Add leptospirosis

references_cache/DOI_10.1128_iai.00419-24.md

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+---
+reference_id: "DOI:10.1128/iai.00419-24"
+title: "Unveiling the impact of
+            <i>Leptospira</i>
+            TolC efflux protein on host tissue adherence, complement evasion, and diagnostic potential"
+authors:
+- Saswat Hota
+- Manish Kumar
+journal: Infection and Immunity
+year: '2024'
+doi: 10.1128/iai.00419-24
+content_type: abstract_only
+---
+
+# Unveiling the impact of
+            <i>Leptospira</i>
+            TolC efflux protein on host tissue adherence, complement evasion, and diagnostic potential
+**Authors:** Saswat Hota, Manish Kumar
+**Journal:** Infection and Immunity (2024)
+**DOI:** [10.1128/iai.00419-24](https://doi.org/10.1128/iai.00419-24)
+
+## Content
+
+ABSTRACT
+
+
+
+              The TolC family protein of
+              Leptospira
+              is a type I outer membrane efflux protein. Phylogenetic analysis revealed significant sequence conservation among pathogenic
+              Leptospira
+              species (83%–98% identity) compared with intermediate and saprophytic species. Structural modeling indicated a composition of six β-strands and 10 α-helices arranged in two repeats, resembling bacterial outer membrane efflux proteins. Recombinant TolC (rTolC), expressed in a heterologous host and purified via Ni-NTA chromatography, maintained its secondary structural integrity, as verified by circular dichroism spectroscopy. Polyclonal antibodies against rTolC detected native TolC expression in pathogenic
+              Leptospira
+              but not in nonpathogenic ones. Immunoassays and detergent fractionation assays indicated surface localization of TolC. The rTolC’s recognition by sera from leptospirosis-infected hosts across species suggests its utility as a diagnostic marker. Notably, rTolC demonstrated binding affinity for various extracellular matrix components, including collagen and chondroitin sulfate A, as well as plasma proteins such as factor H, C3b, and plasminogen, indicating potential roles in tissue adhesion and immune evasion. Functional assays demonstrated that rTolC-bound FH retained cofactor activity for C3b cleavage, highlighting TolC’s role in complement regulation. The rTolC protein inhibited both the alternative and the classical pathway-mediated membrane attack complex (MAC) deposition
+              in vitro
+              . Blocking surface-expressed TolC on leptospires using specific antibodies reduced FH acquisition by
+              Leptospira
+              and increased MAC deposition on the spirochete. These findings indicate that TolC contributes to leptospiral virulence by promoting host tissue colonization and evading the immune response, presenting it as a potential target for diagnostic and therapeutic strategies.

references_cache/DOI_10.1128_mbio.01906-24.md

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+---
+reference_id: "DOI:10.1128/mbio.01906-24"
+title: "Gut microbiota-derived butyrate improved acute leptospirosis in hamster
+            <i>via</i>
+            promoting macrophage ROS mediated by HDAC3 inhibition"
+authors:
+- Xi Chen
+- Xufeng Xie
+- Ni Sun
+- Xin Liu
+- Jiuxi Liu
+- Wenlong Zhang
+- Yongguo Cao
+journal: mBio
+year: '2024'
+doi: 10.1128/mbio.01906-24
+content_type: abstract_only
+---
+
+# Gut microbiota-derived butyrate improved acute leptospirosis in hamster
+            <i>via</i>
+            promoting macrophage ROS mediated by HDAC3 inhibition
+**Authors:** Xi Chen, Xufeng Xie, Ni Sun, Xin Liu, Jiuxi Liu, Wenlong Zhang, Yongguo Cao
+**Journal:** mBio (2024)
+**DOI:** [10.1128/mbio.01906-24](https://doi.org/10.1128/mbio.01906-24)
+
+## Content
+
+ABSTRACT
+
+
+
+              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.

