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Leptospirosis is a re-emerging worldwide zoonotic disease. Infected patients and animals often exhibit intestinal symptoms. Mounting evidence suggests that host immune responses to bacterial infection are closely associated with intestinal homeostasis. Our previous research has shown that the gut microbiota can protect the host from acute leptospirosis, while the specific bacterial metabolic mediators participating in the pathogenesis remain to be identified. Short-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota that play a role in immune regulation. However, whether SCFAs are the key to protecting the host against leptospirosis and the underlying regulatory mechanisms are unknown. In this study, our results showed that the SCFA butyrate is involved in ameliorating leptospirosis. The depletion of SCFAs by antibiotic cocktail treatment reduced survival time after Leptospira infection while supplementation with butyrate but not acetate or propionate significantly amelioration of leptospirosis. In vitro experiments showed that butyrate treatment enhanced the intracellular bactericidal activity mediated by reactive oxygen species (ROS) production. Mechanistically, butyrate functions as a histone deacetylase 3 inhibitor (HDAC3i) to promote ROS production via monocarboxylate transporter (MCT). The protection of butyrate against acute leptospirosis mediated by ROS was also proven in vivo . Collectively, our data provide evidence that the butyrate-MCT-HDAC3i-ROS signaling axis is a potential therapeutic target for acute leptospirosis. Our work not only interprets the microbial metabolite signaling involved in transkingdom interactions between the host and gut microbiota but also provides a possible target for developing a prevention strategy for acute leptospirosis., Importance: Leptospirosis is a worldwide zoonotic disease caused by Leptospira . An estimated 1 million people are infected with leptospirosis each year. Studies have shown that healthy gut microbiota can protect the host against leptospirosis but the mechanism is not clear. This work elucidated the mechanism of gut microbiota protecting the host against acute leptospirosis. Here, we find that butyrate, a metabolite of gut microbiota, can improve the survival rate of hamsters with leptospirosis by promoting the bactericidal activity of macrophages. Mechanistically, butyrate upregulates reactive oxygen species (ROS) levels after macrophage infection with Leptospira by inhibiting HDAC3. This work confirms the therapeutic potential of butyrate in preventing acute leptospirosis and provides evidence for the benefits of the macrophage-HDAC3i-ROS axis., Competing Interests: The authors declare no conflict of interest.

Leptospirosis is an emerging infectious disease caused by pathogenic Leptospira spp. Humans and some mammals can develop severe forms of leptospirosis accompanied by a dysregulated inflammatory response, which often results in death. The gut microbiota has been increasingly recognized as a vital element in systemic health. However, the precise role of the gut microbiota in severe leptospirosis is still unknown. Here, we aimed to explore the function and potential mechanisms of the gut microbiota in a hamster model of severe leptospirosis. Our study showed that leptospires were able to multiply in the intestine, cause pathological injury, and induce intestinal and systemic inflammatory responses. 16S rRNA gene sequencing analysis revealed that Leptospira infection changed the composition of the gut microbiota of hamsters with an expansion of Proteobacteria. In addition, gut barrier permeability was increased after infection, as reflected by a decrease in the expression of tight junctions. Translocated Proteobacteria were found in the intestinal epithelium of moribund hamsters, as determined by fluorescence in situ hybridization, with elevated lipopolysaccharide (LPS) levels in the serum. Moreover, gut microbiota depletion reduced the survival time, increased the leptospiral load, and promoted the expression of proinflammatory cytokines after Leptospira infection. Intriguingly, fecal filtration and serum from moribund hamsters both increased the transcription of TNF-α , IL-1β , IL-10 , and TLR4 in macrophages compared with those from uninfected hamsters. These stimulating activities were inhibited by LPS neutralization using polymyxin B. Based on our findings, we identified an LPS neutralization therapy that significantly improved the survival rates in severe leptospirosis when used in combination with antibiotic therapy or polyclonal antibody therapy. In conclusion, our study not only uncovers the role of the gut microbiota in severe leptospirosis but also provides a therapeutic strategy for severe leptospirosis., Competing Interests: XX, XC, SZ, JL, WZ, YC No competing interests declared, (© 2024, Xie et al.)

