BACKGROUND: Currently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive.
METHODS: In this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation.
RESULTS: Compared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid β-oxidation by upregulating key enzymes to maintain lipid homeostasis.
CONCLUSIONS: Our findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL.

This case report summarizes the experience from diagnosis and treatment of a patient with repeated high fever, hepatosplenomegaly and pancytopenia. Following exclusion of bacterial, viral, fungal infections and hematological diseases, metagenomic next-generation sequencing of the patient\'s peripheral blood revealed Leishmania infantum infection, and rK39 rapid diagnostic test showed positive for anti-Leishmania antibody, while microscopic examination of bone marrow smears identified Leishmania amastigotes. Therefore, the case was definitively diagnosed as visceral leishmaniasis, and given anti-infective treatment with sodium antimony gluconate and hormone, hepatoprotection, elevation of white blood cell counts and personalized nursing. Then, the case was cured and discharged from hospital. Metagenomic next-generation sequencing is of great value in etiological detection of fever patients with unknown causes, which deserves widespread clinical applications.
［摘要］ 1 例患者因 “反复高热、肝脾肿大、伴全血细胞减少待查” 收住入院, 排除细菌、病毒、真菌感染及血液系统疾病 后, 采集患者外周血行宏基因组二代测序, 结果显示婴儿利什曼原虫感染。rk39 快速诊断试剂检测显示抗利什曼原虫抗 体阳性, 骨髓涂片检出利什曼原虫无鞭毛体, 最终确诊为内脏利什曼病。给予葡萄糖酸锑钠、激素进行抗感染、保肝、升 白细胞等治疗及个性化护理后, 患者康复出院。宏基因组测序技术在不明原因发热患者病因检测中具有重要价值, 值得 临床推广应用。.

OBJECTIVE: To understand the epidemiological distribution characteristics of mountain-type zoonotic visceral leishmaniasis (MT-ZVL) in Yangquan City, Shanxi Province, China, from 2006 to 2021, to explore the influencing factors leading to the re-emergence of the epidemic, and to provide a basis for the formulation of targeted control strategies.
METHODS: Case information spanning from 2006 to 2021 in Yangquan City was collected for a retrospective case-control study conducted from June to September 2022. A 1:3 matched ratio was employed. A questionnaire was utilized to gather data on basic information, demographic characteristics, awareness of MT-ZVL knowledge, residence, and dog breeding and living habits. The study employed a multifactorial conditional stepwise logistic regression model to analyze the influencing factors.
RESULTS: A total of 508 subjects was analyzed. Risk factors for MT-ZVL included the use of soil/stone/concrete as building materials (OR = 3.932), presence of nearby empty/stone stack houses (OR = 2.515), dog breeding (OR = 4.215), presence of stray dogs (OR = 2.767), and neighbor\'s dog breeding (OR = 1.953). Protective factors comprised knowledge of MT-ZVL (OR = 0.113) and using mosquito repellents (OR = 0.388). The findings indicate significant associations between environmental and behavioral factors and MT-ZVL incidence in Yangquan City, Shanxi Province, China, from 2006 to 2021. These results underscore the importance of public awareness campaigns and targeted interventions aimed at reducing exposure to risk factors and promoting protective measures to mitigate the re-emergence of MT-ZVL outbreaks.
CONCLUSIONS: House building materials, presence of neighboring empty houses, breeding domestic dogs and distribution of stray dogs surrounding the home are risk factors for MT-ZVL. Awareness of MT-ZVL and implementation of preventive measures during outdoor activities in summer and autumn are protective and may reduce the risk of MT-ZVL.

Little is known about the immune response of lizards to Leishmania parasties. In this study, we conducted the first liver transcriptome analysis of two lizards (Phrynocephalus przewalskii and Eremias multiocellata) challenged with L. donovani, endemic to the steppe desert region of northwestern China. Our results revealed that multiple biological processes and immune-related signaling pathways are closely associated with the immune response to experimental L. donovani infection in the two lizards, and that both lizards show similar changes to mammals in terms of immunity to Leishmania. However, the interspecific divergence of the two lizards leads to different transcriptomic changes. In particular, in contrast to P. przewalskii, the challenged E. mutltiocellata was characterized by the induction of down-regulation of most DEGs. These findings will contribute to the scarce resources on lizard immunity and provide a reference for further research on immune mechanisms in reptiles.

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7-15 days) and five days (interquartile range, 3.75-9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases ( P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39 IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH.