references_cache/DOI_10.1128_spectrum.03135-22.md

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+---
+reference_id: "DOI:10.1128/spectrum.03135-22"
+title: "Use of an Integrated Multi-Omics Approach To Identify Molecular Mechanisms and Critical Factors Involved in the Pathogenesis of
+            <i>Leptospira</i>"
+authors:
+- Sridhar Kavela
+- Pallavi Vyas
+- Jusail CP
+- Sandeep K. Kushwaha
+- Subeer S. Majumdar
+- Syed M. Faisal
+journal: Microbiology Spectrum
+year: '2023'
+doi: 10.1128/spectrum.03135-22
+content_type: abstract_only
+---
+
+# Use of an Integrated Multi-Omics Approach To Identify Molecular Mechanisms and Critical Factors Involved in the Pathogenesis of
+            <i>Leptospira</i>
+**Authors:** Sridhar Kavela, Pallavi Vyas, Jusail CP, Sandeep K. Kushwaha, Subeer S. Majumdar, Syed M. Faisal
+**Journal:** Microbiology Spectrum (2023)
+**DOI:** [10.1128/spectrum.03135-22](https://doi.org/10.1128/spectrum.03135-22)
+
+## Content
+
+Leptospirosis is a zoonotic disease of global importance. It is caused by a Gram-negative bacterial spirochete of the genus
+            Leptospira
+            .

references_cache/DOI_10.1371_journal.pntd.0012449.md

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+---
+reference_id: "DOI:10.1371/journal.pntd.0012449"
+title: "Clinical presentation of human leptospirosis in febrile patients: Urabá, Colombia"
+authors:
+- Pablo Uribe-Restrepo
+- Janeth Perez-Garcia
+- Margarita Arboleda
+- Claudia Munoz-Zanzi
+- Piedad Agudelo-Florez
+journal: PLOS Neglected Tropical Diseases
+year: '2024'
+doi: 10.1371/journal.pntd.0012449
+content_type: abstract_only
+---
+
+# Clinical presentation of human leptospirosis in febrile patients: Urabá, Colombia
+**Authors:** Pablo Uribe-Restrepo, Janeth Perez-Garcia, Margarita Arboleda, Claudia Munoz-Zanzi, Piedad Agudelo-Florez
+**Journal:** PLOS Neglected Tropical Diseases (2024)
+**DOI:** [10.1371/journal.pntd.0012449](https://doi.org/10.1371/journal.pntd.0012449)
+
+## Content
+
+Background
+Leptospirosis is responsible for various clinical syndromes, classically linked with fever and acute kidney injury.
+
+
+Methodology/Principal findings
+A prospective multicenter observational study was conducted in six health institutions in the region of Urabá, Colombia. Enrollment was based on leptospirosis-compatible clinical syndrome and a positive preliminary serological test, with PCR used to confirm the disease. Clinical data were collected using a standard questionnaire at enrollment, complemented with a review of clinical records. A total of 100 patients were enrolled, 37% (95% CI 27.0–46.9%) had a positive PCR result confirming acute leptospirosis. The most frequent symptoms in patients with a positive PCR test were headache (91.9%; 34/37), chills and sweating (80.6%; 29/37), nausea (75%; 27/37), dizziness (74.3%; 26/37), vomiting (61.1%; 22/37), congestion (56.8%; 21/37), and conjunctival suffusion (51.4%; 19/37). The frequency of clinical signs classically described in leptospirosis was low: jaundice (8.3%; 3/36) and anuria/oliguria (21.6%; 8/37). An increased neutrophile percentage was reported in 60.6% (20/33) of patients. The presence of complications was 21.6% (8/37), with pulmonary complications being the most frequent (75.0% 6/8). One confirmed case died resulting in a fatality of 2.7% (95% CI 0.5–13.8).
+
+
+Conclusions/Significance
+Leptospirosis should be considered within the differential diagnoses of an undifferentiated acute febrile syndrome. Leptospirosis presents diagnostic challenges due to limitations in both clinical and laboratory diagnosis thus it is important to improve understanding of disease presentation and identify signs and symptoms that might help differentiate it from other causes of febrile illness.

