Viral hepatitis and the immunological response: a review

Introduction: In Brazil, viral hepatitis is infectious disease of compulsory notification and is considered a serious public health problem. Infections with A, B, C, D or E viruses trigger the activation of immune system molecules and cells at the level of innate and acquired immunity. Objective: The present study aimed to review the knowledge about viral hepatitis and the immune system's performance against these infections. Methods: This is a literature overview from academic books and scientific articles available in the Scientific Electronic Library Online, US National Library of Medicine National Institutes of Health and Google Scholar databases. Having as key words hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E and immune system. The relevant articles corresponding to the period between 1974 and 2017 were selected. Development: Viral hepatitis is characterized by inflammation in liver cells caused by groups of viruses that have hepatotropism in common. The diagnosis is made through serological methods and molecular biology techniques. The approach of the immune system in relation to the combat of this infection follows same particularities. Conclusion: This review demonstrated that the determination of the etiologic agent is essential for the conduct to be taken with the infected individual. Moreover, the immune system is directed related to the viruses elimination, presenting some particularities. In addition, this review highlights that the vaccination is the main responsible for reducing people infected by viruses A and B

Partial purification and functional characterization of Ts19 Frag-I, a novel toxin from Tityus serrulatus scorpion venom

Abstract\ud \ud Background\ud The yellow scorpion Tityus serrulatus (Ts) is responsible for the highest number of accidents and the most severe scorpion envenoming in Brazil. Although its venom has been studied since the 1950s, it presents a number of orphan peptides that have not been studied so far. The objective of our research was to isolate and identify the components present in the fractions VIIIA and VIIIB of Ts venom, in order to search for a novel toxin. The major isolated toxins were further investigated for macrophage modulation.\ud \ud \ud Methods\ud The fractions VIIIA and VIIIB, obtained from Ts venom cation exchange chromatography, were rechromatographed on a C18 column (4.6 × 250 mm) followed by a reversed-phase chromatography using another C18 column (2.1 × 250 mm). The main eluted peaks were analyzed by MALDI-TOF and Edman’s degradation and tested on macrophages.\ud \ud \ud Results\ud The previously described toxins Ts2, Ts3-KS, Ts4, Ts8, Ts8 propeptide, Ts19 Frag-II and the novel peptide Ts19 Frag-I were isolated from the fractions VIIIA and VIIIB. Ts19 Frag-I, presenting 58 amino acid residues, a mass of 6,575 Da and a theoretical pI of 8.57, shares high sequence identity with potassium channel toxins (KTx). The toxins Ts4, Ts3-KS and the partially purified Ts19 Frag-I did not produce cytotoxic effects on macrophage murine cells line (J774.1). On the other hand, Ts19 Frag-I induced the release of nitric oxide (NO) by macrophages, while Ts4 and Ts3-KS did not affect the NO production at the tested concentration (50 μg/mL). At the same concentration, Ts19 Frag-I and Ts3-KS increased the production of interleukin-6 (IL-6). Ts19 Frag-I and Ts4 did not induce the release of IL-10, IL-1β or tumor necrosis factor-α by macrophage cells using the tested concentration (50 μg/mL).\ud \ud \ud Conclusions\ud We partially purified and determined the complete sequence and chemical/physical parameters of a new β-KTx, denominated Ts19 Frag-I. The toxins Ts4, Ts3-KS and Ts19 Frag-I showed no cytotoxicity toward macrophages and induced IL-6 release. Ts19 Frag-I also induced the release of NO, suggesting a pro-inflammatory activity.This study received financial support from the from the State of São Paulo\ud Research Foundation (FAPESP – scholarship to FAC n. 2012/13590-8 and\ud MBP n. 2012/12954-6), Coordination for the Improvement of Higher\ud Education Personnel (CAPES – scholarship to PCL), National Council for\ud Scientific and Technological Development (CNPq – grant n. 303689/2013-7)\ud and the Support Nucleus for Research on Animal Toxins (NAP-TOXAN-USP,\ud grant n. 12-125432.1.3). The authors would like to thank Prof. Dr. Norberto\ud Peporine Lopes for providing the MALDI-TOF mass spectrometer used in this\ud study. The authors also acknowledge the biologist Luiz Henrique Anzaloni Pedrosa\ud for extracting the scorpion venom and Iara Aimê Cardoso for technical assistance.\ud Thanks are also due to the Center for the Study of Venoms and Venomous\ud Animals (CEVAP) of UNESP for enabling the publication of this special collection\ud (CNPq process 469660/2014-7)

Pros and cons of different therapeutic antibody formats for recombinant antivenom development.

