San Raffaele Telethon Institute for Gene Therapy
Mechanisms of inflammation in health and disease
Inflammation is a vital process that the immune system executes to remove injurious stimuli and initiate the healing process. Failure to efficiently resolve inflammatory insults can have severe consequences for tissue maintenance and function, leading to chronic inflammatory diseases. The laboratory's overarching goal is to understand the inflammatory response pathways and molecular mechanisms that orchestrate immune dysfunction in autoinflammatory diseases and develop improved targeted therapies that positively impact the health outcomes of patients, often children, living with these conditions.
Alessandra Mortellaro received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 841780) for the project entitled “Development of gene therapy and genome editing strategies to treat adenosine deaminase 2 deficiency”.
Our research focuses on two areas:
- Adenosine deaminase 2 deficiency (DADA2) is a newly identified autoinflammatory syndrome caused by autosomal recessive mutations in the ADA2 gene. The most common presentations of DADA2 are cutaneous and cerebral vasculopathy, stroke, systemic inflammation, hematological and immunological manifestations. If undiagnosed, patients with DADA2 can have a fatal outcome, and current treatments are unsatisfactory. Therefore, there is an urgent unmet medical need for this otherwise life-threatening disease. The clinical presentation suggests that immune dysregulation may be the primary cause of DADA2 pathophysiology, but currently, there is a complete lack of information on the role of ADA2 in immune regulation. Our group is working towards identifying the cellular and molecular mechanisms responsible for DADA2, with the final goal to initiate a first-in-human gene therapy clinical trial.
- During homeostasis, the process of hematopoietic stem cell (HSC) renewal and the production of lineage-committed progenitors are tightly controlled to maintain daily blood cell production. Upon immunological stress, such as infection and inflammation, there is a high demand for leukocytes to replace cells and increase immune surveillance. HSCs can sense microbial components using innate cell receptors. NOD-like receptors (NLRs) are intracellular pattern recognition receptors, essential components of the innate immunity network. Although HSCs express these receptors, it is unclear whether NLRs could regulate hematopoiesis. Our group studies the role of NLRs in shaping HSC fate and blood output under physiological conditions and after inflammatory insults and in the context of chronic inflammatory diseases.
Our studies will collectively provide the molecular and cellular bases of inflammation, which can be exploited to pave the way for new strategies to hasten its resolution in patients affected by chronic inflammatory conditions.
Zoccolillo M, Brigida I, Barzaghi F, Scala S, Jofra Hernández R, Basso Ricci L, Colantuoni M, Pettinato E, Sergi Sergi L, Milardi G, Capasso A, Lombardo A, Gregori A, Schena F, Cesaro S, Conti F, Pession A, Gattorno M, Lee PY, Naldini L, Cicalese MP, Aiuti A, Mortellaro A. Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency. Blood Adv. 2021 Aug 24;5(16):3174-3187. PMID: 34424322.
Jofra Hernández R, Calabria A, Sanvito F, De Mattia F, Farinelli G, Scala S, Visigalli I, Carriglio N, De Simone M, Vezzoli M, Cecere F, Migliavacca M, Basso-Ricci L, Omrani M, Benedicenti F, Norata R, Rancoita PMV, Di Serio C, Albertini P, Cristofori P, Naldini L, Gentner B, Montini E, Aiuti A, Mortellaro A. Hematopoietic Tumors in a Mouse Model of X-linked Chronic Granulomatous Disease after Lentiviral Vector-Mediated Gene Therapy. Mol Ther. 2020 Sep 23:S1525-0016(20)30487. PMID: 33010230.
Javanmard Khameneh H, Leong KWK, Mencarelli A, Vacca M, Mambwe B, Neo K, Tay A, Zolezzi F, Lee B, Mortellaro A. The Inflammasome Adaptor ASC Intrinsically Limits CD4+ T-Cell Proliferation to Help Maintain Intestinal Homeostasis. Front Immunol. 2019 Jul 15;10:1566. PMID: 3137981
Pal A, Neo K, Rajamani L, Ferrer FJ, Lane DP, Verma CS, Mortellaro A. Inhibition of NLRP3 inflammasome activation by cell-permeable stapled peptides. Sci Rep. 2019; 9(1):4913. PMID: 3089460
Mencarelli A, Khameneh HJ, Fric J, Vacca M, El Daker S, Janela B, Tang JP, Nabti S, Balachander A, Lim TS, Ginhoux F, Ricciardi-Castagnoli P, Mortellaro A. Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis. Nat Commun. 2018;9(1):1102. PMID: 29549257.
