Alessandra Pontillo
Universidade de Sao Paulo, Brazil
Title: Genetics of inflammasome: From monogenic rare syndromes to complex diseases
Biography
Biography: Alessandra Pontillo
Abstract
Inflammasomes are cytoplasmic complexes capable of triggering the inflammatory cascade through the activation of caspase-1, and the consequent production of inflammatory cytokines IL-1ß and IL-18. Different inflammasome receptors (NLRP-1, NLRP-3, NLRC-4, AIM-2, IFI-16 and pyrin) are activated by distinct pathogens and/or damage molecular patterns, contributing to innate immune response in a stimulus- and cell/tissue-dependent way. Mouse genetic models have revealed the mechanistic details of inflammasome activation and its role in physiologic immune response, however little is known about the action of inflammasome in humans. Genetic studies within the human population uncover mutations and polymorphic variants in inflammasome components resulting in gain-of-function of caspase-1, and the consequent development of rare monogenic inflammatory diseases (auto-inflammatory syndromes) as well as of complex disorders which common in general population. Our group demonstrated the association of inflammasome genes in different multifactorial diseases. Candidate gene analysis have shown a significant association of inflammasome genes with a wide range of disorders, including infections (HIV-1, HPV and mycobacteria), autoimmune diseases (type-1 diabetes, SLE, celiac disease and multiple sclerosis), neurodegenerative disorders (Alzheimer and Parkinson disease), cancer (melanoma and cervical cancer) and metabolic syndromes (renal failure and obesity), revealing the contribution of one or another inflammasome in the pathogenesis of specific diseases. Deeper investigations are still going on to further depict the involvement of inflammasome dysregulation in the pathogenesis of such diseases.
Figure 1: Schematic representation of inflammasome complex with its several intracellular innate immune receptors and gene-specific SNPs.
References:
1. Da Silva W C, Oshiro T M, de Sá D C, Franco D D, Festa Neto C, Pontillo A (2016) Genotyping and differential expression analysis of inflammasome genes in sporadic malignant melanoma reveal novel contribution of CARD8, IL1B and IL18 in melanoma susceptibility and progression. Cancer Genet. 209(10): 474-480.
2. Souza de Lima D, Ogusku M M, Sadahiro A, Pontillo A (2016) Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis. Infect Genet. Evol. 41: 240-4.
3. Pontillo A, Crovella S (2016) NOD-like receptors: a tail from plants to mammals through invertebrates. Curr. Protein Pept. Sci. 2016 Mar 17.
4. Santos M L, Reis E C, Bricher P N, Sousa T N, Brito C F, Lacerda M V, Fontes C J, Carvalho L H, Pontillo A (2016) Contribution of inflammasome genetics in Plasmodium vivax malaria. Infect Genet Evol. 40: 162-6.
5. Pontillo A, Bricher P, Leal V N, Lima S, Souza P R, Crovella S (2016) Role of inflammasome genetics in susceptibility to HPV infection and cervical cancer development. J. Med. Virol. 88(9): 1646-51.