8^th Molecular Immunology & Immunogenetics Congress

Biography

Biography: Dhêmerson Souza de Lima

Abstract

Statement of the Problem: Tuberculosis (TB) is still a major public health problem worldwide, and it is estimated that 1/3 of world population could be latently infected by Mycobacterium spp. Active TB represents a big challenge for treatment due to the natural resistance of bacteria to common antibiotics, and to the emergence of multidrug resistant strains. The development of active disease results from the host inability to effectively counteract the bacteria. In this context, both innate and acquired immunity have been taken in account as important factors for protection against TB. Nod like receptors (NLRs) and the cytoplasmic complex known as inflammasome are responsible for caspase-1 activation and the consequent production of active form of the pro-inflammatory cytokines IL-1ß and IL-18. Experimental models have showed that M. tuberculosis activates NLRP3-inflammasome and IL-1ß production. Aim of this project is to evaluate the contribution of inflammasome in human TB.

Methodology & Theoretical Orientation: The distribution of 14 single polymorphisms (SNPs) in 9 selected inflammasome genes was evaluated in a case/control cohort of Amazon TB patients (allele-specific Taqman assays and qPCR). Inflammasome activation was then analyzed in human peripheral blood monocytes-derived macrophages (MDM) stimulated with M. tuberculosis (BCG or H37Rv) by the meaning of IL-1β and IL-18 production (ELISA), gene expression modulation (gene-specific Taqman assays and qPCR). Experiments were done in the presence of common NLRP3 inflammasome activators (ATP, LPS), or inhibitors (parthenolide).

Conclusion & Significance: Polymorphisms in inflammasome genes contributes to control (NLRP3, CTSB) or development (P2X7) of active pulmonary TB. M. tuberculosis induced dramatic release of IL-1β and IL-18 from MDM, and the increase of NLRP3, IL1B and IL18 genes expression, suggesting that both indirect (through NF-kB) and direct (through caspase-1) activation of inflammasome are involved in the response. Preliminary data showed that this activation is significantly inhibited by parthenolide, confirming the involvement of inflammasome in response to M tuberculosis in human MDM. Associated SNPs positively correlated with IL-1ß and/or IL-18 production in MDM. Further experiments are going on to fully elucidate the contribution of inflammasome in TB.

Figure 1: The SNPs NLRP3 rs10754558 and CTSB rs8898 contribute to protection against the development of active pulmonary TB, however P2X7 rs2230911 is associated to increased susceptibility to active pulmonary TB. Increased activation of NLRP3-inflammasome is beneficial against the development of active pulmonary TB

References:

1. Souza de Lima D, Ogusku M M, Sadahiro A, Pontillo A (2016). Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis. Infection, Genetics and Evolution Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases 41: 240-2445.