Visceral leishmaniasis is a parasitic disease transmitted by Phlebotomus chinensis that poses a great threat to human health. Historically, visceral leishmaniasis was predominantly prevalent in northwestern regions of Sichuan Province. Following the founding of the People\'s Republic of China, large-scale integrated interventions had been implemented in visceral leishmaniasis-endemic areas of Sichuan Province, including identification and treatment of visceral leishmaniasis patients, elimination of infected dogs, Ph. chinensis control and health education. This review summarizes the prevalence of visceral leishmaniasis, discusses the control strategy of visceral leishmaniasis and analyzes the challenges of elimination of visceral leishmaniasis based on the One Health concept in Sichuan Province, so as to provide insights into elimination of visceral leishmaniasis in the province.
［摘要］ 内脏利什曼病是一种由白蛉传播、严重危害人体健康的寄生虫病。四川省内脏利什曼病主要流行于该省西北 部地区, 且历史较久。中华人民共和国成立后, 四川省在内脏利什曼病流行区大规模开展以查治病人、消灭病犬、控制白 蛉等措施为主的综合性防治, 取得了一定成就。本文分析了四川省内脏利什曼病流行现状, 结合全健康理念探讨了四川 省内脏利什曼病防治策略和消除工作所面临的困难与挑战, 以期为四川省内脏利什曼病消除提供参考。.

OBJECTIVE: To construct an evaluation index system for the capability of comprehensive control of mountain-type zoonotic visceral leishmaniasis based on the One Health concept, so as to provide insights into the control and elimination of mountain-type zoonotic visceral leishmaniasis using the One Health approach.
METHODS: A preliminary evaluation index system was constructed based on literature review, panel discussions and field surveys. Thirty-three experts were selected from 7 provincial disease control and prevention centers in Beijing Municipality, Hebei Province, Shanxi Province, Henan Province, Sichuan Province, Shaanxi Province and Gansu Province where mountain-type zoonotic visceral leishmaniasis was endemic, and two rounds of expert consultations were conducted to screen the indicators. The positive coefficient, degree of concentration, degree of coordination, and authority of the experts were calculated, and the normalized weights of each index were calculated with the analytic hierarchy process.
RESULTS: The response rates of questionnaires during two rounds of expert consultation were both 100.00% (33/33), and the authority coefficients of the experts were 0.86 and 0.88, respectively. The coefficients of coordination among experts on the rationality, importance, and operability of the indicators were 0.392, 0.437, 0.258, and 0.364, 0.335, 0.263, respectively (all P values < 0.05). Following screening, the final evaluation index system included 3 primary indicators, 17 secondary indicators, and 50 tertiary indicators. The normalized weights of primary indicators \"external environment\", \"internal support\" and \"comprehensive control\" were 16.98%, 38.73% and 44.29%, respectively. Among the secondary indicators of the primary indicator \"external environment\", the highest weight was seen for natural environment (66.67%), and among the secondary indicators of the primary indicator \"internal support\", the lowest weight was seen for the scientific research for visceral leishmaniasis control (8.26%), while other indicators had weights of 12.42% to 13.38%. Among the secondary indicators of the primary indicator \"comprehensive control\", the weight was 16.67% for each indicator.
CONCLUSIONS: An evaluation index system has been constructed for the capability of comprehensive control of mountain-type zoonotic visceral leishmaniasis based on the One Health concept. In addition to assessment of the effect of conventional mountain-type zoonotic visceral leishmaniasis control measures, this index system integrates the importance of top-level design, organizational management, and implementation of control measures, and includes indicators related to multi-sectoral cooperation.
［摘要］ 目的 基于全健康理念构建犬源型内脏利什曼病 (mountain-type zoonotic visceral leishmaniasis, MT-ZVL) 综合治 理能力评估指标体系, 从全健康的整体视角探索遏制该病疫情回升的切入点, 以促进其控制与消除。方法 在文献分析 基础上, 结合课题组讨论、现场调查等初步构建指标体系。在北京、河北、山西、河南、四川、陕西、甘肃7个MT-ZVL流行 省 (直辖市) 的省级疾病预防控制中心, 选择33名专家开展两轮专家咨询, 对指标进行筛选, 并计算专家积极系数、专家 意见集中程度、专家意见协调程度、专家权威程度, 采用层次分析法计算各指标归一化权重。结果 两轮专家咨询法问 卷回收率均为100.00% (33/33), 专家权威系数分别为0.86和0.88, 指标合理性、重要性、可操作性的专家意见协调系数分 别为0.392、0.437、0.258和0.364、0.335、0.263 (P 均< 0.05)。经过筛选, 最终形成的指标体系包括3个一级指标、17个二 级指标、50个三级指标。“外部环境”、“内部支持”、“综合治理” 3个一级指标归一化权重分别为16.98%、38.73%、44.29%; “外部环境” 的二级指标中, “自然环境” 权重最高 (66.67%); “内部支持” 的二级指标中, “内脏利什曼病防治科学研究” 权 重最低 (8.26%), 其他指标权重在12.42%~13.38%; “综合治理” 的二级指标中, 各指标权重均为16.67%。结论 构建了 基于全健康理念的MT-ZVL综合治理能力评估指标体系。该指标体系在兼顾传统MT-ZVL防治效果评估的同时, 综合考 虑了顶层设计、组织管理和防治措施落实的重要性, 纳入了多部门协作相关指标。.

