Immunomodulatory treatment with thalidomide in experimental leptospirosis in Golden Syrian hamsters (Mesocricetus auratus)

Soares, Luciane Marieta; Macêdo, Juliana Targino Silva Almeida e; Azevedo, Everton Cruz de; Santos, Cleiton Silva; Sampaio, Marina de Queiroz; Santos, Andréia C.; Reis, Mitermayer Galvão dos; Athanazio, Daniel Abensur

doi:10.1093/trstmh/trt112

Cited by 9 publications

(5 citation statements)

References 31 publications

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“…To explore the effect of LPS neutralization on severe leptospirosis, six-week-old male or female hamsters were inoculated intraperitoneally with 10 7 leptospires. Treatments were started immediately after detection of the first death regardless of the assigned group [19]. Group 1: saline control (400 μL/hamster, i.p.…”

Section: Methodsmentioning

confidence: 99%

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Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis

Xie,

Chen,

Zhang

et al. 2024

Preprint

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Leptospirosis is an emerging infectious disease caused by pathogenicLeptospiraspp. 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 thatLeptospirainfection 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 LPS levels in the serum. Moreover, gut microbiota depletion reduced the survival time, increased the leptospiral load, and promoted the expression of proinflammatory cytokines afterLeptospirainfection. Intriguingly, fecal filtration and serum from moribund hamsters both increased the transcription ofTNF-α,IL-1β,IL-10, andTLR4in 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.

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Section: Methodsmentioning

confidence: 99%

“…Treatments were started immediately after detection of the first death regardless of the assigned group [19] . Group 1: saline control (400 μL/hamster, i.p.…”

Section: Experimental Infections Part I Hamster Infectionmentioning

confidence: 99%

Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis

Xie,

Chen,

Zhang

et al. 2024

Preprint

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“…Leptospirosis is tightly associated with inflammatory storms [8]. However, the therapeutic effect of immunosuppressant did not achieve the desired effect [9]. Combined with the gene expression profiles of golden hamsters and mice, we found that after infection with Leptospira, the gene expression of hamster's lags that of tolerant mice [10].…”

Section: Introductionmentioning

confidence: 91%

The pre-activated immune response induced by LPS protects host from leptospirosis

Chen

Xie

et al. 2020

PLoS ONE

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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.

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“…Thus the early inflammatory response is important to resist leptospirosis. That is why some immunosuppressive drugs, such as thalidomide and cyclosporine, fail to cure leptospirosis [8,9]. TLRs acting as pattern recognition receptors (PRRs) can recognize a variety of pathogen-associated molecular patterns (PAMPs) [10].…”

Section: Introductionmentioning

confidence: 99%

Increased inflammation with crude E. coli LPS protects against acute leptospirosis in hamsters

Zhang

Xie

Wang

et al. 2020

Emerging Microbes & Infections

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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.

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Immunomodulatory treatment with thalidomide in experimental leptospirosis in Golden Syrian hamsters (Mesocricetus auratus)

Abstract: Thalidomide had minimal impact on survival in the late treatment of leptospirosis hamster model.

Cited by 9 publications

References 31 publications

Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis

Neutralizing gut-derived lipopolysaccharide as a novel therapeutic strategy for severe leptospirosis

The pre-activated immune response induced by LPS protects host from leptospirosis

Increased inflammation with crude E. coli LPS protects against acute leptospirosis in hamsters

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