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Functional and genetic characterization of dendritic cells from HIV-1 patients stimulated with flagellin

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Edione Cristina dos Reis
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
Defense date:
Examining board members:
Alessandra Pontillo; Renato Santana de Aguiar; Tárcio Teodoro Braga; Telma Miyuki Oshiro Sumida
Advisor: Alessandra Pontillo

NLRP3 inflammasome plays a key role in dendritic cells (DC) activation in response to vaccine adjuvants, however we previously showed that it is not properly activated in DC of HIV&#43 patients (HIV-DC), explaining, at least in part, the poor response to immunization of these patients. Taking in account that several cytoplasmic receptors are able to activate inflammasome, and that bacterial components are considered as a novel and efficient adjuvant, we postulated that bacterial flagellin (FLG), a natural ligand of NAIP/NLRC4 inflammasome, could rescue the activation of the complex in HIV-DC. The aim of this work was evaluate the capacity of FLG to properly activate DC, especially HIV-DC, through the stimulation of inflammasome. For this, healthy donors (HD) and HIV&#43 patients were recruited for peripheral blood monocytes isolation and DC obtainment. DC activation by FLG was evaluated by the meaning of phenotypic profile, cytokines secretion and ability to stimulate CD4&#43T lymphocytes proliferation and IFN-&#947 production. Caspase-1 cleavage, genes expression, NLRP3 and NLRC4 specks formation were analysed to verify inflammasome activation. FLG properly activated HD-DC and HIV-DC, and it was able to stimulate inflammasome activation in both types of cells. Of note FLG induced a higher IL-1&#223 production in HIV-DC compared to LPS. Interestingly, while in HD-DC FLG activated both NLRC4 and NLRP3 specks, in HIV-DC NLRP3 specks resulted significantly diminished reduced. Moreover, NLRC4 and NLRP3 appeared to co-localized in the complex. In conclusion, FLG by-passes NLRP3-inflammasome defect in HIV-DC, through the activation of NAIP/NLRC4, indicating a possible future use of the bacterial component as an efficient adjuvant in immunocompromised individuals. (AU)

FAPESP's process: 15/17373-0 - Genetic and functional characterization of dendritic cells of HIV + patients stimulated with flagellin: implementation of immunotherapy against HIV-1
Grantee:Edione Cristina dos Reis
Support Opportunities: Scholarships in Brazil - Doctorate