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      Echis carinatus snake venom metalloprotease-induced toxicities in mice: Therapeutic intervention by a repurposed drug, Tetraethyl thiuram disulfide (Disulfiram)

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          Abstract

          Echis carinatus (EC) is known as saw-scaled viper and it is endemic to the Indian subcontinent. Envenoming by EC represents a major cause of snakebite mortality and morbidity in the Indian subcontinent. Zinc (Zn ++) dependent snake venom metalloproteases (SVMPs) present in Echis carinatus venom (ECV) is well known to cause systemic hemorrhage and coagulopathy in experimental animals. An earlier report has shown that ECV activates neutrophils and releases neutrophil extracellular traps (NETs) that blocks blood vessels leading to severe tissue necrosis. However, the direct involvement of SVMPs in the release of NETs is not clear. Here, we investigated the direct involvement of EC SVMPs in observed pathological symptoms in a preclinical setup using specific Zn ++ metal chelator, Tetraethyl thiuram disulfide (TTD)/disulfiram. TTD potently antagonizes the activity of SVMPs-mediated ECM protein degradation in vitro and skin hemorrhage in mice. In addition, TTD protected mice from ECV-induced footpad tissue necrosis by reduced expression of citrullinated H3 (citH3) and myeloperoxidase (MPO) in footpad tissue. TTD also neutralized ECV-induced systemic hemorrhage and conferred protection against lethality in mice. Moreover, TTD inhibited ECV-induced NETosis in human neutrophils and decreased the expression of peptidyl arginine deiminase (PAD) 4, citH3, MPO, and p-ERK. Further, we demonstrated that ECV-induced NETosis and tissue necrosis are mediated via PAR-1-ERK axis. Overall, our results provide an insight into SVMPs-induced toxicities and the promising protective efficacy of TTD can be extrapolated to treat severe tissue necrosis complementing anti-snake venom (ASV).

          Author summary

          India has highest incidence of deaths due to snakebite in the world. Echis carinatus (EC) is known as saw-scaled viper and its bite causes major mortality and morbidity in the Indian subcontinent. The abundant presence of zinc (Zn ++) metalloproteases in Echis carinatus venom (ECV) is responsible for local tissue necrosis. An earlier report has shown that ECV activates neutrophils and leads to NETosis that blocks blood vessels leading to tissue necrosis. However, the toxin in ECV responsible for NETosis has not addressed. Here we investigated the Echis carinatus venom metalloproteases (ECVMPs) are responsible for NETosis and its associated tissue necrosis using Zn ++ specific chelator, Tetraethyl thiuram disulfide (TTD). TTD inhibited ECVMPs-induced skin hemorrhage and footpad tissue necrosis by reduced expression of citrullinated H3 (citH3) and myeloperoxidase (MPO) in mice footpad tissue. TTD also neutralized ECV-induced systemic hemorrhage and conferred protection against lethality in mice. Moreover, TTD inhibited ECV-induced NETosis in human neutrophils and decreased the expression of p-ERK and NETosis markers. Further, we demonstrated that ECV-induced NETosis and tissue necrosis is mediated via PAR-1-ERK axis. Overall, our results provide an insight into SVMPs-induced toxicities and the promising protective efficacy of TTD can be extrapolated to treat severe tissue necrosis complementing anti-snake venom (ASV).

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          Most cited references72

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          Neutrophil extracellular traps kill bacteria.

          Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.
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            Neutrophil recruitment and function in health and inflammation.

            Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.
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              Protein measurement with the Folin phenol reagent.

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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                2 February 2021
                February 2021
                : 15
                : 2
                : e0008596
                Affiliations
                [1 ] Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, India
                [2 ] The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
                [3 ] Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, Karnataka, India
                Liverpool School of Tropical Medicine, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0003-3177-030X
                https://orcid.org/0000-0002-7818-2460
                https://orcid.org/0000-0002-9735-765X
                https://orcid.org/0000-0001-6506-891X
                https://orcid.org/0000-0003-3284-4163
                Article
                PNTD-D-20-01263
                10.1371/journal.pntd.0008596
                7880489
                33529194
                7e566765-0308-45cf-88e4-24d1608567ef
                © 2021 Rudresha et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 July 2020
                : 3 January 2021
                Page count
                Figures: 7, Tables: 0, Pages: 24
                Funding
                Funded by: University Grants Commission of India
                Award ID: MRP-MAJOR-BIOC-2013-12157
                Award Recipient :
                Funded by: Science and Engineering Research Board, Department of Science and Technology, Government of India
                Award ID: EEQ/2017/000737
                Award Recipient :
                The study was funded by the University Grants Commission of India, a statutory body set up by the Government of India under Ministry of Education (MRP-MAJOR-BIOC-2013-12157 to BSV) and Science and Engineering Research Board, a statutory body under the Department of Science and Technology, Government of India (EEQ/2017/000737 to RR). Funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Necrosis
                Medicine and Health Sciences
                Clinical Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Vascular Medicine
                Hemorrhage
                Biology and Life Sciences
                Toxicology
                Toxic Agents
                Toxins
                Venoms
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxic Agents
                Toxins
                Venoms
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Neutrophils
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Neutrophils
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Neutrophils
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Neutrophils
                Biology and Life Sciences
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Medical Conditions
                Tropical Diseases
                Neglected Tropical Diseases
                Snakebite
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Nucleases
                Deoxyribonucleases
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Hydrolases
                Nucleases
                Deoxyribonucleases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Hydrolases
                Nucleases
                Deoxyribonucleases
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Reptiles
                Squamates
                Snakes
                Biology and Life Sciences
                Zoology
                Animals
                Vertebrates
                Amniotes
                Reptiles
                Squamates
                Snakes
                Custom metadata
                vor-update-to-uncorrected-proof
                2021-02-12
                All relevant data are within the manuscript and its Supporting information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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