Leptospirosis, a globally significant zoonotic disease caused by pathogenic Leptospira, continues to threaten the health and public safety of both humans and animals. Current clinical treatment of leptospirosis mainly relies on antibiotics but their efficacy in severe cases is controversial. Passive immunization has a protective effect in the treatment of infectious diseases. In addition, chicken egg yolk antibody (IgY) has gained increasing attention as a safe passive immunization agent. This study aimed to investigate whether hens produce specific IgY after immunization with inactivated Leptospira and the protective effect of specific IgY against leptospirosis. First, it was demonstrated that specific IgY could be extracted from the eggs of hens vaccinated with inactivated Leptospira and that specific IgY can specifically recognize and bind homotypic Leptospira with a high titre, as shown by MAT and ELISA. Next, we tested the therapeutic effects of IgY in early and late leptospirosis using a hamster model. The results showed that early specific IgY treatment increased the survival rate of hamsters to 100%, alleviated pathological damage to the liver, kidney, and lung, reduced leptospiral burden, and restored haematological indices as well as functional indicators of the liver and kidney. The therapeutic effect of early specific IgY was comparable to that of doxycycline. Late IgY treatment also enhanced the survival rate of hamsters and improved the symptoms of leptospirosis similar to early IgY treatment. However, the therapeutic effect of late IgY treatment was better when combined with doxycycline. Furthermore, no Leptospira colonization was observed in the kidneys, livers, or lungs of the surviving hamsters treated with specific IgY. Mechanistically, IgY was found to inhibit the growth and adhesion to cells of Leptospira. In conclusion, passive immunotherapy with specific IgY can be considered an effective treatment for leptospirosis, and may replace antibiotics regarding its therapeutic effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Leptospirosis, caused by pathogenic leptospira, is a neglected infectious disease that causes acute kidney injury, bleeding disorders, and even death. People can become infected with leptospirosis when they travel into epidemic areas. Except for vaccines and antibiotics, there are few reports of other drugs about prevention of leptospirosis. In this study, we show that the natural molecular compound, astragalus polysaccharides (APS), prevents against acute leptospirosis in hamsters. Pretreatment with APS improved the survival rate of hamsters with more minor organ damage and lower leptospira burden. After pretreatment with APS, the expression levels of leptospira-induced TLR2, TLR4, and TNF-α were enhanced. The priming effect of APS was studied in vitro. The data showed that leptospira-induced expressions of TNF-α and IL-1β were higher in APS-primed peritoneal macrophage, with enhanced glucose consumption and lactate production. Transcriptomic analysis revealed that pretreatment with APS down regulated respiratory chain and mitochondrial function, up regulated glycolysis related gene expressions. After pretreatment with glycolysis inhibitor (2-DG), the priming effect of APS in leptospira infection was inhibited. Our results indicated that pretreatment with natural molecular compound, APS, protected against acute leptospirosis in hamsters by priming effect through enhanced glycolysis., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Leptospirosis is a re-emerging zoonotic disease worldwide. Intestinal bleeding is a common but neglected symptom in severe leptospirosis. The regulatory mechanism of the gut microbiota on leptospirosis is still unclear. In this study, we found that Leptospira interrogans infection changed the composition of the gut microbiota in mice. Weight loss and an increased leptospiral load in organs were observed in the gut microbiota-depleted mice compared with those in the control mice. Moreover, fecal microbiota transplantation (FMT) to the microbiota-depleted mice reversed these effects. The phagocytosis response and inflammatory response in bone marrow-derived macrophages and thioglycolate-induced peritoneal macrophages were diminished in the microbiota-depleted mice after infection. However, the phagocytosis response and inflammatory response in resident peritoneal macrophage were not affected in the microbiota-depleted mice after infection. The diminished macrophage disappearance reaction (bacterial entry into the peritoneum acutely induced macrophage adherence to form local clots and out of the fluid phase) led to an increased leptospiral load in the peritoneal cavity in the microbiota-depleted mice. In addition, the impaired capacity of macrophages to clear leptospires increased leptospiral dissemination in Leptospira-infected microbiota-depleted mice. Our study identified the microbiota as an endogenous defense against L. interrogans infection. Modulating the structure and function of the gut microbiota may provide new individualized preventative strategies for the control of leptospirosis and related spirochetal infections., (© 2021. The Author(s), under exclusive licence to International Society for Microbial Ecology.)