Vacca M, Böhme J, Zambetti LP, Khameneh HJ, Paleja BS, Laudisi F, Ho AWS, Neo K, Leong KWK, Marzuki M, Lee B, Poidinger M, Santambrogio L, Tsenova L, Zolezzi F, De Libero G, Singhal A, Mortellaro A. NLRP10 in dendritic cells enhances IFNg production by antigen-specific T cells. Front Immunol. 2017;8:1462. PMID: 29163529.
Diamond CE, Leong KWK, Vacca M, Rivers-Auty J, Brough D, Mortellaro A. Salmonella Typhimurium-induced IL-1 release from primary human monocytes requires NLRP3 and occurs in the absence of pyroptosis. Sci Rep. 2017;7(1):6861. PMID: 28761045.
Ho AWS, Spreafico R, Khameneh HJ, Derks H, Quek HQY, Mortellaro A. The Syk-NFAT-IL-2 pathway in dendritic cells is required for optimal sterile immunity elicited by alum adjuvants. J Immunol. 2017 Jan 1;198(1):196-204. PMID: 27895176.
Viganò E, Diamond CE, Spreafico R, Balachander A, Sobota RM, Mortellaro A. Human caspase-4 and caspase-5 regulate the one-step non-canonical inflammasome activation in monocytes. Nat Commun. 2015 Oct 28;6:8761. PMID: 2650836
Laudisi F, Spreafico R, Evrard M, Hughes TR, Mandriani B, Kandasamy M, Morgan BP, Sivasankar B, Mortellaro A. Cutting edge: The NLRP3 inflammasome links complement-mediated inflammation and IL-1b release. J Immunol. 2013 Aug 1;191(3):1006- [Reviewed in F1000Prime, f1000.com/prime/718046840]. PMID: 23817414.
Licandro G, Khor HL, Beretta O, Lai J, Derks H, Laudisi F, Conforti-Andreoni C, Qian HL, Teng GG, Ricciardi-Castagnoli P, Mortellaro A. The NLRP3 inflammasome affects DNA damage responses after oxidative and genotoxic stress in dendritic cells. Eur J Immunol. 2013 Aug;43(8):2126-37. [Selected for cover image and Editorial Commentary]. PMID: 23619996.
Conforti-Andreoni C, Spreafico R, Qian HL, Riteau N, Ryffel B, Ricciardi-Castagnoli P, and Mortellaro A. Uric acid-driven Th17 differentiation requires inflammasome-derived IL-1 and IL-18. J Immunol. 2011 Dec;187(11):5842-50. PMID: 22058415.
Mortellaro A, Hernandez RJ, Guerrini MM, Carlucci F, Tabucchi A, Ponzoni M, Sanvito F, Doglioni C, Di Serio C, Biasco L, Follenzi A, Naldini L, Bordignon C, Roncarolo MG, Aiuti A. Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)-deficient mice and corrects their immune and metabolic defects. Blood. 2006 Nov;108(9):2979-88. PMID: 16835374.
Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, Morecki S, Andolfi G, Tabucchi A, Carlucci F, Marinello E, Cattaneo F, Vai S, Servida P, Miniero R, Roncarolo MG, Bordignon C. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002 Jun;296(5577):2410-3. PMID: 12089448.
Aiuti A, Vai S, Mortellaro A, Casorati G, Ficara F, Andolfi G, Ferrari G, Tabucchi A, Carlucci F, Ochs HD, Notarangelo LD, Roncarolo MG, Bordignon C. Immune reconstitution in ADA-SCID after PBL gene therapy and discontinuation of enzyme replacement. Nat Med. 2002 May;8(5):423-5. PMID: 11984564.