Activation of immune system in pulmonary Paracoccidioidomycosis. Factors of fungus and of the host which influence the severity of the disease

• Grant number: 04/14518-2
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2005
• End date: August 31, 2010
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Vera Lucia Garcia Calich
• Grantee: Vera Lucia Garcia Calich
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Paracoccidioidomycosis (PCM) is the most prevalent deep mycosis in Latin America and presents a wide spectrum of clinical and immunological manifestations. Our group established a genetically controlled murine model of PCM, where A/Sn mice develop an infection which mimics the benign disease (immune responses which favor cellular immunity) and B10.A animals present the progressive disseminated form of PCM (preferential activation of B cells and impairment of cellular immune responses). This pattern of immunological reactivity led us to postulate that the Th1/Th2 paradigm of immune response could be applied to explain the resistant/susceptible patterns in experimental PCM. Cytokines studies, mainly in the pulmonary model of infection, have confirmed that production of IFN-Y, TNF-a and IL-12 are linked with resistance but more complex immunological mechanisms, not Th1/Th2 mediated, are associated with genetic susceptibility to P. brasiliensis infection. We are now proposing further studies in our experimental pulmomary model of PCM. We intend to expand our studies on the influence of some cells and mediators of innate immunity (macrophages, NK cells, nitric oxide, IL-10, leucotrienes, P. brasiliensis lipids, TLR-4, chemokines) in the adaptative immunity and severity of pulmonary PCM. We also intend to further explore the role of TDC8 and TCD4 lymphocytes in the immunoprotection against P. brasiliensis infection. Several approaches, genetic strains of mice as well as immunomanipulations will be used to reach a better comprehension of the immunoprotective mechanisms operating in pulmonary PCM. After i.t. infection with on million yeast cells, mice will be studied regarding the severity of infection in lungs, liver and spleen, production of specific isotypes, delayed hypersensitivity reactions, levels of pulmonary and hepatic cytokines and organs histopathology. In addition, studies on the cellular composition of bronchoalveolar lavage fluids and lung infiltrating lymphocytes will be performed. When required, the activation of these cells will be evaluated by the expression of adhesion and co-stimulatory molecules besides the characterization of its ability to secrete pro - and anti inflammatory mediators. (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)

COSTA, TANIA A.; BAZAN, SILVIA B.; FERIOTTI, CLAUDIA; ARAUJO, ELISEU F.; BASSI, ENIO J.; LOURES, FLAVIO V.; CALICH, VERA L. G.. In Pulmonary Paracoccidioidomycosis IL-10 Deficiency Leads to Increased Immunity and Regressive Infection without Enhancing Tissue Pathology. PLoS Neglected Tropical Diseases, v. 7, n. 10, OCT 2013. (04/14518-2, 11/51258-2)

FERIOTTI, CLAUDIA; LOURES, FLAVIO V.; DE ARAUJO, ELISEU FRANK; DA COSTA, TANIA ALVES; CALICH, VERA L. G.. Mannosyl-Recognizing Receptors Induce an M1-Like Phenotype in Macrophages of Susceptible Mice but an M2-Like Phenotype in Mice Resistant to a Fungal Infection. PLoS One, v. 8, n. 1, JAN 30 2013. (04/14518-2)

BERNARDINO, SIMONE; PINA, ADRIANA; FELONATO, MAIRA; COSTA, TANIA A.; DE ARAUJO, ELISEU FRANK; FERIOTTI, CLAUDIA; BAZAN, SILVIA BOSCHI; KELLER, ALEXANDRE C.; LEITE, KATIA R. M.; CALICH, VERA L. G.. TNF-alpha and CD8(+) T Cells Mediate the Beneficial Effects of Nitric Oxide Synthase-2 Deficiency in Pulmonary Paracoccidioidomycosis. PLoS Neglected Tropical Diseases, v. 7, n. 8, AUG 2013. (04/14518-2, 11/51258-2)