Antibody technologies are being increasingly applied in the field of toxinology. Fuelled by the many advances in immunology, synthetic biology, and antibody research, different approaches and antibody formats are being investigated for the ability to neutralize animal toxins. These different molecular formats each have their own therapeutic characteristics. In this review, we provide an overview of the advances made in the development of toxin-targeting antibodies, and discuss the benefits and drawbacks of different antibody formats in relation to their ability to neutralize toxins, pharmacokinetic features, propensity to cause adverse reactions, formulation, and expression for research and development (R&D) purposes and large-scale manufacturing. A research trend seems to be emerging towards the use of human antibody formats as well as camelid heavy-domain antibody fragments due to their compatibility with the human immune system, beneficial therapeutic properties, and the ability to manufacture these molecules cost-effectively

Snakebite Clinics and Pathogenesis: From Preclinical to Resource Mapping Studies

Amidst the global healthcare landscape, the menace of snakebite envenoming (SBE) has persisted, silently afflicting millions and annually claiming tens of thousands of lives [...

Revealing the Function and the Structural Model of Ts4: Insights into the “Non-Toxic” Toxin from Tityus serrulatus Venom

The toxin, previously described as a “non-toxic” toxin, was isolated from the scorpion venom of Tityus serrulatus (Ts), responsible for the most severe and the highest number of accidents in Brazil. In this study, the subtype specificity and selectivity of Ts4 was investigated using six mammalian Nav channels (Nav1.2→Nav1.6 and Nav1.8) and two insect Nav channels (DmNav1 and BgNav). The electrophysiological assays showed that Ts4 specifically inhibited the fast inactivation of Nav1.6 channels, the most abundant sodium channel expressed in the adult central nervous system, and can no longer be classified as a “non-toxic peptide”. Based on the results, we could classify the Ts4 as a classical α-toxin. The Ts4 3D-structural model was built based on the solved X-ray Ts1 3D-structure, the major toxin from Ts venom with which it shares high sequence identity (65.57%). The Ts4 model revealed a flattened triangular shape constituted by three-stranded antiparallel β-sheet and one α-helix stabilized by four disulfide bonds. The absence of a Lys in the first amino acid residue of the N-terminal of Ts4 is probably the main responsible for its low toxicity. Other key amino acid residues important to the toxicity of α- and β-toxins are discussed here

A gamut of undiscovered electrophysiological effects produced by Tityus serrulatus toxin 1 on NaV-type isoforms

In the last decades, Ts1 has not only been the subject of many studies, it has also been considered as a very useful tool to investigate NaV channels and to explore the exact role of NaV channels in channelopathies. Ts1 is believed to modulate the activation process of NaV upon interaction at the neurotoxin binding site 4. Our aim was to carry out an in depth functional characterization of Ts1 on a wide array of Nav channels, in order to investigate its mechanism of action and to verify if Ts1 can indeed be considered as a prototype site 4 selective toxin, valid for all the Nav isoforms we know currently. Ts1 has been subjected to an in-depth functional investigation on 9 NaV isoforms expressed in Xenopus laevis oocytes. Ts1 does not only interfere with the activation process but also modulates the inactivation in a bell-shaped voltage-dependent matter. Furthermore, Ts1 altered the ion selectivity through insect NaV. without influencing the tetrodotoxin selectivity of the channels. Finally, Ts1 was also found to inhibit the sodium current through the cardiac Nav1.5 isoform. On the basis of the totally unexpected plethora of Nav modulations as induced by Ts1, we demonstrate that caution is required in interpretation the in vivo experiments when using Ts1. The electrophysiological characterization of Ts1 indeed shows that the general accepted contours of NaV binding sites are much more obscure than believed and that interpretation of NaV pharmacology upon toxin binding is more complex than believed thus far.publisher: Elsevier articletitle: A gamut of undiscovered electrophysiological effects produced by Tityus serrulatus toxin 1 on NaV-type isoforms journaltitle: Neuropharmacology articlelink: http://dx.doi.org/10.1016/j.neuropharm.2015.03.027 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.status: publishe

Fatal Rattlesnake Envenomation in Northernmost Brazilian Amazon: A Case Report and Literature Overview

Snakebite envenomations are classified as Category A Neglected Tropical Diseases by the World Health Organization. In Brazil, 405 snake species are distributed among 11 families, with the genera Bothrops and Crotalus being the most studied and main responsible for severe and lethal envenomations. In the country, Crotalus genus (i.e., rattlesnakes) is represented by Crotalus durissus species, showing seven different subspecies distributed along the country, including Crotalus durissus ruruima, which inhabits Roraima, the Brazilian nothermost state from Amazon forest. Here, we report a fatal case of a severe envenomation following a rattlesnake bite. The patient presented classic crotalic neurological signs and symptoms such as ptosis, drooling of saliva, sluggishness, macroscopic hematuria, and oliguria, which evolved to acute kidney failure (AKF) and hemodynamic instability. Although the patient was treated with the specific antivenom therapy, the severe envenomation resulted in three cardiac arrests and death of the victim in less than 38 h. This study discusses the causes of the patient death, the features of rattlesnake venom-induced AKF, and shows evidences that the Brazilian crotalic antivenom should be improved to treat rattlesnake envenomations caused by C. d. ruruima venom in Roraima state