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Functional studies of human paracoccidioidomycosis innate immunity as an approach to reveal a new primary immunodeficiency

Grant number: 11/51875-1
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2012
Effective date (End): June 30, 2015
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Antonio Condino Neto
Grantee:Lena Friederike Schimke
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Paracoccidioidomycosis (PCM) is an endemic systemic mycosis in Latin America caused by the fungus Paracoccidioides brasiliensis and clinically characterized by granulomatous lesions, primarily manifesting in the lungs and further disseminating to other organs, such as skin, mucosa and lymph nodes. However, there are individuals infected with P. brasiliensis who never develop the disease and the underlying mechanisms responsible for susceptibility or resistance remain to be clarified. Furthermore, the variation of disease outcome and host-pathogen interactions suggest a genetic predisposition leading to specific immune dysfunction against P. brasiliensis resulting in the development of PCM in some individuals. To date, the monogenic cause of over 100 well described primary immunodeficiencies (PID) is known leading to a better understanding about immune mechanisms of susceptibility to different fungal pathogens. Usually patients with PID reveal susceptibility to a variety of pathogens including fungi. In addition, the association of monogenic defects with Mendelian Susceptibility to Mycobacterial Disease or Chronic Mucocutaneous Candidiasis indicate that inborn defects of immunity can also result in susceptibility restricted to specific pathogens. Although PCM has not been commonly associated with PID, the first two patients with well described PIDs and PCM were described in Brazil: one with deficiency in the beta-1 subunit of the 11L-12/IL-23 receptor and another with CD40L. Neutrophil abnormalities were found in the latter in an ongoing project in our laboratory (FAPESP, 2006/52483-1, 2008/58800-4). This prompted us to further investigate defects in innate immunity and related innate immune responses in patients with PCM. Our aim to advance the knowledge about host defense mechanisms against this fungus may reveal novel mutations in genes associated with PIDs or uncover additional genes associated with susceptibility to PCM as a consequence of a Mendelian Susceptibility to Paraccoccidiodomycosis Disease (MSPD). (AU)