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Understanding the local reactions induced by Loxosceles venoms and their main toxins

Grant number: 20/03718-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2020
Effective date (End): August 31, 2022
Field of knowledge:Biological Sciences - Immunology - Immunochemistry
Principal researcher:Denise Vilarinho Tambourgi
Grantee:Bruna Fernandes Pinto
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling, AP.CEPID

Abstract

Loxoscelism is the clinical condition caused by the bite of spiders of the genus Loxosceles, whose most common symptom is dermonecrosis. Enevnoming by brown spiders can cause more severe symptoms such as intravascular hemolysis, intravascular coagulation and impaired renal function, the main cause of death. Sphingomyelinase D (SMase D) is the key component, present in the venom and responsible for triggering cutaneous and systemic symptoms, acting on the hydrolysis of sphingomyelin and lysophosphatidylcholine. These enzymes are classified into class I and II. Such isoforms differ not only in structure but also in toxic activity, with class I enzymes being more toxic than those of class II. Results of our group demonstrated that the complement system participates in the development of cutaneous loxoscelism through the recruitment of neutrophils, as a consequence of the generation of C5a and the membrane attack complex. Tests in which Complement depletion was promoted showed an important reduction in neutrophil infiltration, although hemorrhage and dissociation of collagen fibers have still been observed. However, it was found that the expression of extracellular matrix metalloproteases, induced by venom sphingomyelinases, is possibly one of the main factors involved in the pathogenesis of cutaneous loxoscelism. The overexpression of MMPs is described in the literature as an important factor in the progression of tumors, Atherosclerosis, Aortic Aneurysms and Asthma, a mong others. All of these aspects make MMPs important therapeutic targets for the development of drugs capable of inhibiting their activities. Several studies have shown that tetracycline and its derivatives have, in addition to microbicidal activity, immunomodulatory properties and inhibitory action on the production of extracellular matrix metalloproteases. Our experiments with human keratinocytes, treated with brown spider venom and tetracycline, demonstrated the ability of this drug to prevent cell death and reduce the secretion of MMPs. In vivo tests with rabbits inoculated with venom or SMase D showed the effectiveness of using tetracycline to control dermonecrotic lesions. This data set allowed our group to start, at the end of 2018, a phase 3 clinical trial, to assess the ability of a tetracycline ointment to control the dermonecrotic lesion produced by the brown spider bite in humans. Given this context, the objective of the present study is to analyze the gene expression in human keratinocytes in response to the action of Loxosceles venoms and different classes of SMases D, and their modulation by the use of tetracycline. These analyzes will allow us to identify the differentially expressed genes, signaling pathways (focusing on inflammation, apoptosis, complement activation, ADAMS and MMPs) involved in the development of cutaneous loxoscelism. (AU)

News published in Agência FAPESP Newsletter about the scholarship: