Primary Immunodeficiencies (PIDs) are a group of rare genetic diseases characterized by an altered innate and adaptive immune system, leading to increased susceptibility to infections, and risk of autoimmunity and cancer. Without treatment, many of these conditions are fatal and require early intervention. SR-TIGET was one of the pioneer institute bringing hematopoietic stem / progenitor cell (HSPC) gene therapy (GT) from preclinical studies to successful clinical applications in adenosine deaminase type 1 (ADA)-deficient severe combined immunodeficiency (SCID) and Wiskott-Aldrich syndrome (WAS). Our group is working towards the identification of the genetic bases and the pathophysiological processes underlying PIDs and autoimmune/autoinflammatory diseases with the goal of developing novel ex vivo gene and cell therapy strategies for such conditions. We are currently investigating the molecular and cellular mechanisms linked to mutations in the CECR1 gene encoding the adenosine deaminase type 2 (ADA2) protein with the final goal to develop a gene therapy approach for these diseases.
We are also currently investigating the impact of gain-of-function mutations in genes encoding nucleotide oligomerization domain (NOD)-like receptors (NLRs) and inflammasome proteins (i.e. NLRP3, NLRC4, and Pyrin), a specialized group of proteins that play a critical role in the recognition of intracellular pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Some NLR proteins form large complexes, called inflammasomes, which activate caspase-1 and induce the production of active IL-1β and IL-18, as well as an inflammatory form of programmed cell death (also known as pyroptosis). Patients suffer from an autoinflammatory syndrome, characterized by short and recurrent attacks of fever, skin rash, amyloidosis, joint pain, fatigue. Our group is currently investigating the genetic bases of these autoinflammatory syndromes.
Collectively, these studies will contribute to advance our knowledge of PIDs and autoinflammatory disorders and improve patients’ care.
Alessandra received her undergraduate degree in Biological Sciences from the University of Milan, Italy, in 1998. She then moved to San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) where in 2005 she obtained her Ph.D. in Cellular and Molecular Biology co-sponsored by the Open University of London (UK) and the Vita-Salute University San Raffaele (Milan, Italy) under the supervision of Prof. Maria Grazia Roncarolo and Dr. Alessandro Aiuti. During this period, Alessandra significantly contributed to the development of gene therapy trials for ADA-SCID by infusions of retrovirally transduced PBL or CD34+ cells. She also studied the efficacy and safety of gene therapy mediated by lentiviral vectors in the ADA-deficient animal model. In 2006, Alessandra joined the laboratory of Prof. Paola Castagnoli at the Department of Biotechnology and Biosciences, University of Milano-Bicocca, where she studied the molecular mechanisms triggered by pathogens (i.e. M. tuberculosis) and endogenous danger signals alerting the immune system. In 2008, Alessandra moved to Singapore Immunology Network (SIgN), Agency for Technology and Research (A*STAR), in Singapore as Research Scientist, and participated in the establishment of SIgN as new and vibrant international human Immunology Research Institute. From 2011-2018, she has been a Principal Investigator at SIgN, with responsibility for a group of 6 scientists. The research interests of Alessandra’s laboratory lied mainly in the understanding of the innate molecular mechanisms driving inflammation and autoimmunity in mice and humans, as well as implications of the inflammasome in immune regulation and disease pathogenesis. These studies have been complemented by investigating patients with autoinflammatory and autoimmune disorders. Knock-out mouse models were developed to identify new druggable targets in inflammatory disease models. In 2017 Alessandra returned to SR-Tiget, San Raffaele Scientific Institute.
The aim of the lab is to investigate the molecular link between mutations in immune genes causing Primary Immunodeficiencies and defects in innate immunity, which is an integral part of the body’s defense against microbes. We are also exploring whether lentiviral-mediated gene therapy mediated by hematopoietic stem and progenitor cells, and gene editing represent a therapeutic approach for Primary Immunodeficiencies associated with autoinflammation (i.e. ADA2 deficiency), as well as Cryopyrinopathies and other inflammatory disorders caused by gain-of-function mutations in genes encoding nucleotide oligomerization domain (NOD)-like receptors (NLRs) and inflammasome proteins.
- Mencarelli A, Khameneh HJ, Fric J, et al., Mortellaro A. Calcineurin-mediated
IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis. Nat commun. 2018 Mar 16;9(1):1102.
- Mencarelli A, Vacca M, Khameneh HJ, et al., Mortellaro A. Calcineurin B in CD4+ T cells prevents autoimmune colitis by negatively regulating the JAK/STAT pathway. Front Immunol. 2018 Feb 19;9:261.
- Vacca M, Bohme J, Zambetti LP, et al., Mortellaro A. NLRP10 enhances CD4+ T-cell-mediated IFNγ response via regulation of dendritic cell-derived IL-12 release. Front Immunol. 2017 Nov 2;8:1462.
- Diamond CE, Leong KWK, Vacca M, et al., Mortellaro A. Salmonella typhimurium-induced IL-1 release from primary human monocytes requires NLRP3 and occurs in the absence of pyroptosis. Sci rep. 2017 Jul 31;7(1):6861.
- Bist P, Cheong WS, Ng A, Dikshit N, Kim BH, Pulloor NK, Khameneh HJ, Hedl M, Shenoy AR, Balamuralidhar V, Malik NBA, Hong M, Neutzner A, Chin KC, Kobayashi KS, Bertoletti A, Mortellaro A, Abraham C, MacMicking JD, Xavier RJ, Sukumaran B. E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. Nat Commun. 2017 Jun 28;8:15865.
- Dikshit N, Kale SD, Khameneh HJ, Balamuralidhar V, Tang CY, Kumar P, Lim TP, Tan TT, Kwa AL, Mortellaro A, Sukumaran B. NLRP3 inflammasome pathway has a critical role in the host immunity against clinically relevant Acinetobacter baumannii pulmonary infection. Mucosal Immunol. 2018 Jan;11(1):257-272.
- Khameneh HJ, Ho AW, Laudisi F, Derks H, Kandasamy M, Sivasankar B, Teng GG, Mortellaro A. C5a Regulates IL-1β Production and Leukocyte Recruitment in a Murine Model of Monosodium Urate Crystal-Induced Peritonitis. Front Pharmacol. 2017 Jan 23;8:10.
- Khameneh HJ, Ho AW, Spreafico R, Derks H, Quek HQ, 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.
- Diamond C, Bagnall J, Spiller DG, White MR, Mortellaro A, Paszek P, Brough D. Investigating
IL-1β Secretion Using Real-Time Single-Cell Imaging. Methods Mol Biol. 2016;1417:75-88.
- Martín-Sánchez F, Diamond C, Zeitler M, Gomez AI, Baroja-Mazo A, Bagnall J, Spiller D, White M, Daniels MJ, Mortellaro A, Peñalver M, Paszek P, Steringer JP, Nickel W, Brough D, Pelegrín P. Inflammasome-dependent IL-1β release depends upon membrane permeabilisation. Cell Death Differ. 2016 Jul;23(7):1219-31.
- Viganò E, Diamond CE, Spreafico R, et al., 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.
- Zelante T, Wong AY, Ping TJ, Chen J, Sumatoh HR, Viganò E, Hong Bing Y, Lee B, Zolezzi F, Fric J, Newell EW, Mortellaro A, Poidinger M, Puccetti P, Ricciardi-Castagnoli P. CD103+ Dendritic Cells Control Th17 Cell Function in the Lung. Cell Rep. 2015 Sep 22;12(11):1789-801.
- Andiappan AK, Melchiotti R, Poh TY, et al., Mortellaro A, Wang DY, Poidinger M, Larbi A, Zolezzi F, Rotzschke O. Genome-wide analysis of the genetic regulation of gene expression in human neutrophils. Nat Commun. 2015 Aug 10;6:7971.
- Diamond CE, Khameneh HJ, Brough D, Mortellaro A. Novel perspectives on non-canonical inflammasome activation. Immunotargets Ther. 2015 Jul 24;4:131-41
- Li L, Ng DS, Mah WC, Almeida FF, Rahmat SA, Rao VK, Leow SC, Laudisi F, Peh MT, Goh AM, Lim JS, Wright GD, Mortellaro A, Taneja R, Ginhoux F, Lee CG, Moore PK, Lane DP. A unique role for p53 in the regulation of M2 macrophage polarization. Cell Death Differ. 2015 Jul;22(7):1081-93.
- Khameneh HJ, Mortellaro A. NLRC4 gets out of control. Nat Genet. 2014 Oct;46(10):1048-9.
- Zhou Q, Ho AWS, Schlitzer A, et al., Mortellaro A, Ginhoux F, Kemeny DM. GM-CSF-licensed CD11b+ lung DCs orchestrate Th2 immunity to Blomia tropicalis. J Immunol. 2014 July 15;193(2):496-509.
- Zambetti LP, Mortellaro A. NLRPs, microbiota, and gut homeostasis: unravelling the connection. J Pathol. 2014 Aug;233(4):321-30.
- Goh AX, Bertin-Maghit S, Ping Yeo S, Ho AW, Derks H, Mortellaro A, Wang CI. A novel human anti-interleukin-1 neutralizing monoclonal antibody showing in vivo efficacy. MAbs. 2014 May-June;6(3):764-72.
- Viganò E, Mortellaro A. Caspase-11: the driving factor for noncanonical inflammasomes. Eur J Immunol. 2013 Sep;43(9):2240-5.
- 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-1 release. J Immunol. 2013 Aug 1;191(3):1006-10.
- Licandro G, Ling Khor H, Beretta O, Lai J, Derks H, Laudisi F, Conforti-Andreoni C, Liang Qian H, 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.
- Zambetti LP, Laudisi F, Licandro G, Ricciardi-Castagnoli P, Mortellaro A. The rhapsody of NLRPs: master players of inflammation…and a lot more. Immunol Res. 2012 Sep;53(1-3):78-90.
- Fric J, Lim CX, Koh EG, Hofmann B, Chen J, Tay HS, Mohammad Isa SA, Mortellaro A, Ruedl C, Ricciardi-Castagnoli P. Calcineurin/NFAT signaling inhibits myeloid hematopoiesis. EMBO Mol Med. 2012 Apr,4(4):269-85.
- Min L, Isa SA, Fam WN, Sze SK, Beretta O, Mortellaro A, Ruedl C. Synergism between curdlan and GM-CSF confers a strong inflammatory signature to dendritic cells. J Immunol. 2012 Feb;188(4):1789-98.
- Conforti-Andreoni C, Spreafico R, Qian HL, Riteau N, Ryffel B, Ricciardi-Castagnoli P, Mortellaro A. Uric acid-driven Th17 differentiation requires inflammasome-derived IL-1 and IL-18. J Immunol. 2011 Dec;187(11):5842-50.
- Mortellaro A, Ricciardi-Castagnoli P. From vaccine practice to vaccine science: the contribution of human immunology to the prevention of infectious disease. Immunol Cell Biol. 2011 Mar;89(3):332-9.
- Conforti-Andreoni C, Ricciardi-Castagnoli P, Mortellaro A. The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond. Cell Mol Immunol. 2011 Mar;8(2):135-45.
- Conforti-Andreoni C, Beretta O, Licandro G, Qian HL, Urbano M, Vitulli F, Ricciardi-Castagnoli P, Mortellaro A. Synergism of NOD2 and NLRP3 activators promotes a unique transcriptional profile in murine dendritic cells. J Leukoc Biol. 2010 Dec; 88(6):1207-1216.
- Spreafico R, Ricciardi-Castagnoli P, Mortellaro A. The controversial relationship between NLRP3, alum, danger signals and the next-generation adjuvants. Eur J Immunol. 2010 Mar;40(3):638-42.
- Mortellaro A, Robinson L, Ricciardi-Castagnoli P. Spotlight on Mycobacteria and dendritic cells: will novel targets to fight tuberculosis emerge? EMBO Mol Med. 2009 Apr;1(1):19-29.
- Mortellaro A, Wong SC, Fric J, Ricciardi-Castagnoli P. The need to identify myeloid dendritic cell progenitors in human blood. Trends Immunol. 2010 Jan;31(1):18-23.
- Mortellaro A, Conforti-Andreoni C, Fric J, Ricciardi-Castagnoli P. Dendritic cells as sensors of environmental perturbations. Microbes Infect. 2008 Jul;10(9):990-4.
- Tailleux L*, Waddell SJ*, Pelizzola M*, Mortellaro A*, Withers M, Tanne A, Castagnoli PR, Gicquel B, Stoker NG, Butcher PD, Foti M, Neyrolles O. Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages. PLoS One. 2008 Jan 2;3(1):e1403. (*, first co-authorship).
- 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.
- Guazzi V, Aiuti F, Mezzaroma I, Mazzetta F, Andolfi G, Mortellaro A, Pierdominici M, Fantini R, Marziali M, Aiuti A. Assessment of thymic output in common variable immunodeficiency patients by evaluation of T cell receptor excision circles. Clin Exp Immunol. 2002 Aug;129(2):346-53.
- Aiuti A, Slavin S, Aker M, et al., 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.
- 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.
- Mortellaro A, Songia S, Gnocchi P, Ferrari M, Fornasiero C, D’Alessio R, Isetta A, Colotta F, Golay J. New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation. J Immunol. 1999 Jun;162(12):7102-9.
- Songia S, Mortellaro A, Taverna S, Fornasiero C, Scheiber EA, Erba E, Colotta F, Mantovani A, Isetta AM, Golay J. Characterization of the new immunosuppressive drug undecylprodigiosin in human lymphocytes: retinoblastoma protein, cyclin-dependent kinase-2, and cyclin-dependent kinase-4 as molecular targets. J Immunol. 1997 Apr;158(8):3987-95.