references_cache/DOI_10.1371_journal.pone.0312466.md

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+---
+reference_id: "DOI:10.1371/journal.pone.0312466"
+title: "Role of Toll-like receptor 2 during infection of Leptospira spp: A systematic review"
+authors:
+- Chamila Kappagoda
+- Indika Senavirathna
+- Thilini Agampodi
+- Suneth Buddhika Agampodi
+journal: PLOS ONE
+year: '2024'
+doi: 10.1371/journal.pone.0312466
+content_type: abstract_only
+---
+
+# Role of Toll-like receptor 2 during infection of Leptospira spp: A systematic review
+**Authors:** Chamila Kappagoda, Indika Senavirathna, Thilini Agampodi, Suneth Buddhika Agampodi
+**Journal:** PLOS ONE (2024)
+**DOI:** [10.1371/journal.pone.0312466](https://doi.org/10.1371/journal.pone.0312466)
+
+## Content
+
+The involvement of Toll-like receptor 2 (TLR2) in leptospirosis is poorly understood. Our systematic review examined its role across in-vitro, in-vivo, ex-vivo, and human studies. Original articles published in English up to January 2024, exploring the role of TLR2 during leptospirosis, were selected from databases including PubMed, Web of Science, Scopus, Trip, and Google Scholar. Cochrane guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed by this systematic review. The National Institute of Health Quality Assessment tool, Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool, and Office of Health Assessment and Translation extended tool were used to assess the risk of bias of the studies. Out of 2458 studies retrieved, 35 were selected for the systematic review. These comprised 3 human, 17 in-vitro, 5 in-vivo, 3 ex-vivo, and 7 studies with combined experimental models. We assessed the direct TLR2 expression and indirect TLR2 involvement via the secretion/mRNA expression of immune effectors during leptospirosis. Notably, we observed the secretion/mRNA expression of several cytokines (IL6, IL8, IL-1β, TNFα, IFNγ, IL10, CCL2/MCP-1, CCL10, COX2, CXCL1/KC, CXCL2/MIP2) and immune effectors (hBD2, iNOS, Fibronectin, Oxygen, and Nitrogen reactive species) as key aspects of host TLR2 responses during leptospirosis. Even though increased TLR2 expression in in-vivo and in-vitro studies was evident, human studies reported mixed results showing that the postulated effect of TLR2 response based on other studies may not be valid for human leptospirosis. Besides the role of TLR2 in response to leptospirosis, the involvement of TLR4 and TLR5 was identified in in-vitro and in-vivo studies. TLR2 expression is inconclusive during human leptospirosis and further studies are needed to examine the immune effector regulation, through TLR2 for mitigating the harmful effects and promoting effective immune responses.

references_cache/DOI_10.3138_jammi-2023-0033.md

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+---
+reference_id: "DOI:10.3138/jammi-2023-0033"
+title: "Extracorporeal life support for severe leptospirosis: Case series and narrative review"
+authors:
+- Lazar Milovanovic
+- Gurmeet Singh
+- Derek Townsend
+- Jayan Nagendran
+- Wendy Sligl
+journal: Journal of the Association of Medical Microbiology and Infectious Disease Canada
+year: '2024'
+doi: 10.3138/jammi-2023-0033
+content_type: abstract_only
+---
+
+# Extracorporeal life support for severe leptospirosis: Case series and narrative review
+**Authors:** Lazar Milovanovic, Gurmeet Singh, Derek Townsend, Jayan Nagendran, Wendy Sligl
+**Journal:** Journal of the Association of Medical Microbiology and Infectious Disease Canada (2024)
+**DOI:** [10.3138/jammi-2023-0033](https://doi.org/10.3138/jammi-2023-0033)
+
+## Content
+
+Introduction: Leptospirosis can be associated with multi-system organ failure (MSOF) and significant morbidity and mortality. Extracorporeal life support (ECLS) has been used as salvage therapy for severe leptospirosis complicated by acute respiratory distress syndrome (ARDS). Current knowledge in this field is limited, with no standardized treatment approaches. We aim to describe the literature to date on the use of ECLS in patients with leptospirosis, highlighting associations, outcomes, and complications. Methods: We report on the successful use of ECLS in two cases of severe leptospirosis and conduct a narrative review of the literature. Using a search strategy developed in consultation with a medical librarian and validated across pre-selected articles, several databases were searched. We included case reports, case series, cohort studies, and prospective studies of adult patients with confirmed leptospirosis undergoing ECLS. Editorials, surveys, or opinion articles without primary patient data were excluded. Overall mortality was our primary outcome. Results: Two cases of previously healthy males presenting with ARDS due to leptospiral infection are described. Literature review identified 25 articles containing 43 reported cases of patients treated with ECLS for severe leptospirosis. Patients were mostly young and male. Overall mortality was 16%. The most common complication recognized was acute renal failure requiring renal replacement therapy. Additional complications included diffuse intravascular coagulation, necrotizing pancreatitis, and limb ischemia. Conclusion: Leptospirosis should be considered in patients with epidemiologic exposure(s) presenting with critical illness, including ARDS and MSOF. ECLS is a viable rescue strategy in severe leptospirosis, even with established MSOF.

