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Evaluation of plasmid DNA vaccine containing the gene of 60kDa heat shock protein from Paracoccidioides brasiliensis as therapy against experimental paracoccidiodomycosis in mice

Abstract

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by fungus Paracoccidioides brasiliensis or P. lutzii. The disease is autochthonous in Latin America, and the highest number of cases occur in Brazil. The disease manifests mainly as a progressive pulmonary infection that is characterized by a chronic granulomatous inflammation and tissue fibrosis. Depending on host and fungal factors, PCM can range from asymptomatic infection to severe disseminated disease. The response of the host to the fungus is dependent on the cellular immune response. Protection is related to a preponderance of the type 1 helper T lymphocytes (Th1), with production of interferon (IFN-) ³ and tumor necrosis factor (TNF-) ±, while the Th2 response, with production of interleukin (IL-) 4, IL-5, IL-10, makes it impossible to control fungal growth, causing active disease and dissemination of the fungus by the organism. Stress proteins (Hsp) are molecules that play a number of physiological roles within the cell, among them the correct folding process of newly synthesized proteins. Thus, when cells are subjected to stressor events, for example, thermal stress, infection, radiation, there is an increase in the production of these Hsp. Although the exact location of Hsp60 in Paracoccidioides spp. has not yet been determined, it is known that in mammals it is located within the mitochondria. When released by mammalian cells, Hsp60 is recognized by the immune system as a sign of cellular injury, which leads to the release of inflammatory mediators, with the presentation of these molecules by the antigen-presenting cells. Hsp60 appears to be important in the course of PCM, since sera from patients infected with Paracoccidioides spp. recognize this protein. Recently, our group showed that treatment of P. brasiliensis-infected mice with Hsp60 from that fungus induced increased fungal load and inflammation. In order to evaluate whether another way of presenting Hsp60 to the immune system could alter the response and be beneficial in the experimental PCM, in this study we will look for another form of induction of immune response against Hsp60, that is, the use of vaccine plasmid cloned with the Hsp60 gene from P. brasiliensis (pVAX1-tHsp60). To do so, mice will be infected with P. brasiliensis yeasts and, on day 20 after infection, they wiil be treated with pVAX1-tHsp60. To verify if the treatments were beneficial, test animals and controls will be analyzed for fungal load, inflammatory conditions and production of cytokines. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FABRÍCIO FREITAS FERNANDES; NAYLA S. PITANGUI; GABRIELA PERON; CLARISSA X. R. VALIM; VÍVIAN M. MAZUCATO; ALINE F. OLIVEIRA; THIAGO A. DA SILVA; MARIA-CRISTINA ROQUE-BARREIRA; ADEMILSON PANUNTO-CASTELO. Expression of Hsp60 and its cell location in Paracoccidioides brasiliensis. Revista do Instituto de Medicina Tropical de São Paulo, v. 62, p. -, 2020. Web of Science Citations: 0.
SOUZA, IGOR EMILIANO L.; FERNANDES, FABRICIO F.; SCHIAVONI, MARIA CRISTINA L.; SILVA, CELIO L.; PANUNTO-CASTELO, ADEMILSON. Therapeutic effect of DNA vaccine encoding the 60-kDa-heat shock protein from Paracoccidoides brasiliensis on experimental paracoccidioidomycosis in mice. Vaccine, v. 37, n. 37, p. 5607-5613, SEP 3 2019. Web of Science Citations: 1.
COSTA, MARCELO VIEIRA; LANDGRAF, TAISE NATALI; CORREA, PRISCILA C.; LEMOS SOUZA, IGOR EMILIANO; FERNANDES, FABRICIO FREITAS; PANUNTO-CASTELO, ADEMILSON. Quantitation of pulmonary fungal burden in Paracoccidioides brasiliensis-infected mice by real-time PCR. Revista do Instituto de Medicina Tropical de São Paulo, v. 61, 2019. Web of Science Citations: 1.

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