Leptospirosis is a global zoonotic disease with outcomes ranging from subclinical infection to fatal Weil's syndrome. In addition to antibiotics, some immune activators have shown protective effects against leptospirosis. However, the unclear relationship between Leptospira and cytokines has limited the development of antileptospiral immunomodulators. In this study, the particular role of interleukin-10 (IL-10) in leptospirosis was explored by using IL-10-defective (IL-10 -/- ) hamsters. After Leptospira infection, an improved survival rate, reduced leptospiral burden, and alleviation of organ lesions were found in IL-10 -/- hamsters compared with wild-type (WT) hamsters. In addition, the levels of expression of the IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) genes and the level of nitric oxide (NO) were higher in IL-10 -/- hamsters than in WT hamsters. Our results indicate that IL-10 deficiency protects hamsters from Leptospira infection.

Leptospirosis, caused by pathogenic Leptospira species, is an essential but neglected zoonosis. There are more than 300 serovars of pathogenic Leptospira, while inactivated bacteria offers only short-term serovar-specific protection. Leptospirosis treatment is mainly dependent on the use of antibiotics. However, the side effects of antibiotics and the risk of antibiotic resistance remain major problems. Thus, alternative agents which are fewer side effects on humans and efficient in leptospirosis would be welcome. Many studies have reported that polysaccharides could be used as immunostimulants in treating infection and cancer. In this study, we examined the protective effect of polysaccharides isolated from Iris against leptospirosis. To our knowledge, it is the first time to report Iris polysaccharides (IP) as an immunostimulant in treating infection. The results showed that IP treatment significantly increased the survival rate of hamsters challenged by a lethal dose of leptospires. Besides, the tissue injury and leptospiral load were reduced in IP-treated infection group compared with the untreated infection group at 4 days post-infection (p.i.). Intriguingly, IP treatment sustained intense immune response at 4 days p.i. analyzed by qPCR. The results exhibited that the gene expression of TLR2 and TLR4 was significantly increased in the group coinjected with IP and leptospires than in the infected controls. And the expression of IL-1β and TNF-α were also up-regulated after IP treatment, except the expression of IL-1β in the kidney. Our results not only broaden the medicinal value of Iris, but also provide a competent candidate for the control of Leptospira infection., (Copyright © 2021. Published by Elsevier Ltd.)

Leptospirosis is an important global zoonosis caused by pathogenic Leptospira. It is estimated that more than 1 million people are infected by Leptospira each year, and the death toll is about 60,000. Some studies showed that delayed immune response was associated with severe leptospirosis, and TLR4 was very important in the control of leptospirosis. In this study, we aimed to explore the effect of the classical activator (LPS) of TLR4 on leptospirosis in susceptible and resistant hosts. The results showed that LPS pretreatment increased the survival rate of hamsters to 80%. And LPS pre-treatment also significantly reduced the leptospiral load and alleviated the pathological injury in organs of hamsters and mice. The result detected by ELISA in mice showed that the levels of TNF-α and IL-1β were increased in the LPS-treated group compared to the control group before infection. However, two days after infection, the level of cytokines in LPS group was down-regulated compared with that in control group. In addition, in vitro results showed that LPS pre-treatment enhanced the phagocytosis and bactericidal ability of macrophages on Leptospira. Collectively, our results indicated that the pre-activated immune response induced by LPS enhanced the ability of host against leptospirosis., Competing Interests: The authors have declared that no competing interests exist.

Leptospirosis is a worldwide zoonotic disease that causes acute kidney injury, liver disease, bleeding disorders, and even death. Treatment of the disease is largely dependent on the use of antibiotics, but recent studies on pathogenesis of leptospirosis have shown that immunomodulation may also be an effective treatment for this disease. Since the delay in inflammation correlates with higher pathogenicity of leptospira, we studied the effect of inducing inflammation on leptospirosis by using TLR4 activator LPS. In accordance with our hypothesis, treatment with LPS protected against leptospirosis by enhancing the inflammatory response in hamsters. The gene expression levels of TLR2, TLR4, NLRP3 and inflammatory factors were higher in LPS-treated group during leptospira infection in hamsters. Although the levels of NO and iNOS were higher in LPS-treated group than in Leptospira-infected group, the protective effect induced by LPS is iNOS-independent. Treatment with LPS induced higher anti-leptospira IgG level than infection with leptospira alone. Then, expressions of costimulatory molecules and maturation markers were analysed. The data showed that treatment with LPS enhanced the expression of CD40, CD80 and CD86. Our results indicate that increased inflammation induced by LPS derived from Escherichia coli ( E. coli ) protects against leptospirosis in hamsters.

Leptospirosis, caused by pathogenic Leptospira species, has emerged as an important neglected zoonotic disease. Few studies have reported the preventable effects of immunoregulators, except for antibiotics, against leptospirosis. Generally, immunostimulatory agents are considered effective for enhancing innate immune responses. Many studies have found that beta-glucan (β-glucan) could be a potent and valuable immunostimulant for improving immune responses and controlling diseases. In this study, we investigated the preventable role of β-glucan against Leptospira infection in hamsters. First, β-glucan was administered 24 h prior to, during and after infection. The results showed that β-glucan increased the survival rate to 100%, alleviated tissue injury, and decreased leptospire loads in target organs. Additionally, we found using quantitative real-time PCR that application of β-glucan significantly enhanced the expression of Toll-like receptor (TLR) 2, interleukin (IL)-1β and iNOS at 2 dpi (days post infection) and reduced the increase of TLR2, IL-1β and iNOS induced by Leptospira at 5 dpi. Furthermore, to induce memory immunity, β-glucan was administered 5 days prior to infection. β-Glucan also significantly increased the survival rates and ameliorated pathological damage to organs. Moreover, we demonstrated that β-glucan-trained macrophages exhibited elevated expression of proinflammatory cytokines (IL-1β and IL-6) in vitro, indicating that β-glucan induces an enhanced inflammatory response against Leptospira infection. These results indicate that administration of β-glucan and other immunostimulants could be potential valuable options for the control of Leptospira infection., Competing Interests: The authors have declared that no competing interests exist.