references_cache/DOI_10.3389_fmicb.2023.1199660.md

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+---
+reference_id: "DOI:10.3389/fmicb.2023.1199660"
+title: "Evaluation of Leptospira interrogans knockdown mutants for LipL32, LipL41, LipL21, and OmpL1 proteins"
+authors:
+- Luis G. V. Fernandes
+- Aline F. Teixeira
+- Ana L. T. O. Nascimento
+journal: Frontiers in Microbiology
+year: '2023'
+doi: 10.3389/fmicb.2023.1199660
+content_type: abstract_only
+---
+
+# Evaluation of Leptospira interrogans knockdown mutants for LipL32, LipL41, LipL21, and OmpL1 proteins
+**Authors:** Luis G. V. Fernandes, Aline F. Teixeira, Ana L. T. O. Nascimento
+**Journal:** Frontiers in Microbiology (2023)
+**DOI:** [10.3389/fmicb.2023.1199660](https://doi.org/10.3389/fmicb.2023.1199660)
+
+## Content
+
+IntroductionLeptospirosis is a worldwide zoonosis caused by pathogenic and virulent species of the genus Leptospira, whose pathophysiology and virulence factors remain widely unexplored. Recently, the application of CRISPR interference (CRISPRi) has allowed the specific and rapid gene silencing of major leptospiral proteins, favoring the elucidation of their role in bacterial basic biology, host-pathogen interaction and virulence. Episomally expressed dead Cas9 from the Streptococcus pyogenes CRISPR/Cas system (dCas9) and single-guide RNA recognize and block transcription of the target gene by base pairing, dictated by the sequence contained in the 5′ 20-nt sequence of the sgRNA.MethodsIn this work, we tailored plasmids for silencing the major proteins of L. interrogans serovar Copenhageni strain Fiocruz L1-130, namely LipL32, LipL41, LipL21 and OmpL1. Double- and triple-gene silencing by in tandem sgRNA cassettes were also achieved, despite plasmid instability.ResultsOmpL1 silencing resulted in a lethal phenotype, in both L. interrogans and saprophyte L. biflexa, suggesting its essential role in leptospiral biology. Mutants were confirmed and evaluated regarding interaction with host molecules, including extracellular matrix (ECM) and plasma components, and despite the dominant abundance of the studied proteins in the leptospiral membrane, protein silencing mostly resulted in unaltered interactions, either because they intrinsically display low affinity to the molecules assayed or by a compensation mechanism, where other proteins could be upregulated to fill the niche left by protein silencing, a feature previously described for the LipL32 mutant. Evaluation of the mutants in the hamster model confirms the augmented virulence of the LipL32 mutant, as hinted previously. The essential role of LipL21 in acute disease was demonstrated, since the LipL21 knockdown mutants were avirulent in the animal model, and even though mutants could still colonize the kidneys, they were found in markedly lower numbers in the animals' liver. Taking advantage of higher bacterial burden in LipL32 mutant-infected organs, protein silencing was demonstrated in vivo directly in leptospires present in organ homogenates.DiscussionCRISPRi is now a well-established, attractive genetic tool that can be applied for exploring leptospiral virulence factors, leading to the rational for designing more effective subunit or even chimeric recombinant vaccines.

references_cache/DOI_10.3389_fmicb.2024.1403765.md

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+---
+reference_id: "DOI:10.3389/fmicb.2024.1403765"
+title: "Current treatment options for leptospirosis: a mini-review"
+authors:
+- Pavlo Petakh
+- Payam Behzadi
+- Valentyn Oksenych
+- Oleksandr Kamyshnyi
+journal: Frontiers in Microbiology
+year: '2024'
+doi: 10.3389/fmicb.2024.1403765
+content_type: abstract_only
+---
+
+# Current treatment options for leptospirosis: a mini-review
+**Authors:** Pavlo Petakh, Payam Behzadi, Valentyn Oksenych, Oleksandr Kamyshnyi
+**Journal:** Frontiers in Microbiology (2024)
+**DOI:** [10.3389/fmicb.2024.1403765](https://doi.org/10.3389/fmicb.2024.1403765)
+
+## Content
+
+Leptospirosis, one of the most common global zoonotic infections, significantly impacts global human health, infecting more than a million people and causing approximately 60,000 deaths annually. This mini-review explores effective treatment strategies for leptospirosis, considering its epidemiology, clinical manifestations, and current therapeutic approaches. Emphasis is placed on antibiotic therapy, including recommendations for mild and severe cases, as well as the role of probiotics in modulating the gut microbiota. Furthermore, novel treatment options, such as bacteriophages and newly synthesized/natural compounds, are discussed, and the findings are expected to provide insights into promising approaches for combating leptospirosis.