BACKGROUND: Visceral leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Macrophages serve as the primary host cells for L. donovani, the immune response capability of these host cells is crucial for parasites\' intracellular survival. L. donovani peptidyl-prolyl cis/trans isomerase Cyclophilin A (LdCypA) is a key protein for L. donovani intracellular proliferation, while the molecular mechanism conducive to intracellular survival of parasites remains elusive.
METHODS: In this study, we generated a macrophage cell line overexpressing LdCyPA to investigate its role in controlling host immunity and promoting intracellular immune escape of L. donovani.
RESULTS: It was discovered that the overexpression of the LdCyPA cell line regulated the host immune response following infection by downregulating the proportion of M1-type macrophages, promoting the secretion of the anti-inflammatory factor IL-4, and inhibiting the secretion of pro-inflammatory factors like IL-12, IFN-γ, TNF-α, and INOS. Transcriptome sequencing and mechanistic validation, meanwhile, demonstrated that cells overexpressing LdCyPA controlled the immune responses that followed infection by blocking the phosphorylation of P38 and JNK1/2 proteins in the MAPK signaling pathway and simultaneously increasing the phosphorylation of ERK proteins, which helped the L. donovani escape immune recognition.
CONCLUSIONS: Our findings thus pave the way for the development of host-directed antiparasitic drugs by illuminating the pro-Leishmania survival mechanism of L. donovani cyclophilin A and exposing a novel immune escape strategy for L. donovani that targets host cellular immune regulation.

BACKGROUND: Leishmaniasis is mainly prevalent in tropical and subtropical developing countries, where chronic undernutrition often co-exists. Undernutrition is reported to promote the progression of leishmaniasis, but its immune mechanisms have not been fully elucidated.
METHODS: To simulate chronic undernutrition of patients in epidemic areas and explore the immune mechanism of undernutrition promoting leishmaniasis, BALB/c mouse models with different nutritional imbalances were established, including undernutrition 75%, undernutrition 65% and obesity mouse models. After infection with Leishmania donovani in these model mice, we focused on evaluating the progress of leishmaniasis in the spleen and liver, the expression of important immunosuppressive and immunoactivation molecules, and changes of spleen transcriptome. The immune signaling pathways enriched by differentially expressed genes and hub genes were analyzed.
RESULTS: The results showed that among the mouse infection models, undernutrition 75% + infection group had the highest parasite load in the spleen and liver at the 8th week post-infection, possibly due to the continuous increase of PD-1, PD-L1 and TCR. Spleen RNA-seq results suggested that some immune signaling pathways were downregulated in undernutrition 75% + infection group, including neutrophil extracellular trap formation, IL-17 signaling pathway, natural killer cell-mediated cytotoxicity, etc. Among them, neutrophil extracellular trap formation pathway had the largest number of downregulated genes. This also explained why undernutrition 75% + infection group had the highest parasite load. Through PPI network analysis, hub genes such as Lcn2, Ltf, Mpo, Dnaja1, Hspa1a, Hspa1b and Hsph1 were screened out and might play important roles in the process of undernutrition promoting leishmaniasis.
CONCLUSIONS: Undernutrition upregulated PD-1 and PD-L1 expression and downregulated immune signaling pathways in mice with visceral leishmaniasis. The signaling pathways and hub genes may serve as drug targets or intervention targets for the treatment of leishmaniasis patients with undernutrition.

Visceral leishmaniasis (VL) represents the most severe form of Leishmaniasis infection, often resulting in fatality without timely treatment. Previous studies have found that immunosuppression increases the risk of VL disease progression and mortality, and the total immunoglobulin G (IgG) levels in peripheral blood vary before and after treatment. However, the distinct levels and roles of IgG subclasses in VL have not been documented yet. This study aims to elucidate the characteristics and clinical significance of IgG subclasses in VL.
A total of 43 cases newly-diagnosed with VL were enrolled in the cohort. We measured the levels of IgG subclasses before and after standard treatment and conducted assessments of bone marrow features. In addition, we analysed other haematological indices and examined the variations in IgG subclasses, as well as their correlation with clinical and laboratory factors.
The levels of total IgG, IgG1, and the ratios of both IgG1/IgG and IgG1/IgG2 decreased significantly after treatment, whereas the ratios of IgG2/ IgG showed an obvious increase. The VL patients without hyperglobulinemia displayed significant lower IgG1/IgG2 ratios, but higher IgG2/IgG ratios compared with those with hyperglobulinemia. In addition, VL patients with positive bone marrow amastigotes had significant higher IgG1/IgG and IgG1/IgG2 ratios, but lower IgG2/IgG ratios. IgG subclasses were correlated with abnormal blood test results, particularly immunological elements including IgM and Complement 4 (C4).
IgG1 and IgG2 exhibited contrasting changes after treatment in VL patients. The features of bone marrow and laboratory tests indicated that IgG1 and IgG2 serve different roles in the progression of VL. The ratios of IgG subclasses may be more precise indicators to evaluate immune reaction in VL than traditional total IgG.