Currently, accumulating evidence is challenging subtherapeutic therapy. Low-dose Norfloxacin (Nor) has been reported to suppress the immune response and worsen leptospirosis. In this study, we investigated the influence of low-dose Nor (0.03 μg/ml, 0.06 μg/ml, 0.125 μg/ml) on leptospiral gene expression and analyzed the immunomodulatory effects of low-dose Nor-treated leptospires in J774A.1 cells. To study the expression profiles of low-dose Nor-treated leptospires, we chose LipL71/LipL21 as reference genes determined by the geNorm applet in this experiment. The results showed that low-dose Nor up-regulated the expression of FlaB and inhibited the expression of 16S rRNA, LipL32, LipL41, Loa22, KdpA, and KdpB compared with the untreated leptospires. These results indicated that low-dose Nor could regulate leptospiral gene expression. Using RT-PCR, the gene expression of IL-1β and TNF-α in J774A.1 cells was detected. Nor-treated leptospires induced higher expression levels of both IL-1β and TNF-α. However, when analyzed by ELISA, the release of mature IL-1β was reduced compared with that observed in cells induced with no Nor-treated leptospires, although the TNF-α protein level showed no significant change. Our study indicated that the gene expression of leptospires could be modulated by low-dose Nor, which induced less IL-1β release in J774A.1 cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Antibiotics play an important role in the treatment of leptospirosis. Many antibiotics at appropriate concentrations improved the survival rate and alleviated tissue injury, while, when dosing strategies fall below subtherapeutic levels, worse therapeutic effects are seen. In the present study, we investigated the efficacy of low-dose norfloxacin (10, 20 and 30 mg/kg) and ciprofloxacin (1, 2 and 5 mg/kg) against leptospirosis in a hamster model using Leptospira interrogans serovar Icterohaemorrhagiae. The histopathology and bacterial loads of target organs (liver, kidney and lung) were also studied by treatment with norfloxacin at the dose of 10 mg/kg in this model. Using RT-PCR, the expression of inflammatory factor IL-1β and TNF-α was analyzed by comparing the norfloxacin and untreated group. All untreated animals, serving as a negative control, displayed 50% survival rate, while hamsters treated with norfloxacin at the dose of 10 and 20 mg/kg and ciprofloxacin at the dose of 1 and 2 mg/kg showed a lower survival rate than the untreated group. Furthermore, norfloxacin at the dose of 10 mg/kg increased bacterial loads and aggravated tissue injury of target organs. The delayed induction of IL-1β and TNF-α was found in tissues of norfloxacin group. Our study indicates an increased risk associated with low-dose norfloxacin and ciprofloxacin in leptospirosis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Leptospirosis, caused by Leptospira, is one of the most important of neglected emerging zoonotic diseases that has important impacts on public health worldwide. Polyclonal antibody (pcAb) therapy is a potential method to process a series of pathogens for which there are limited determination of treatment, such as leptospirosis. First, we evaluated the efficacy of pcAb, derived from the sera of rabbits inoculated with Leptospira, against homotype (Leptospira interrogans serovar Lai) or heterotype (Leptospira interrogans serovar Autumnalis) Leptospira infection in a lethal hamster model. The pcAb treatment improved survival compared to the controls. The histopathology's of the infected kidney, liver and lung were also examined by hematoxylin and eosin staining. Using real-time quantitative PCR, we determined that most of the leptospires in the primary organs were almost completely removed by pcAb. In the second experiment, treatments, including antibiotic, pcAb, and combination, were started immediately after occurrence of the first serious sickness mouse in any group. No significant difference in survival rate between pcAb group and antibiotic group was found, but the combination therapy group significantly improved survival rate compared to the others (P<0.05). We conclude that the rabbit pcAb treatment may cure both the homotype and the heterotype lethal Leptospira infections in hamster, and combination therapy improved survival compared to antibiotic group in the late treatment of homotype leptospirosis., Competing Interests: The authors have declared that no competing interests exist.

