culture system that B-1 cells trigger IL-10 production by L. major-infected macrophages. Furthermore, the increased secretion of IL-10 was attributed to the presence of the lipid mediator PGE2 in supernatants of L. major-infected macrophages. The presence of B-1 cells also favors the production of lipid bodies by infected macrophages. In contrast, we failed to obtain the same effect on parasite replication inside L. major-infected macrophages when the B-1 cells were isolated from IL-10 knockout mice. CONCLUSION Our results show that elevated levels of PGE2 and IL-10 produced by B-1 cells increase L. major growth, as indicated by the number of parasites in cell cultures.

Leishmania donovani:Immune response and immune evasion with emphasis on PD-1/PDL-1 pathway and role of autophagy

Leishmania donovani is one of the causative agents of visceral leishmaniasis.The immune response against Leishmania depends on CD4^(+)T helper type 1 cells.The immune system is unable to combat Leishmania because the parasite can exert several immune suppressive mechanisms that facilitate escaping the immune responses.One of these mechanisms is the up-regulation of programmed death-1/programmed death ligand-1 pathway which causes T cells to undergo exhaustion.Autophagy is strongly linked to the immune response,with some research indicating that activating autophagy reduces the immune response to some intracellular pathogens,while others indicate that activating autophagy limits the growth of intracellular pathogens.Leishmania was found to subvert the host defense mechanisms for its own persistence,such as Leishmania-induced autophagy modulation.Leishmania was reported to activate autophagy in different studies,thus getting a dual benefit by evading the immune system and simultaneously utilizing the autophagy byproducts as nutrients.In this review,we introduced different immune evasion/suppressive mechanisms used by Leishmania,and different immunotherapies which were developed accordingly.We focused on the programmed death-1/programmed death ligand-1 pathway as well as autophagy with the potential interplay of both mechanisms.