Leptospirosis, caused by pathogenic spirochetes, is a zoonotic disease of global importance. The detailed pathogenesis of leptospirosis is still unclear, which limits the ideal treatment of leptospirosis. In this study, we analyzed the expression of Toll-like receptor 2 (TLR2) and TLR4 in target organs of both resistant mice and susceptible hamsters after Leptospira interrogans serovar Autumnalis infection. TLR2 but not TLR4 transcripts in mouse organs contrasted with delayed induction and overexpression in hamster organs. Coinjection of leptospires and the TLR2 agonist Pam3CSK4 into hamsters improved their survival rate, alleviated tissue injury, and decreased the abundance of leptospires in target organs. The production of interleukin-10 (IL-10) from tissues was enhanced in hamsters of the group coinjected with leptospires and Pam3CSK4 compared with the leptospira-injected group. Similarly, IL-10 levels in TLR2-deficient mice were lower than those in wild-type mice. A high ratio of IL-10/tumor necrosis factor alpha (TNF-α) levels was found in both infected wild-type mice and hamsters coinjected with leptospires and Pam3CSK4. Moreover, TLR2-dependent IL-10 expression was detected in peritoneal macrophages after leptospira infection. Our data demonstrate that coinjection of leptospires and Pam3CSK4 alleviates the pathology of leptospirosis in hamsters; this effect may result from the enhanced expression of TLR2-dependent IL-10., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Leptospirosis is a re-emerging zoonotic disease that significantly impacts animals and human health worldwide. China has diverse climate types, providing a suitable environment for transmitting and surviving pathogenic Leptospira and its host animals. Despite the substantial reduction in the prevalence of leptospirosis, it continues to be a significant zoonotic disease of public health concern in China. This literature review aimed to provide a concise overview of the current status of leptospirosis in China, the findings from epidemiologic studies on leptospirosis, and the impact of animal and environmental factors on leptospirosis. Leptospirosis is commonly observed in subtropical and tropical cities in China, especially cities with ample water resources in the southern Yangtze River basin. Epidemiologic studies have identified Leptospira interrogans and L. borgpetersenii as the predominant pathogenic species responsible for leptospirosis in China. Leptospira serotypes prevalent in one part of China are related to the serotypes prevalent in the dominant local rodent species and these animals may threaten public health safety as carriers. Given the potential increase in the risk of leptospirosis due to extreme climate change, it is crucial to raise awareness among stakeholders and promote the adoption of a comprehensive approach to prevent and control the continuous transmission and sudden outbreaks of leptospirosis. [ABSTRACT FROM AUTHOR]

Leptospirosis is a significant worldwide zoonotic infectious disease that infects a wide range of animals and humans. Leptospira will colonize the animal's urinary and reproductive systems and be excreted with urine, potentially causing a wide range of infections. Dogs are an essential host for Leptospira, and epidemiological investigation studies of leptospirosis must be conducted to clarify the prevalence of leptospirosis and to reduce the risk of transmission to humans. This study aimed to investigate the seroepidemiology of leptospiral infection in dogs from Changchun, China, using Microscopic Agglutination Test (MAT). A total of 1053 canine blood samples were collected and tested by MAT. The positive rate of MAT was approximately 19.1%. The main prevalent Leptospira serogroups were L. Icterohaemorrhagiae (8.1%), L. Canicola (7.6%), L. Australis (5.3%), L. Ballum (4.7%) and L. Pyrogenes (4.2%). No statistically significant difference among different varieties, sexes and sampling seasons (p > 0.05), except the age (p < 0.05). The seropositive rate was much higher in adult and aged dogs than in juvenile dogs. Our results showed the seroprevalence and the prevalent serogroup of Canine leptospirosis in Changchun, China. [ABSTRACT FROM AUTHOR]

Leptospirosis is a worldwide re-emerging zoonosis caused by pathogenic Leptospira. Inflammatory storms induced by Leptospira are the reason to induce immunoparalysis and organ failures. Antibiotics are still the current mainstream treatment for leptospirosis. In addition to their antibacterial action, the immunomodulatory function of antibiotics has been paid more and more attention. In this study, the role of norfloxacin on Leptospira -induced inflammation was investigated. Treatment with norfloxacin down-regulated Leptospira -induced IL-1β and TNF-α both in vivo and vitro models. Further study showed that norfloxacin inhibited Leptospira -induced phosphorylation of p65 and ERK. Norfloxacin also inhibited the Leptospira -induced NLRP3 inflammasome activation with the increased level of Na/K–ATPase Pump β1 subunit and decreased level of Kcnk6. These results indicated that norfloxacin suppressed Leptospira -induced inflammation through inhibiting p65 and ERK phosphorylation and NLRP3 inflammasome activation. Norfloxacin may be a potential candidate for suppressing inflammatory storms caused by Leptospira. • Nor suppresses Leptospira -induced inflammation. • Nor inhibits the phosphorylation of p65 and ERK during Leptospira infection. • Nor inhibits Leptospira -induced NLRP3 inflammasome activation. • Nor up regulates the expression of Na/Kβ1 subunit, down regulates the expression of Kcnk6 during Leptospira infection. [ABSTRACT FROM AUTHOR]